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Sample records for normal breast morphogenesis

  1. Expression and functional role of sprouty-2 in breast morphogenesis.

    Science.gov (United States)

    Sigurdsson, Valgardur; Ingthorsson, Saevar; Hilmarsdottir, Bylgja; Gustafsdottir, Sigrun M; Franzdottir, Sigridur Rut; Arason, Ari Jon; Steingrimsson, Eirikur; Magnusson, Magnus K; Gudjonsson, Thorarinn

    2013-01-01

    Branching morphogenesis is a mechanism used by many species for organogenesis and tissue maintenance. Receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR) and the sprouty protein family are believed to be critical regulators of branching morphogenesis. The aim of this study was to analyze the expression of Sprouty-2 (SPRY2) in the mammary gland and study its role in branching morphogenesis. Human breast epithelial cells, breast tissue and mouse mammary glands were used for expression studies using immunoblotting, real rime PCR and immunohistochemistry. Knockdown of SPRY2 in the breast epithelial stem cell line D492 was done by lentiviral transduction of shRNA constructs targeting SPRY2. Three dimensional culture of D492 with or without endothelial cells was done in reconstituted basement membrane matrix. We show that in the human breast, SPRY2 is predominantly expressed in the luminal epithelial cells of both ducts and lobuli. In the mouse mammary gland, SPRY2 expression is low or absent in the virgin state, while in the pregnant mammary gland SPRY2 is expressed at branching epithelial buds with increased expression during lactation. This expression pattern is closely associated with the activation of the EGFR pathway. Using D492 which generates branching structures in three-dimensional (3D) culture, we show that SPRY2 expression is low during initiation of branching with subsequent increase throughout the branching process. Immunostaining locates expression of phosphorylated SPRY2 and EGFR at the tip of lobular-like, branching ends. SPRY2 knockdown (KD) resulted in increased migration, increased pERK and larger and more complex branching structures indicating a loss of negative feedback control during branching morphogenesis. In D492 co-cultures with endothelial cells, D492 SPRY2 KD generates spindle-like colonies that bear hallmarks of epithelial to mesenchymal transition. These data indicate that SPRY2 is an important regulator of

  2. Expression and functional role of sprouty-2 in breast morphogenesis.

    Directory of Open Access Journals (Sweden)

    Valgardur Sigurdsson

    Full Text Available Branching morphogenesis is a mechanism used by many species for organogenesis and tissue maintenance. Receptor tyrosine kinases (RTKs, including epidermal growth factor receptor (EGFR and the sprouty protein family are believed to be critical regulators of branching morphogenesis. The aim of this study was to analyze the expression of Sprouty-2 (SPRY2 in the mammary gland and study its role in branching morphogenesis. Human breast epithelial cells, breast tissue and mouse mammary glands were used for expression studies using immunoblotting, real rime PCR and immunohistochemistry. Knockdown of SPRY2 in the breast epithelial stem cell line D492 was done by lentiviral transduction of shRNA constructs targeting SPRY2. Three dimensional culture of D492 with or without endothelial cells was done in reconstituted basement membrane matrix. We show that in the human breast, SPRY2 is predominantly expressed in the luminal epithelial cells of both ducts and lobuli. In the mouse mammary gland, SPRY2 expression is low or absent in the virgin state, while in the pregnant mammary gland SPRY2 is expressed at branching epithelial buds with increased expression during lactation. This expression pattern is closely associated with the activation of the EGFR pathway. Using D492 which generates branching structures in three-dimensional (3D culture, we show that SPRY2 expression is low during initiation of branching with subsequent increase throughout the branching process. Immunostaining locates expression of phosphorylated SPRY2 and EGFR at the tip of lobular-like, branching ends. SPRY2 knockdown (KD resulted in increased migration, increased pERK and larger and more complex branching structures indicating a loss of negative feedback control during branching morphogenesis. In D492 co-cultures with endothelial cells, D492 SPRY2 KD generates spindle-like colonies that bear hallmarks of epithelial to mesenchymal transition. These data indicate that SPRY2 is an

  3. Intersection of FOXO- and RUNX1-mediated gene expression programs in single breast epithelial cells during morphogenesis and tumor progression.

    Science.gov (United States)

    Wang, Lixin; Brugge, Joan S; Janes, Kevin A

    2011-10-04

    Gene expression networks are complicated by the assortment of regulatory factors that bind DNA and modulate transcription combinatorially. Single-cell measurements can reveal biological mechanisms hidden by population averages, but their value has not been fully explored in the context of mRNA regulation. Here, we adapted a single-cell expression profiling technique to examine the gene expression program downstream of Forkhead box O (FOXO) transcription factors during 3D breast epithelial acinar morphogenesis. By analyzing patterns of mRNA fluctuations among individual matrix-attached epithelial cells, we found that a subset of FOXO target genes was jointly regulated by the transcription factor Runt-related transcription factor 1 (RUNX1). Knockdown of RUNX1 causes hyperproliferation and abnormal morphogenesis, both of which require normal FOXO function. Down-regulating RUNX1 and FOXOs simultaneously causes widespread oxidative stress, which arrests proliferation and restores normal acinar morphology. In hormone-negative breast cancers lacking human epidermal growth factor receptor 2 (HER2) amplification, we find that RUNX1 down-regulation is strongly associated with up-regulation of FOXO1, which may be required to support growth of RUNX1-negative tumors. The coordinate function of these two tumor suppressors may provide a failsafe mechanism that inhibits cancer progression.

  4. DEAR1 is a dominant regulator of acinar morphogenesis and an independent predictor of local recurrence-free survival in early-onset breast cancer.

    Directory of Open Access Journals (Sweden)

    Steven T Lott

    2009-05-01

    Full Text Available Breast cancer in young women tends to have a natural history of aggressive disease for which rates of recurrence are higher than in breast cancers detected later in life. Little is known about the genetic pathways that underlie early-onset breast cancer. Here we report the discovery of DEAR1 (ductal epithelium-associated RING Chromosome 1, a novel gene encoding a member of the TRIM (tripartite motif subfamily of RING finger proteins, and provide evidence for its role as a dominant regulator of acinar morphogenesis in the mammary gland and as an independent predictor of local recurrence-free survival in early-onset breast cancer.Suppression subtractive hybridization identified DEAR1 as a novel gene mapping to a region of high-frequency loss of heterozygosity (LOH in a number of histologically diverse human cancers within Chromosome 1p35.1. In the breast epithelium, DEAR1 expression is limited to the ductal and glandular epithelium and is down-regulated in transition to ductal carcinoma in situ (DCIS, an early histologic stage in breast tumorigenesis. DEAR1 missense mutations and homozygous deletion (HD were discovered in breast cancer cell lines and tumor samples. Introduction of the DEAR1 wild type and not the missense mutant alleles to complement a mutation in a breast cancer cell line, derived from a 36-year-old female with invasive breast cancer, initiated acinar morphogenesis in three-dimensional (3D basement membrane culture and restored tissue architecture reminiscent of normal acinar structures in the mammary gland in vivo. Stable knockdown of DEAR1 in immortalized human mammary epithelial cells (HMECs recapitulated the growth in 3D culture of breast cancer cell lines containing mutated DEAR1, in that shDEAR1 clones demonstrated disruption of tissue architecture, loss of apical basal polarity, diffuse apoptosis, and failure of lumen formation. Furthermore, immunohistochemical staining of a tissue microarray from a cohort of 123 young

  5. Normal morphogenesis of epithelial tissues and progression of epithelial tumors

    Science.gov (United States)

    Wang, Chun-Chao; Jamal, Leen; Janes, Kevin A.

    2011-01-01

    Epithelial cells organize into various tissue architectures that largely maintain their structure throughout the life of an organism. For decades, the morphogenesis of epithelial tissues has fascinated scientists at the interface of cell, developmental, and molecular biology. Systems biology offers ways to combine knowledge from these disciplines by building integrative models that are quantitative and predictive. Can such models be useful for gaining a deeper understanding of epithelial morphogenesis? Here, we take inventory of some recurring themes in epithelial morphogenesis that systems approaches could strive to capture. Predictive understanding of morphogenesis at the systems level would prove especially valuable for diseases such as cancer, where epithelial tissue architecture is profoundly disrupted. PMID:21898857

  6. MicroRNA-200c-141 and ∆Np63 are required for breast epithelial differentiation and branching morphogenesis.

    Science.gov (United States)

    Hilmarsdóttir, Bylgja; Briem, Eirikur; Sigurdsson, Valgardur; Franzdóttir, Sigrídur Rut; Ringnér, Markus; Arason, Ari Jon; Bergthorsson, Jon Thor; Magnusson, Magnus Karl; Gudjonsson, Thorarinn

    2015-07-15

    The epithelial compartment of the breast contains two lineages, the luminal- and the myoepithelial cells. D492 is a breast epithelial cell line with stem cell properties that forms branching epithelial structures in 3D culture with both luminal- and myoepithelial differentiation. We have recently shown that D492 undergo epithelial to mesenchymal transition (EMT) when co-cultured with endothelial cells. This 3D co-culture model allows critical analysis of breast epithelial lineage development and EMT. In this study, we compared the microRNA (miR) expression profiles for D492 and its mesenchymal-derivative D492M. Suppression of the miR-200 family in D492M was among the most profound changes observed. Exogenous expression of miR-200c-141 in D492M reversed the EMT phenotype resulting in gain of luminal but not myoepithelial differentiation. In contrast, forced expression of ∆Np63 in D492M restored the myoepithelial phenotype only. Co-expression of miR-200c-141 and ∆Np63 in D492M restored the branching morphogenesis in 3D culture underlining the requirement for both luminal and myoepithelial elements for obtaining full branching morphogenesis in breast epithelium. Introduction of a miR-200c-141 construct in both D492 and D492M resulted in resistance to endothelial induced EMT. In conclusion, our data suggests that expression of miR-200c-141 and ∆Np63 in D492M can reverse EMT resulting in luminal- and myoepithelial differentiation, respectively, demonstrating the importance of these molecules in epithelial integrity in the human breast. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  7. The 18-kDa translocator protein (TSPO disrupts mammary epithelial morphogenesis and promotes breast cancer cell migration.

    Directory of Open Access Journals (Sweden)

    Xiaoting Wu

    Full Text Available Mitochondria play important roles in cancer progression and have emerged as viable targets for cancer therapy. Increasing levels of the outer mitochondrial membrane protein, 18-kDa translocator protein (TSPO, are associated with advancing breast cancer stage. In particular, higher TSPO levels are found in estrogen receptor (ER-negative breast tumors, compared with ER-positive tumors. In this study, we sought to define the roles of TSPO in the acquisition of breast cancer malignancy. Using a three-dimensional Matrigel culture system, we determined the impact of elevated TSPO levels on mammary epithelial morphogenesis. Our studies demonstrate that stable overexpression of TSPO in mammary epithelial MCF10A acini drives proliferation and provides partial resistance to luminal apoptosis, resulting in enlarged acinar structures with partially filled lumen that resemble early stage breast lesions leading to breast cancer. In breast cancer cell lines, TSPO silencing or TSPO overexpression significantly altered the migratory activity. In addition, we found that combination treatment with the TSPO ligands (PK 11195 or Ro5-4864 and lonidamine, a clinical phase II drug targeting mitochondria, decreased viability of ER-negative breast cancer cell lines. Taken together, these data demonstrate that increases in TSPO levels at different stages of breast cancer progression results in the acquisition of distinct properties associated with malignancy. Furthermore, targeting TSPO, particularly in combination with other mitochondria-targeting agents, may prove useful for the treatment of ER-negative breast cancer.

  8. Epithelial progenitor cell lines as models of normal breast morphogenesis and neoplasia

    DEFF Research Database (Denmark)

    Petersen, Ole William; Gudjonsson, Thorarinn; Villadsen, René

    2003-01-01

    The majority of human breast carcinomas exhibit luminal characteristics and as such, are most probably derived from progenitor cells within the luminal epithelial compartment. This has been subdivided recently into at least three luminal subtypes based on gene expression patterns. The value of kn...

  9. Evidence of two distinct functionally specialized fibroblast lineages in breast stroma

    DEFF Research Database (Denmark)

    Morsing, Mikkel; Klitgaard, Marie Christine; Jafari Kermani, Abbas

    2016-01-01

    Background The terminal duct lobular unit (TDLU) is the most dynamic structure in the human breast and the putative site of origin of human breast cancer. Although stromal cells contribute to a specialized microenvironment in many organs, this component remains largely understudied in the human...... conditions followed by analysis of adipogenic and osteogenic differentiation. To test whether the two fibroblast lineages are functionally imprinted by their site of origin, single cell sorted CD271low/MUC1high normal breast luminal epithelial cells are plated on fibroblast feeders for the observation...... fibroblast lineages exist in the normal human breast, of which the lobular fibroblasts have properties in common with mesenchymal stem cells and support epithelial growth and morphogenesis. We propose that lobular fibroblasts constitute a specialized microenvironment for human breast luminal epithelial...

  10. Scribble is required for normal epithelial cell–cell contacts and lumen morphogenesis in the mammalian lung

    Science.gov (United States)

    Yates, Laura L.; Schnatwinkel, Carsten; Hazelwood, Lee; Chessum, Lauren; Paudyal, Anju; Hilton, Helen; Romero, M. Rosario; Wilde, Jonathan; Bogani, Debora; Sanderson, Jeremy; Formstone, Caroline; Murdoch, Jennifer N.; Niswander, Lee A.; Greenfield, Andy; Dean, Charlotte H.

    2013-01-01

    During lung development, proper epithelial cell arrangements are critical for the formation of an arborized network of tubes. Each tube requires a lumen, the diameter of which must be tightly regulated to enable optimal lung function. Lung branching and lumen morphogenesis require close epithelial cell–cell contacts that are maintained as a result of adherens junctions, tight junctions and by intact apical–basal (A/B) polarity. However, the molecular mechanisms that maintain epithelial cohesion and lumen diameter in the mammalian lung are unknown. Here we show that Scribble, a protein implicated in planar cell polarity (PCP) signalling, is necessary for normal lung morphogenesis. Lungs of the Scrib mouse mutant Circletail (Crc) are abnormally shaped with fewer airways, and these airways often lack a visible, ‘open’ lumen. Mechanistically we show that Scrib genetically interacts with the core PCP gene Vangl2 in the developing lung and that the distribution of PCP pathway proteins and Rho mediated cytoskeletal modification is perturbed in ScribCrc/Crc lungs. However A/B polarity, which is disrupted in Drosophila Scrib mutants, is largely unaffected. Notably, we find that Scrib mediates functions not attributed to other PCP proteins in the lung. Specifically, Scrib localises to both adherens and tight junctions of lung epithelia and knockdown of Scrib in lung explants and organotypic cultures leads to reduced cohesion of lung epithelial cells. Live imaging of Scrib knockdown lungs shows that Scrib does not affect bud bifurcation, as previously shown for the PCP protein Celsr1, but is required to maintain epithelial cohesion. To understand the mechanism leading to reduced cell–cell association, we show that Scrib associates with β-catenin in embryonic lung and the sub-cellular distribution of adherens and tight junction proteins is perturbed in mutant lung epithelia. Our data reveal that Scrib is required for normal lung epithelial organisation and lumen

  11. Enhancer of the rudimentary gene homologue (ERH expression pattern in sporadic human breast cancer and normal breast tissue

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    Knüchel Ruth

    2008-05-01

    Full Text Available Abstract Background The human gene ERH (Enhancer of the Rudimentary gene Homologue has previously been identified by in silico analysis of four million ESTs as a gene differentially expressed in breast cancer. The biological function of ERH protein has not been fully elucidated, however functions in cell cycle progression, pyrimidine metabolism a possible interaction with p21(Cip1/Waf1 via the Ciz1 zinc finger protein have been suggested. The aim of the present study was a systematic characterization of ERH expression in human breast cancer in order to evaluate possible clinical applications of this molecule. Methods The expression pattern of ERH was analyzed using multiple tissue northern blots (MTN on a panel of 16 normal human tissues and two sets of malignant/normal breast and ovarian tissue samples. ERH expression was further analyzed in breast cancer and normal breast tissues and in tumorigenic as well as non-tumorigenic breast cancer cell lines, using quantitative RT-PCR and non-radioisotopic in situ hybridization (ISH. Results Among normal human tissues, ERH expression was most abundant in testis, heart, ovary, prostate, and liver. In the two MTN sets of malignant/normal breast and ovarian tissue,ERH was clearly more abundantly expressed in all tumours than in normal tissue samples. Quantitative RT-PCR analyses showed that ERH expression was significantly more abundant in tumorigenic than in non-tumorigenic breast cancer cell lines (4.5-fold; p = 0.05, two-tailed Mann-Whitney U-test; the same trend was noted in a set of 25 primary invasive breast cancers and 16 normal breast tissue samples (2.5-fold; p = 0.1. These findings were further confirmed by non-radioisotopic ISH in human breast cancer and normal breast tissue. Conclusion ERH expression is clearly up-regulated in malignant as compared with benign breast cells both in primary human breast cancer and in cell models of breast cancer. Since similar results were obtained for ovarian

  12. Normalized glandular dose (DgN) coefficients for flat-panel CT breast imaging

    International Nuclear Information System (INIS)

    Thacker, Samta C; Glick, Stephen J

    2004-01-01

    The development of new digital mammography techniques such as dual-energy imaging, tomosynthesis and CT breast imaging will require investigation of optimal camera design parameters and optimal imaging acquisition parameters. In optimizing these acquisition protocols and imaging systems it is important to have knowledge of the radiation dose to the breast. This study presents a methodology for estimating the normalized glandular dose to the uncompressed breast using the geometry proposed for flat-panel CT breast imaging. The simulation uses the GEANT 3 Monte Carlo code to model x-ray transport and absorption within the breast phantom. The Monte Carlo software was validated for breast dosimetry by comparing results of the normalized glandular dose (DgN) values of the compressed breast to those reported in the literature. The normalized glandular dose was then estimated for a range of breast diameters from 10 cm to 18 cm using an uncompressed breast model with a homogeneous composition of adipose and glandular tissue, and for monoenergetic x-rays from 10 keV to 120 keV. These data were fit providing expressions for the normalized glandular dose. Using these expressions for the DgN coefficients and input variables such as the diameter, height and composition of the breast phantom, the mean glandular dose for any spectra can be estimated. A computer program to provide normalized glandular dose values has been made available online. In addition, figures displaying energy deposition maps are presented to better understand the spatial distribution of dose in CT breast imaging

  13. Quantification of Estrogen Receptor Expression in Normal Breast Tissue in Postmenopausal Women With Breast Cancer and Association With Tumor Subtypes.

    Science.gov (United States)

    Gulbahce, H Evin; Blair, Cindy K; Sweeney, Carol; Salama, Mohamed E

    2017-09-01

    Estrogen exposure is important in the pathogenesis of breast cancer and is a contributing risk factor. In this study we quantified estrogen receptor (ER) alpha expression in normal breast epithelium (NBR) in women with breast cancer and correlated it with breast cancer subtypes. Tissue microarrays were constructed from 204 breast cancer patients for whom normal breast tissue away from tumor was available. Slides stained with ER were scanned and expression in normal terminal duct lobular epithelium was quantitated using computer-assisted image analysis. ER expression in normal terminal duct lobular epithelium of postmenopausal women with breast cancer was significantly associated with estrogen and triple (estrogen, progesterone receptors, and HER2) negative phenotypes. Also increased age at diagnosis was significantly associated with ER expression in NBR. ER positivity in normal epithelium did not vary by tumor size, lymph node status, tumor grade, or stage. On the basis of quantitative image analysis, we confirm that ER expression in NBR increases with age in women with breast cancer, and report for the first time, a significant association between ER expression in NBR with ER-negative and triple-negative cancers in postmenopausal women.

  14. Altered expression of estrogen receptor-α variant messenger RNAs between adjacent normal breast and breast tumor tissues

    International Nuclear Information System (INIS)

    Leygue, Etienne; Dotzlaw, Helmut; Watson, Peter H; Murphy, Leigh C

    2000-01-01

    Using semiquantitative reverse transcription-polymerase chain reaction assays, we investigated the expression of variant messenger RNAs relative to wild-type estrogen receptor (ER)-α messenger RNA in normal breast tissues and their adjacent matched breast tumor tissues. Higher ER variant truncated after sequences encoding exon 2 of the wild-type ER-α (ERC4) messenger RNA and a lower exon 3 deleted ER-α variant (ERD3) messenger RNA relative expression in the tumor compartment were observed in the ER-positive/PR-positive and the ER-positive subsets, respectively. A significantly higher relative expression of exon 5 deleted ER-α varient (ERD5) messenger RNA was observed in tumor components overall. These data demonstrate that changes in the relative expression of ER-α variant messenger RNAs occur between adjacent normal and neoplastic breast tissues. We suggest that these changes might be involved in the mechanisms that underlie breast tumorigenesis. Estrogen receptor (ER)-α and ER-β are believed to mediate the action of estradiol in target tissues. Several ER-α and ER-β variant messenger RNAs have been identified in both normal and neoplastic human tissues. Most of these variants contain a deletion of one or more exons of the wild-type (WT) ER messenger RNAs. The putative proteins that are encoded by these variant messenger RNAs would therefore be missing some functional domains of the WT receptors, and might interfere with WT-ER signaling pathways. The detection of ER-α variants in both normal and neoplastic human breast tissues raised the question of their possible role in breast tumorigenesis. We have previously reported an increased relative expression of exon 5 deleted ER-α variant (ERD5) messenger RNA and of another ER-α variant truncated of all sequences following the exon 2 of the WT ER-α (ERC4) messenger RNA in breast tumor samples versus independent normal breast tissues. In contrast, a decreased relative expression of exon 3 deleted ER

  15. HER2 induced EMT and tumorigenicity in breast epithelial progenitor cells is inhibited by coexpression of EGFR

    OpenAIRE

    Ingthorsson, Saevar; Andersen, K; Hilmarsdóttir, Bylgja; Mælandsmo, Gunhild M; Magnusson, Magnus Karl; Gudjonsson, Thorarinn

    2015-01-01

    The members of the epidermal growth factor receptor (EGFR) kinase family are important players in breast morphogenesis and cancer. EGFR2/HER2 and EGFR expression have a prognostic value in certain subtypes of breast cancer such as HER2-amplified, basal-like and luminal type B. Many clinically approved small molecular inhibitors and monoclonal antibodies have been designed to target HER2, EGFR or both. There is, however, still limited knowledge on how the two receptors are expressed in normal ...

  16. A comparison of body image, marital satisfaction, and public health among breast cancer patients with breast evacuation, breast keeping and normal people in Tehran

    Directory of Open Access Journals (Sweden)

    Zahra Esfandiari

    2015-09-01

    Full Text Available Abstract Purpose and background: despite outstanding breakthroughs in medical sciences, breast cancer is still considered one of the most important disease and the most prevalent women cancer and the second reason of death among them. The present study was conducted aiming to compare public health and marital satisfaction among breast cancer patients with breast evacuation, breast keeping and normal women in Tehran. Material and methods: the method of the present study, due to the lack of interference to alter the research variables, was causal comparative. The statistical population included all women with breast cancer and normal women in the city of Tehran. From these people in each group (breast cancer patients with breast evacuation, breast keeping and normal people 80 individuals were selected through available sampling from clients of medical centers and special hospitals in Tehran during October 2012 to December 2013. The applied instruments were the questionnaires of public health, body image, and marital satisfaction. The achieved data were analyzed via one-way ANOVA and Tukey test by SPSS software. Findings: the results of the analysis showed that there is a significant difference between the mean scores of marital satisfaction, body image and public health in three groups (women with cancer who evacuated their breast, those who didn't and normal ones(p<0.01. Conclusion: according to the findings of the present study the women with breast cancer are in more different state in variables of marital satisfaction, mental health and body image comparing to normal group. So it seems necessary for cancer treatment centers to consider psychological treatment courses for these people.

  17. Serum estradiol levels associated with specific gene expression patterns in normal breast tissue and in breast carcinomas

    International Nuclear Information System (INIS)

    Haakensen, Vilde D; Børresen-Dale, Anne-Lise; Helland, Åslaug; Bjøro, Trine; Lüders, Torben; Riis, Margit; Bukholm, Ida K; Kristensen, Vessela N; Troester, Melissa A; Homen, Marit M; Ursin, Giske

    2011-01-01

    High serum levels of estradiol are associated with increased risk of postmenopausal breast cancer. Little is known about the gene expression in normal breast tissue in relation to levels of circulating serum estradiol. We compared whole genome expression data of breast tissue samples with serum hormone levels using data from 79 healthy women and 64 breast cancer patients. Significance analysis of microarrays (SAM) was used to identify differentially expressed genes and multivariate linear regression was used to identify independent associations. Six genes (SCGB3A1, RSPO1, TLN2, SLITRK4, DCLK1, PTGS1) were found differentially expressed according to serum estradiol levels (FDR = 0). Three of these independently predicted estradiol levels in a multivariate model, as SCGB3A1 (HIN1) and TLN2 were up-regulated and PTGS1 (COX1) was down-regulated in breast samples from women with high serum estradiol. Serum estradiol, but none of the differentially expressed genes were significantly associated with mammographic density, another strong breast cancer risk factor. In breast carcinomas, expression of GREB1 and AREG was associated with serum estradiol in all cancers and in the subgroup of estrogen receptor positive cases. We have identified genes associated with serum estradiol levels in normal breast tissue and in breast carcinomas. SCGB3A1 is a suggested tumor suppressor gene that inhibits cell growth and invasion and is methylated and down-regulated in many epithelial cancers. Our findings indicate this gene as an important inhibitor of breast cell proliferation in healthy women with high estradiol levels. In the breast, this gene is expressed in luminal cells only and is methylated in non-BRCA-related breast cancers. The possibility of a carcinogenic contribution of silencing of this gene for luminal, but not basal-like cancers should be further explored. PTGS1 induces prostaglandin E2 (PGE2) production which in turn stimulates aromatase expression and hence increases the

  18. Aspiration cytology of radiation-induced changes of normal breast epithelium

    International Nuclear Information System (INIS)

    Bondeson, L.

    1987-01-01

    From a case illustrated, it appears that irradiation may induce changes in normal breast epithelium indistinguishable from malignancy by means of aspiration cytology. This fact must be considered in the choice of diagnostic methods for the evaluation of lesions in irradiated breast tissue

  19. Role of Stroma-Derived Extracellular Matrix in Regulation of Growth and Hormonal Responsiveness of Normal and Cancerous Human Breast Epithelium

    National Research Council Canada - National Science Library

    Woodward, Terry

    1997-01-01

    Specific extracellular matrix (ECM) proteins and their cellular receptors (integrins) are required for normal mammary gland morphogenesis and differentiation, while their expression is dramatically altered during tumorigenesis...

  20. Breast Cancer Heterogeneity Examined by High-Sensitivity Quantification of PIK3CA, KRAS, HRAS, and BRAF Mutations in Normal Breast and Ductal Carcinomas

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    Meagan B. Myers

    2016-04-01

    Full Text Available Mutant cancer subpopulations have the potential to derail durable patient responses to molecularly targeted cancer therapeutics, yet the prevalence and size of such subpopulations are largely unexplored. We employed the sensitive and quantitative Allele-specific Competitive Blocker PCR approach to characterize mutant cancer subpopulations in ductal carcinomas (DCs, examining five specific hotspot point mutations (PIK3CA H1047R, KRAS G12D, KRAS G12V, HRAS G12D, and BRAF V600E. As an approach to aid interpretation of the DC results, the mutations were also quantified in normal breast tissue. Overall, the mutations were prevalent in normal breast and DCs, with 9/9 DCs having measureable levels of at least three of the five mutations. HRAS G12D was significantly increased in DCs as compared to normal breast. The most frequent point mutation reported in DC by DNA sequencing, PIK3CA H1047R, was detected in all normal breast tissue and DC samples and was present at remarkably high levels (mutant fractions of 1.1 × 10−3 to 4.6 × 10−2 in 4/10 normal breast samples. In normal breast tissue samples, PIK3CA mutation levels were positively correlated with age. However, the PIK3CA H1047R mutant fraction distributions for normal breast tissues and DCs were similar. The results suggest PIK3CA H1047R mutant cells have a selective advantage in breast, contribute to breast cancer susceptibility, and drive tumor progression during breast carcinogenesis, even when present as only a subpopulation of tumor cells.

  1. β class II tubulin predominates in normal and tumor breast tissues

    International Nuclear Information System (INIS)

    Dozier, James H; Hiser, Laree; Davis, Jennifer A; Thomas, Nancy Stubbs; Tucci, Michelle A; Benghuzzi, Hamed A; Frankfurter, Anthony; Correia, John J; Lobert, Sharon

    2003-01-01

    Antimitotic chemotherapeutic agents target tubulin, the major protein in mitotic spindles. Tubulin isotype composition is thought to be both diagnostic of tumor progression and a determinant of the cellular response to chemotherapy. This implies that there is a difference in isotype composition between normal and tumor tissues. To determine whether such a difference occurs in breast tissues, total tubulin was fractionated from lysates of paired normal and tumor breast tissues, and the amounts of β-tubulin classes I + IV, II, and III were measured by competitive enzyme-linked immunosorbent assay (ELISA). Only primary tumor tissues, before chemotherapy, were examined. Her2/neu protein amplification occurs in about 30% of breast tumors and is considered a marker for poor prognosis. To gain insight into whether tubulin isotype levels might be correlated with prognosis, ELISAs were used to quantify Her2/neu protein levels in these tissues. β-Tubulin isotype distributions in normal and tumor breast tissues were similar. The most abundant β-tubulin isotypes in these tissues were β-tubulin classes II and I + IV. Her2/neu levels in tumor tissues were 5–30-fold those in normal tissues, although there was no correlation between the Her2/neu biomarker and tubulin isotype levels. These results suggest that tubulin isotype levels, alone or in combination with Her2/neu protein levels, might not be diagnostic of tumorigenesis in breast cancer. However, the presence of a broad distribution of these tubulin isotypes (for example, 40–75% β-tubulin class II) in breast tissue, in conjunction with other factors, might still be relevant to disease progression and cellular response to antimitotic drugs

  2. Estrogen and progesterone signalling in the normal breast and its implications for cancer development.

    Science.gov (United States)

    Hilton, Heidi N; Clarke, Christine L; Graham, J Dinny

    2018-05-05

    The ovarian hormones estrogen and progesterone are master regulators of the development and function of a broad spectrum of human tissues, including the breast, reproductive and cardiovascular systems, brain and bone. Acting through the nuclear estrogen (ER) and progesterone receptors (PR), both play complex and essential coordinated roles in the extensive development of the lobular alveolar epithelial structures of the normal breast during puberty, the normal menstrual cycle and pregnancy. The past decade has seen major advances in understanding the mechanisms of action of estrogen and progesterone in the normal breast and in the delineation of the complex hierarchy of cell types regulated by ovarian hormones in this tissue. There is evidence for a role for both ER and PR in driving breast cancer, and both are favourable prognostic markers with respect to outcome. In this review, we summarize current knowledge of the mechanisms of action of ER and PR in the normal breast, and implications for the development and management of breast cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Leptin and Adiponectin Modulate the Self-renewal of Normal Human Breast Epithelial Stem Cells.

    Science.gov (United States)

    Esper, Raymond M; Dame, Michael; McClintock, Shannon; Holt, Peter R; Dannenberg, Andrew J; Wicha, Max S; Brenner, Dean E

    2015-12-01

    Multiple mechanisms are likely to account for the link between obesity and increased risk of postmenopausal breast cancer. Two adipokines, leptin and adiponectin, are of particular interest due to their opposing biologic functions and associations with breast cancer risk. In the current study, we investigated the effects of leptin and adiponectin on normal breast epithelial stem cells. Levels of leptin in human adipose explant-derived conditioned media positively correlated with the size of the normal breast stem cell pool. In contrast, an inverse relationship was found for adiponectin. Moreover, a strong linear relationship was observed between the leptin/adiponectin ratio in adipose conditioned media and breast stem cell self-renewal. Consistent with these findings, exogenous leptin stimulated whereas adiponectin suppressed breast stem cell self-renewal. In addition to local in-breast effects, circulating factors, including leptin and adiponectin, may contribute to the link between obesity and breast cancer. Increased levels of leptin and reduced amounts of adiponectin were found in serum from obese compared with age-matched lean postmenopausal women. Interestingly, serum from obese women increased stem cell self-renewal by 30% compared with only 7% for lean control serum. Taken together, these data suggest a plausible explanation for the obesity-driven increase in postmenopausal breast cancer risk. Leptin and adiponectin may function as both endocrine and paracrine/juxtacrine factors to modulate the size of the normal stem cell pool. Interventions that disrupt this axis and thereby normalize breast stem cell self-renewal could reduce the risk of breast cancer. ©2015 American Association for Cancer Research.

  4. ETS transcription factor ELF5 induces lumen formation in a 3D model of mammary morphogenesis and its expression is inhibited by Jak2 inhibitor TG101348.

    Science.gov (United States)

    Chean, Jennifer; Chen, Charng-Jui; Shively, John E

    2017-10-01

    The loss of expression of a single gene can revert normal tissue to a malignant phenotype. For example, while normal breast has high lumenal expression of CEACAM1, the majority of breast cancers exhibit the early loss of this gene with the concurrent loss of their lumenal phenotype. MCF7 cells that lack CEACAM1 expression and fail to form lumena in 3D culture, regain the normal phenotype when transfected with CEACAM1. In order to probe the mechanism of this gain of function, we treated these cells with the clinically relevant Jak2 inhibitor TG101348 (TG), expecting that disruption of the prolactin receptor signaling pathway would interfere with the positive effects of transfection of MCF7 cells with CEACAM1. Indeed, lumen formation was inhibited, resulting in the down regulation of a set of genes, likely involved in the complex process of lumen formation. As expected, inhibition of the expression of many of these genes also inhibited lumen formation, confirming their involvement in a single pathway. Among the genes identified by the inhibition assay, ETS transcription factor ELF5 stood out, since it has been identified as a master regulator of mammary morphogenesis, and is associated with prolactin receptor signaling. When ELF5 was transfected into the parental MCF7 cells that lack CEACAM1, lumen formation was restored, indicating that ELF5 can replace CEACAM1 in this model system of lumenogenesis. We conclude that the event(s) that led to the loss of expression of CEACAM1 is epistatic in that multiple genes associated with a critical pathway were affected, but that restoration of the normal phenotype can be achieved with reactivation of certain genes at various nodal points in tissue morphogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Endothelial cells stimulate growth of normal and cancerous breast epithelial cells in 3D culture

    Directory of Open Access Journals (Sweden)

    Magnusson Magnus K

    2010-07-01

    Full Text Available Abstract Background Epithelial-stromal interaction provides regulatory signals that maintain correct histoarchitecture and homeostasis in the normal breast and facilitates tumor progression in breast cancer. However, research on the regulatory role of the endothelial component in the normal and malignant breast gland has largely been neglected. The aim of the study was to investigate the effects of endothelial cells on growth and differentiation of human breast epithelial cells in a three-dimensional (3D co-culture assay. Methods Breast luminal and myoepithelial cells and endothelial cells were isolated from reduction mammoplasties. Primary cells and established normal and malignant breast cell lines were embedded in reconstituted basement membrane in direct co-culture with endothelial cells and by separation of Transwell filters. Morphogenic and phenotypic profiles of co-cultures was evaluated by phase contrast microscopy, immunostaining and confocal microscopy. Results In co-culture, endothelial cells stimulate proliferation of both luminal- and myoepithelial cells. Furthermore, endothelial cells induce a subpopulation of luminal epithelial cells to form large acini/ducts with a large and clear lumen. Endothelial cells also stimulate growth and cloning efficiency of normal and malignant breast epithelial cell lines. Transwell and gradient co-culture studies show that endothelial derived effects are mediated - at least partially - by soluble factors. Conclusion Breast endothelial cells - beside their role in transporting nutrients and oxygen to tissues - are vital component of the epithelial microenvironment in the breast and provide proliferative signals to the normal and malignant breast epithelium. These growth promoting effects of endothelial cells should be taken into consideration in breast cancer biology.

  6. Trace elemental correlation study in malignant and normal breast tissue by PIXE technique

    International Nuclear Information System (INIS)

    Raju, G.J. Naga; Sarita, P.; Kumar, M. Ravi; Murty, G.A.V. Ramana; Reddy, B. Seetharami; Lakshminarayana, S.; Vijayan, V.; Lakshmi, P.V.B. Rama; Gavarasana, Satyanarayana; Reddy, S. Bhuloka

    2006-01-01

    Particle induced X-ray emission technique was used to study the variations in trace elemental concentrations between normal and malignant human breast tissue specimens and to understand the effects of altered homeostasis of these elements in the etiology of breast cancer. A 3 MeV proton beam was used to excite the biological samples of normal and malignant breast tissues. The elements Cl, K, Ca, Ti, Cr, Mn, Fe, Ni, Cu, Zn, As, Se, Br, Rb and Sr were identified and their relative concentrations were estimated. Almost all the elements were found to be elevated (p < 0.05, Wilcoxon signed-ranks test) in the cancerous tissues when compared with normal tissues. The excess levels of trace elements observed in the cancerous breast tissues could either be a cause or a consequence of breast cancer. Regarding their role in the initiation or promotion of breast cancer, one possible interpretation is that the elevated levels of Cu, Fe and Cr could have led to the formation of free radicals or other reactive oxygen species (ROS) that adversely affect DNA thereby causing breast cancer, which is mainly attributed to genetic abnormalities. Moreover, since Cu and Fe are required for angiogenesis, elevated concentrations of these elements are likely to promote breast cancer by increasing the blood supply for tumor growth. On the other hand elevated concentrations of elements in breast cancer tissues might also be a consequence of the cancer. This can be understood in terms of the biochemical and histological differences between normal and cancerous breast tissues. Tumors, characterized by unregulated multiplication of cells, need an ever-increasing supply of essential nutrients including trace elements. This probably results in an increased vascularity of malignant tissues, which in turn leads to enhancement of elemental concentrations in tumors

  7. The clinical significance of normal mammograms and normal sonograms in patients with palpable abnormalities of the breast

    International Nuclear Information System (INIS)

    Lee, Jin Hwa; Yoon, Seong Kuk; Choi, Sun Seob; Nam, Kyung Jin; Cho, Se Heon; Kim, Dae Cheol; Kim, Jung Il; Kim, Eun Kyung

    2006-01-01

    We wanted to evaluate the clinical significance of normal mammograms and normal sonograms in patients with palpable abnormalities of the breast. From Apr 2003 to Feb 2005, 107 patients with 113 palpable abnormalities who had combined normal sonographic and normal mammographic findings were retrospectively studied. The evaluated parameters included age of the patients, the clinical referrals, the distribution of the locations of the palpable abnormalities, whether there was a past surgical history, the mammographic densities and the sonographic echo patterns (purely hyperechoic fibrous tissue, mixed fibroglandular breast tissue, predominantly isoechoic glandular tissue and isoechoic subcutaneous fat tissue) at the sites of clinical concern, whether there was a change in imaging and/or the physical examination results at follow-up, and whether there were biopsy results. This study period was chosen to allow a follow-up period of at least 12 months. The patients' ages ranged from 22 to 66 years (mean age: 48.8 years) and 62 (58%) of the 107 patients were between 41 and 50 years old (58%). The most common location of the palpable abnormalities was the upper outer portion of the breast (45%) and most of the mammographic densities were dense patterns (BI-RADS Type 3 or 4: 91%). Our cases showed similar distribution for all the types of sonographic echo patterns. 23 patients underwent biopsy; all the biopsy specimens were benign. For the 84 patients with 90 palpable abnormalities who were followed, there was no interval development of breast cancer in the areas of clinical concern. Our results suggest that we can follow up and prevent unnecessary biopsies in women with palpable abnormalities when both the mammography and ultrasonography show normal tissue, but this study was limited by its small sample size. Therefore, a larger study will be needed to better define the negative predictive value of combined normal sonographic and mammographic findings

  8. Do early premalignant changes in normal breast epithelial cells predict cancer development?

    International Nuclear Information System (INIS)

    Clarke, Robert B; Bundred, Nigel J

    2005-01-01

    A recent report suggests that, in an in vitro model of premalignant breast cells (vHMECs), silencing of INK4A gene is accompanied by over-expression of cyclo-oxygenase (COX)-2. This suggests that COX-2 over-expression may be an early event in breast cancer aetiology permitting clones within the normal epithelium to evade apoptosis, to increase their numbers and perhaps acquire further changes that promote the formation of hyperplasias, and eventually carcinomas. While COX-2 expression in normal breast epithelium in vivo has not been proven to be linked to an increased risk of breast cancer, its over-expression in the premalignant model in vitro does provide preliminary evidence that COX-2 inhibition may be a useful chemoprevention strategy

  9. Comparison of serum lipid profiles between normal controls and breast cancer patients

    Directory of Open Access Journals (Sweden)

    Pikul Laisupasin

    2013-01-01

    Full Text Available Background: Researchers have reported association of plasma/serum lipids and lipoproteins with different cancers. Increase levels of circulating lipids and lipoproteins have been associated with breast cancer risk. Aim: The aim of this study is to compare serum lipid profiles: total-cholesterol (T-CHOL, triglyceride (TG, high density lipoprotein-cholesterol (HDL-C, low density lipoprotein-cholesterol (LDL-C and very low density lipoprotein-cholesterol (VLDL-C between breast cancer patients and normal participants. Materials and Methods: A total of 403 women in this study were divided into two groups in the period during May 2006-April 2007. Blood samples were collected from 249 patients with early stage breast cancer and 154 normal controls for serum lipid profiles (T-CHOL, TG, HDL-C, LDL-C and VLDL-C analysis using Hitachi 717 Autoanalyzer (Roche Diagnostic GmbH, Germany. TG, LDL-C and VLDL-C levels in breast cancer group were significantly increased as compared with normal controls group (P < 0.001, whereas HDL-C and T-CHOL levels were not. Results: The results of this study suggest that increased serum lipid profiles may associate with breast cancer risk in Thai women. Further studies to group important factors including, cancer stages, types of cancer, parity, and menopausal status that may affect to lipid profiles in breast cancer patients along with an investigation of new lipid profiles to clarify most lipid factors that may involve in breast cancer development are needed.

  10. Identification of the boundary between normal breast tissue and invasive ductal carcinoma during breast-conserving surgery using multiphoton microscopy

    Science.gov (United States)

    Deng, Tongxin; Nie, Yuting; Lian, Yuane; Wu, Yan; Fu, Fangmeng; Wang, Chuan; Zhuo, Shuangmu; Chen, Jianxin

    2014-11-01

    Breast-conserving surgery has become an important way of surgical treatment for breast cancer worldwide nowadays. Multiphoton microscopy (MPM) has the ability to noninvasively visualize tissue architectures at the cellular level using intrinsic fluorescent molecules in biological tissues without the need for fluorescent dye. In this study, MPM is used to image the microstructures of terminal duct lobular unit (TDLU), invasive ductal carcinoma and the boundary region between normal and cancerous breast tissues. Our study demonstrates that MPM has the ability to not only reveal the morphological changes of the cuboidal epithelium, basement membrane and interlobular stroma but also identify the boundary between normal breast tissue and invasive ductal carcinoma, which correspond well to the Hematoxylin and Eosin (H and E) images. Predictably, MPM can monitor surgical margins in real time and provide considerable accuracy for resection of breast cancerous tissues intraoperatively. With the development of miniature, real-time MPM imaging technology, MPM should have great application prospects during breast-conserving surgery.

  11. Identification of genes with altered expression in medullary breast cancer vs. ductal breast cancer and normal breast epithelia

    DEFF Research Database (Denmark)

    Gjerstorff, Morten; Benoit, Vivian; Laenkholm, Anne-Vibeke

    2006-01-01

    to both immunological and endogenous cellular factors, although little is known about the distinct biology of MCB that may contribute to the improved outcome of MCB patients. To identify candidate genes, we performed gene array expression analysis of cell lines of MCB, ductal breast cancer and normal......Medullary breast cancer (MCB) is a morphologically and biologically distinct subtype that, despite cytologically highly malignant characteristics, has a favorable prognosis compared to the more common infiltrating ductal breast carcinoma. MCB metastasizes less frequently, which has been attributed...... breast epithelia, and the differential expression of a panel of candidate genes was further validated by quantitative PCR and immunohistochemical analysis of cell lines and tumor biopsies. A limited number of genes, including several members of the GAGE and insulin growth factor binding protein (IGFBP...

  12. Biological responses of progestogen metabolites in normal and cancerous human breast.

    Science.gov (United States)

    Pasqualini, Jorge R; Chetrite, Gérard S

    2010-12-01

    At present, more than 200 progestogen molecules are available, but their biological response is a function of various factors: affinity to progesterone or other receptors, their structure, the target tissues considered, biological response, experimental conditions, dose, method of administration and metabolic transformations. Metabolic transformation is of huge importance because in various biological processes the metabolic product(s) not only control the activity of the maternal hormone but also have an important activity of its own. In this regard, it was observed that the 20-dihydro derivative of the progestogen dydrogesterone (Duphaston®) is significantly more active than the parent compound in inhibiting sulfatase and 17β-hydroxysteroid dehydrogenase in human breast cancer cells. Estrone sulfatase activity is also inhibited by norelgestromin, a norgestimate metabolite. Interesting information was obtained with a similar progestogen, tibolone, which is rapidly metabolized into the active 3α/3β-hydroxy and 4-ene metabolites. All these metabolites can inhibit sulfatase and 17β-hydroxysteroid dehydrogenase and stimulate sulfotransferase in human breast cancer cells. Another attractive aspect is the metabolic transformation of progesterone itself in human breast tissues. In the normal breast progesterone is mainly converted to 4-ene derivatives, whereas in the tumor tissue it is converted mostly to 5α-pregnane derivatives. 20α-Dihydroprogesterone is found mainly in normal breast tissue and possesses antiproliferative properties as well as the ability to act as an anti-aromatase agent. Consequently, this progesterone metabolite could be involved in the control of estradiol production in the normal breast and therefore implicated in one of the multifactorial mechanisms of the breast carcinogenesis process. In conclusion, a better understanding of both natural and synthetic hormone metabolic transformations and their control could potentially provide

  13. Aluminum concentrations in central and peripheral areas of malignant breast lesions do not differ from those in normal breast tissues

    International Nuclear Information System (INIS)

    Rodrigues-Peres, Raquel Mary; Cadore, Solange; Febraio, Stefanny; Heinrich, Juliana Karina; Serra, Katia Piton; Derchain, Sophie F M; Vassallo, Jose; Sarian, Luis Otavio

    2013-01-01

    Aluminum is used in a wide range of applications and is a potential environmental hazard. The known genotoxic effects of aluminum might play a role in the development of breast cancer. However, the data currently available on the subject are not sufficient to establish a causal relationship between aluminum exposure and the augmented risk of developing breast cancer. To achieve maximum sensitivity and specificity in the determination of aluminum levels, we have developed a detection protocol using graphite furnace atomic absorption spectrometry (GFAAS). The objective of the present study was to compare the aluminum levels in the central and peripheral areas of breast carcinomas with those in the adjacent normal breast tissues, and to identify patient and/or tumor characteristics associated with these aluminum levels. A total of 176 patients with breast cancer were included in the study. Samples from the central and peripheral areas of their tumors were obtained, as well as from the surrounding normal breast tissue. Aluminum quantification was performed using GFAAS. The average (mean ± SD) aluminum concentrations were as follows: central area, 1.88 ± 3.60 mg/kg; peripheral area, 2.10 ± 5.67 mg/kg; and normal area, 1.68 ± 11.1 mg/kg. Overall and two-by-two comparisons of the aluminum concentrations in these areas indicated no significant differences. We detected a positive relationship between aluminum levels in the peripheral areas of the tumors, age and menopausal status of the patients (P = .02). Using a sensitive quantification technique we detected similar aluminum concentrations in the central and peripheral regions of breast tumors, and in normal tissues. In addition, we did not detect significant differences in aluminum concentrations as related to the location of the breast tumor within the breast, or to other relevant tumor features such as stage, size and steroid receptor status. The next logical step is the assessment of whether the aluminum

  14. Changes in glycosaminoglycans and proteoglycans of normal breast and fibroadenoma during the menstrual cycle.

    Science.gov (United States)

    de Lima, Cilene Rebouças; de Arimatéa dos Santos Junior, José; Nazário, Afonso Celso Pinto; Michelacci, Yara M

    2012-07-01

    Fibroadenoma is the most common breast tumor in young women, and its growth and metabolism may be under hormonal control. In the present paper we described the proteoglycan (PG) composition and synthesis rate of normal breast and fibroadenoma during the menstrual cycle. Samples of fibroadenoma and adjacent normal breast tissue were obtained at surgery. PGs were characterized by agarose gel electrophoresis and enzymatic degradation with glycosaminoglycan (GAG) lyases, and immunolocalized by confocal microscopy. To assess the synthesis rate, PGs were metabolic labeled by 35S-sulfate. The concentration of PGs in normal breast was higher during the secretory phase. Fibroadenoma contained and synthesized more PGs than their paired controls, but the PG concentrations varied less with the menstrual cycle and, in contrast to normal tissue, peaked in the proliferative phase. The main mammary GAGs are heparan sulfate (HS, 71%-74%) and dermatan sulfate (DS, 26%-29%). The concentrations of both increased in fibroadenoma, but DS increased more, becoming 35%-37% of total. The DS chains contained more β-d-glucuronic acid (IdoUA/GlcUA ratios were >10 in normal breast and 2-7 in fibroadenoma). The 35S-sulfate incorporation rate revealed that the in vitro synthesis rate of DS was higher than HS. Decorin was present in both tissues, while versican was found only in fibroadenoma. In normal breast, the PG concentration varied with the menstrual cycle. It was increased in fibroadenoma, especially DS. PGs are increased in fibroadenoma, but their concentrations may be less sensitive to hormonal control. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Normal parenchymal enhancement patterns in women undergoing MR screening of the breast

    International Nuclear Information System (INIS)

    Jansen, Sanaz A.; Lin, Vicky C.; Giger, Maryellen L.; Li, Hui; Karczmar, Gregory S.; Newstead, Gillian M.

    2011-01-01

    To characterize the kinetic and morphological presentation of normal breast tissue on DCE-MRI in a large cohort of asymptomatic women, and to relate these characteristics to breast tissue density. 335 consecutive breast MR examinations in 229 asymptomatic women undergoing high-risk screening evaluations based on recommendations from the American Cancer Society including strong family history and genetic predisposition were selected for IRB-approved review (average age 49.2 ± 10.5 years). Breast tissue density was assessed on precontrast T 2 -weighted images. Parenchymal enhancement pattern (PEP) was qualitatively classified as minimal, homogeneous, heterogeneous or nodular. Quantitative analysis of parenchymal enhancement kinetics (PEK) was performed, including calculation of initial and peak enhancement percentages (E 1 , E peak ), the time to peak enhancement (T peak ) and the signal enhancement ratio (SER). 41.8% of examinations were classified as minimal, 13.7% homogeneous, 23.9% heterogeneous and 21.2% nodular PEP. Women with heterogeneously or extremely dense breasts exhibited a higher proportion of nodular PEP (44.2% (27/61)) and significantly higher E 1 , and E peak (p < 0.003) compared with those with less dense breasts. Qualitative and quantitative parenchymal enhancement characteristics vary by breast tissue density. In future work, the association between image-derived MR features of the normal breast and breast cancer risk should be explored. (orig.)

  16. Breast cancer subtype distribution is different in normal weight, overweight, and obese women.

    Science.gov (United States)

    Gershuni, Victoria; Li, Yun R; Williams, Austin D; So, Alycia; Steel, Laura; Carrigan, Elena; Tchou, Julia

    2017-06-01

    Obesity is associated with tumor promoting pathways related to insulin resistance and chronic low-grade inflammation which have been linked to various disease states, including cancer. Many studies have focused on the relationship between obesity and increased estrogen production, which contributes to the pathogenesis of estrogen receptor-positive breast cancers. The link between obesity and other breast cancer subtypes, such as triple-negative breast cancer (TNBC) and Her2/neu+ (Her2+) breast cancer, is less clear. We hypothesize that obesity may be associated with the pathogenesis of specific breast cancer subtypes resulting in a different subtype distribution than normal weight women. A single-institution, retrospective analysis of tumor characteristics of 848 patients diagnosed with primary operable breast cancer between 2000 and 2013 was performed to evaluate the association between BMI and clinical outcome. Patients were grouped based on their BMI at time of diagnosis stratified into three subgroups: normal weight (BMI = 18-24.9), overweight (BMI = 25-29.9), and obese (BMI > 30). The distribution of breast cancer subtypes across the three BMI subgroups was compared. Obese and overweight women were more likely to present with TNBC and normal weight women with Her2+ breast cancer (p = 0.008). We demonstrated, for the first time, that breast cancer subtype distribution varied significantly according to BMI status. Our results suggested that obesity might activate molecular pathways other than the well-known obesity/estrogen circuit in the pathogenesis of breast cancer. Future studies are needed to understand the molecular mechanisms that drive the variation in subtype distribution across BMI subgroups.

  17. YAP expression in normal and neoplastic breast tissue: an immunohistochemical study.

    Science.gov (United States)

    Jaramillo-Rodríguez, Yolanda; Cerda-Flores, Ricardo M; Ruiz-Ramos, Ruben; López-Márquez, Francisco C; Calderón-Garcidueñas, Ana Laura

    2014-04-01

    Yes-associated protein (YAP) is a transcriptional factor involved in normal cell proliferation, apoptosis and carcinogenesis; however, its contribution to breast cancer (BC) is still controversial. We undertook this study to compare the expression of YAP by immunohistochemistry (IHC) in normal breast tissue of women without breast cancer (BC) (controls), non-neoplastic breast tissue in women with cancer (internal controls) and in four different subtypes of invasive ductal carcinoma. There were 17 controls and 105 tumor cases (53 luminal A, 15 luminal B, 20 overexpression of HER2 and 17 triple negative cases) studied by IHC. Statistical analysis included χ(2) for linear trend (Extended Mantel-Haenszel). There were 40% of internal controls that showed expression of YAP in myoepithelial cells, whereas in controls expression was 100%. In controls, 3/17 (17.6%) showed cytoplasmic staining in luminal cells. There was a significant difference in nuclear expression between the ductal BC subtypes. Luminal A had 4% of positive cases with <10% of cells affected in each case; in contrast, there were 17-20% of positive cases in the other groups with 50% or more of stained cells. YAP expression in stromal cells was not observed in controls or in triple-negative cases, and luminal B pattern had the highest YAP nuclear expression (20%). YAP showed decreased expression in tumor cells compared with normal breast tissue. These findings are consistent with a role of YAP as a suppressor gene in BC and show differences in YAP expression in different patterns of ductal BC. Copyright © 2014 IMSS. Published by Elsevier Inc. All rights reserved.

  18. Aluminum concentrations in central and peripheral areas of malignant breast lesions do not differ from those in normal breast tissues

    Science.gov (United States)

    2013-01-01

    Background Aluminum is used in a wide range of applications and is a potential environmental hazard. The known genotoxic effects of aluminum might play a role in the development of breast cancer. However, the data currently available on the subject are not sufficient to establish a causal relationship between aluminum exposure and the augmented risk of developing breast cancer. To achieve maximum sensitivity and specificity in the determination of aluminum levels, we have developed a detection protocol using graphite furnace atomic absorption spectrometry (GFAAS). The objective of the present study was to compare the aluminum levels in the central and peripheral areas of breast carcinomas with those in the adjacent normal breast tissues, and to identify patient and/or tumor characteristics associated with these aluminum levels. Methods A total of 176 patients with breast cancer were included in the study. Samples from the central and peripheral areas of their tumors were obtained, as well as from the surrounding normal breast tissue. Aluminum quantification was performed using GFAAS. Results The average (mean ± SD) aluminum concentrations were as follows: central area, 1.88 ± 3.60 mg/kg; peripheral area, 2.10 ± 5.67 mg/kg; and normal area, 1.68 ± 11.1 mg/kg. Overall and two-by-two comparisons of the aluminum concentrations in these areas indicated no significant differences. We detected a positive relationship between aluminum levels in the peripheral areas of the tumors, age and menopausal status of the patients (P = .02). Conclusions Using a sensitive quantification technique we detected similar aluminum concentrations in the central and peripheral regions of breast tumors, and in normal tissues. In addition, we did not detect significant differences in aluminum concentrations as related to the location of the breast tumor within the breast, or to other relevant tumor features such as stage, size and steroid receptor status. The next

  19. The normal breast microenvironment of premenopausal women differentially influences the behavior of breast cancer cells in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Ginsburg Erika

    2010-05-01

    Full Text Available Abstract Background Breast cancer studies frequently focus on the role of the tumor microenvironment in the promotion of cancer; however, the influence of the normal breast microenvironment on cancer cells remains relatively unknown. To investigate the role of the normal breast microenvironment on breast cancer cell tumorigenicity, we examined whether extracellular matrix molecules (ECM derived from premenopausal African-American (AA or Caucasian-American (CAU breast tissue would affect the tumorigenicity of cancer cells in vitro and in vivo. We chose these two populations because of the well documented predisposition of AA women to develop aggressive, highly metastatic breast cancer compared to CAU women. Methods The effects of primary breast fibroblasts on tumorigenicity were analyzed via real-time PCR arrays and mouse xenograft models. Whole breast ECM was isolated, analyzed via zymography, and its effects on breast cancer cell aggressiveness were tested in vitro via soft agar and invasion assays, and in vivo via xenograft models. Breast ECM and hormone metabolites were analyzed via mass spectrometry. Results Mouse mammary glands humanized with premenopausal CAU fibroblasts and injected with primary breast cancer cells developed significantly larger tumors compared to AA humanized glands. Examination of 164 ECM molecules and cytokines from CAU-derived fibroblasts demonstrated a differentially regulated set of ECM proteins and increased cytokine expression. Whole breast ECM was isolated; invasion and soft agar assays demonstrated that estrogen receptor (ER-, progesterone receptor (PR/PR- cells were significantly more aggressive when in contact with AA ECM, as were ER+/PR+ cells with CAU ECM. Using zymography, protease activity was comparatively upregulated in CAU ECM. In xenograft models, CAU ECM significantly increased the tumorigenicity of ER+/PR+ cells and enhanced metastases. Mass spectrometry analysis of ECM proteins showed that only 1

  20. Macro-environment of breast carcinoma: frequent genetic alterations in the normal appearing skins of patients with breast cancer.

    Science.gov (United States)

    Moinfar, Farid; Beham, Alfred; Friedrich, Gerhard; Deutsch, Alexander; Hrzenjak, Andelko; Luschin, Gero; Tavassoli, Fattaneh A

    2008-05-01

    Genetic abnormalities in microenvironmental tissues with subsequent alterations of reciprocal interactions between epithelial and mesenchymal cells play a key role in the breast carcinogenesis. Although a few reports have demonstrated abnormal fibroblastic functions in normal-appearing fibroblasts taken from the skins of breast cancer patients, the genetic basis of this phenomenon and its implication for carcinogenesis are unexplored. We analyzed 12 mastectomy specimens showing invasive ductal carcinomas. In each case, morphologically normal epidermis and dermis, carcinoma, normal stroma close to carcinoma, and stroma at a distant from carcinoma were microdissected. Metastatic-free lymphatic tissues from lymph nodes served as a control. Using PCR, DNA extracts were examined with 11 microsatellite markers known for a high frequency of allelic imbalances in breast cancer. Losses of heterozygosity and/or microsatellite instability were detected in 83% of the skin samples occurring either concurrently with or independently from the cancerous tissues. In 80% of these cases at least one microsatellite marker displayed loss of heterozygosity or microsatellite instability in the skin, which was absent in carcinoma. A total of 41% of samples showed alterations of certain loci observed exclusively in the carcinoma but not in the skin compartments. Our study suggests that breast cancer is not just a localized genetic disorder, but rather part of a larger field of genetic alterations/instabilities affecting multiple cell populations in the organ with various cellular elements, ultimately contributing to the manifestation of the more 'localized' carcinoma. These data indicate that more global assessment of tumor micro- and macro-environment is crucial for our understanding of breast carcinogenesis.

  1. Differentiating cancerous from normal breast tissue by redox imaging

    Science.gov (United States)

    Xu, He N.; Tchou, Julia; Feng, Min; Zhao, Huaqing; Li, Lin Z.

    2015-02-01

    Abnormal metabolism can be a hallmark of cancer occurring early before detectable histological changes and may serve as an early detection biomarker. The current gold standard to establish breast cancer (BC) diagnosis is histological examination of biopsy. Previously we have found that pre-cancer and cancer tissues in animal models displayed abnormal mitochondrial redox state. Our technique of quantitatively measuring the mitochondrial redox state has the potential to be implemented as an early detection tool for cancer and may provide prognostic value. We therefore in this present study, investigated the feasibility of quantifying the redox state of tumor samples from 16 BC patients. Tumor tissue aliquots were collected from both normal and cancerous tissue from the affected cancer-bearing breasts of 16 female patients (5 TNBC, 9 ER+, 2 ER+/Her2+) shortly after surgical resection. All specimens were snap-frozen with liquid nitrogen on site and scanned later with the Chance redox scanner, i.e., the 3D cryogenic NADH/oxidized flavoprotein (Fp) fluorescence imager. Our preliminary results showed that both NADH and Fp (including FAD, i.e., flavin adenine dinucleotide) signals in the cancerous tissues roughly tripled to quadrupled those in the normal tissues (pcancerous tissues than in the normal ones (pcancer and non-cancer breast tissues in human patients and this novel redox scanning procedure may assist in tissue diagnosis in freshly procured biopsy samples prior to tissue fixation. We are in the process of evaluating the prognostic value of the redox imaging indices for BC.

  2. Tumor suppressor function of Syk in human MCF10A in vitro and normal mouse mammary epithelium in vivo.

    Directory of Open Access Journals (Sweden)

    You Me Sung

    2009-10-01

    Full Text Available The normal function of Syk in epithelium of the developing or adult breast is not known, however, Syk suppresses tumor growth, invasion, and metastasis in breast cancer cells. Here, we demonstrate that in the mouse mammary gland, loss of one Syk allele profoundly increases proliferation and ductal branching and invasion of epithelial cells through the mammary fat pad during puberty. Mammary carcinomas develop by one year. Syk also suppresses proliferation and invasion in vitro. siRNA or shRNA knockdown of Syk in MCF10A breast epithelial cells dramatically increased proliferation, anchorage independent growth, cellular motility, and invasion, with formation of functional, extracellular matrix-degrading invadopodia. Morphological and gene microarray analysis following Syk knockdown revealed a loss of luminal and differentiated epithelial features with epithelial to mesenchymal transition and a gain in invadopodial cell surface markers CD44, CD49F, and MMP14. These results support the role of Syk in limiting proliferation and invasion of epithelial cells during normal morphogenesis, and emphasize the critical role of Syk as a tumor suppressor for breast cancer. The question of breast cancer risk following systemic anti-Syk therapy is raised since only partial loss of Syk was sufficient to induce mammary carcinomas.

  3. EphB/syndecan-2 signaling in dendritic spine morphogenesis

    DEFF Research Database (Denmark)

    Ethell, I M; Irie, F; Kalo, M S

    2001-01-01

    We previously reported that the cell surface proteoglycan syndecan-2 can induce dendritic spine formation in hippocampal neurons. We demonstrate here that the EphB2 receptor tyrosine kinase phosphorylates syndecan-2 and that this phosphorylation event is crucial for syndecan-2 clustering and spine...... formation. Syndecan-2 is tyrosine phosphorylated and forms a complex with EphB2 in mouse brain. Dominant-negative inhibition of endogenous EphB receptor activities blocks clustering of endogenous syndecan-2 and normal spine formation in cultured hippocampal neurons. This is the first evidence that Eph...... receptors play a physiological role in dendritic spine morphogenesis. Our observations suggest that spine morphogenesis is triggered by the activation of Eph receptors, which causes tyrosine phosphorylation of target molecules, such as syndecan-2, in presumptive spines....

  4. The case for applying tissue engineering methodologies to instruct human organoid morphogenesis.

    Science.gov (United States)

    Marti-Figueroa, Carlos R; Ashton, Randolph S

    2017-05-01

    Three-dimensional organoids derived from human pluripotent stem cell (hPSC) derivatives have become widely used in vitro models for studying development and disease. Their ability to recapitulate facets of normal human development during in vitro morphogenesis produces tissue structures with unprecedented biomimicry. Current organoid derivation protocols primarily rely on spontaneous morphogenesis processes to occur within 3-D spherical cell aggregates with minimal to no exogenous control. This yields organoids containing microscale regions of biomimetic tissues, but at the macroscale (i.e. 100's of microns to millimeters), the organoids' morphology, cytoarchitecture, and cellular composition are non-biomimetic and variable. The current lack of control over in vitro organoid morphogenesis at the microscale induces aberrations at the macroscale, which impedes realization of the technology's potential to reproducibly form anatomically correct human tissue units that could serve as optimal human in vitro models and even transplants. Here, we review tissue engineering methodologies that could be used to develop powerful approaches for instructing multiscale, 3-D human organoid morphogenesis. Such technological mergers are critically needed to harness organoid morphogenesis as a tool for engineering functional human tissues with biomimetic anatomy and physiology. Human PSC-derived 3-D organoids are revolutionizing the biomedical sciences. They enable the study of development and disease within patient-specific genetic backgrounds and unprecedented biomimetic tissue microenvironments. However, their uncontrolled, spontaneous morphogenesis at the microscale yields inconsistences in macroscale organoid morphology, cytoarchitecture, and cellular composition that limits their standardization and application. Integration of tissue engineering methods with organoid derivation protocols could allow us to harness their potential by instructing standardized in vitro morphogenesis

  5. Searching for biomarkers of developmental toxicity with microarrays: normal eye morphogenesis in rodent embryos

    International Nuclear Information System (INIS)

    Nemeth, Kimberly A.; Singh, Amar V.; Knudsen, Thomas B.

    2005-01-01

    Gene expression arrays reveal the potential linkage of altered gene expression with specific adverse effects leading to disease phenotypes. But how closely do microarray data reflect early physiological or pharmacological measures that predict toxic event(s)? To explore this issue, we have undertaken experiments in early mouse embryos exposed to various teratogens during neurulation stages with the aim of correlating large-scale changes in gene expression across the critical period during exposure. This study reports some of the large-scale changes in gene expression that can be detected in the optic rudiment of the developing mouse and rat embryo across the window of development during which the eye is exceedingly sensitive to teratogen-induced micro-/anophthalmia. Microarray analysis was performed on RNA from the headfold or ocular region at the optic vesicle and optic cup stages when the ocular primordium is enriched for Pax-6, a master control gene for eye morphogenesis. Statistical selection of differentially regulated genes and various clustering techniques identified groups of genes in upward or downward trajectories in the normal optic primordium during early eye development in mouse and rat species. We identified 165 genes with significant differential expression during eye development, and a smaller subset of 58 genes that showed a tight correlation between mouse-rat development. Significantly over-represented functional categories included fatty acid metabolism (up-regulated) and glycolysis (down-regulated). From studies such as these that benchmark large-scale gene expression during normal embryonic development, we may be able to identify the panel of biomarkers that best correlate with species differences and the risks for developmental toxicity

  6. MUC-1-ESA+ progenitor cells in normal benign and malignant human breast epithelial cells

    OpenAIRE

    Lu, Xinquan; Li, Huixiang; Xu, Kejia; Nesland, Jahn M.; Suo, Zhenhe

    2009-01-01

    The existence of mammary epithelial stem/progenitor cells has been demonstrated in MUC-1-/ ESA+ subpopulations of breast epithelial cells. However, knowledge about the expression and localization in benign and malignant breast lesions is unknown. Using a double-staining immunohistochemistry method, we investigated MUC-1-/ESA+ cells in 10 normal breast tissues, 49 cases with fibrocystic disease, 40 fibroadenomas, 36 invasive ductal carcinomas and the breast cancer ce...

  7. Normal breast tissue DNA methylation differences at regulatory elements are associated with the cancer risk factor age.

    Science.gov (United States)

    Johnson, Kevin C; Houseman, E Andres; King, Jessica E; Christensen, Brock C

    2017-07-10

    The underlying biological mechanisms through which epidemiologically defined breast cancer risk factors contribute to disease risk remain poorly understood. Identification of the molecular changes associated with cancer risk factors in normal tissues may aid in determining the earliest events of carcinogenesis and informing cancer prevention strategies. Here we investigated the impact cancer risk factors have on the normal breast epigenome by analyzing DNA methylation genome-wide (Infinium 450 K array) in cancer-free women from the Susan G. Komen Tissue Bank (n = 100). We tested the relation of established breast cancer risk factors, age, body mass index, parity, and family history of disease, with DNA methylation adjusting for potential variation in cell-type proportions. We identified 787 cytosine-guanine dinucleotide (CpG) sites that demonstrated significant associations (Q value breast cancer risk factors. Age-related DNA methylation changes are primarily increases in methylation enriched at breast epithelial cell enhancer regions (P = 7.1E-20), and binding sites of chromatin remodelers (MYC and CTCF). We validated the age-related associations in two independent populations, using normal breast tissue samples (n = 18) and samples of normal tissue adjacent to tumor tissue (n = 97). The genomic regions classified as age-related were more likely to be regions altered in both pre-invasive (n = 40, P = 3.0E-03) and invasive breast tumors (n = 731, P = 1.1E-13). DNA methylation changes with age occur at regulatory regions, and are further exacerbated in cancer, suggesting that age influences breast cancer risk in part through its contribution to epigenetic dysregulation in normal breast tissue.

  8. Evaluation of human epidermal growth factor receptor 2 (HER2) single nucleotide polymorphisms (SNPs) in normal and breast tumor tissues and their link with breast cancer prognostic factors.

    Science.gov (United States)

    Furrer, Daniela; Lemieux, Julie; Côté, Marc-André; Provencher, Louise; Laflamme, Christian; Barabé, Frédéric; Jacob, Simon; Michaud, Annick; Diorio, Caroline

    2016-12-01

    Amplification of the human epidermal growth factor receptor 2 (HER2) gene is associated with worse prognosis and decreased overall survival in breast cancer patients. The HER2 gene contains several polymorphisms; two of the best-characterized HER2 polymorphisms are Ile655Val and Ala1170Pro. The aim of this study was to evaluate the association between these two HER2 polymorphisms in normal breast and breast cancer tissues and known breast cancer prognostic factors in a retrospective cohort study of 73 women with non-metastatic HER2-positive breast cancer. HER2 polymorphisms were assessed in breast cancer tissue and normal breast tissue using TaqMan assay. Ala1170Pro polymorphism in normal breast tissue was associated with age at diagnosis (p = 0.007), tumor size (p = 0.004) and lymphovascular invasion (p = 0.06). Similar significant associations in cancer tissues were observed. No association between the Ile655Val polymorphism and prognostic factors were observed. However, we found significant differences in the distribution of Ile655Val (p = 0.03) and Ala1170Pro (p = 0.01) genotypes between normal breast and breast tumor tissues. This study demonstrates that only the Ala1170Pro polymorphism is associated with prognostic factors in HER2-positive breast cancer patients. Moreover, our results suggest that both HER2 polymorphisms could play a significant role in carcinogenesis in non-metastatic HER2-positive breast cancer women. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. A large-scale study of the ultrawideband microwave dielectric properties of normal, benign and malignant breast tissues obtained from cancer surgeries

    Energy Technology Data Exchange (ETDEWEB)

    Lazebnik, Mariya [Department of Electrical and Computer Engineering, University of Wisconsin, Madison, WI (United States); Popovic, Dijana [Department of Electrical and Computer Engineering, University of Calgary, Calgary, AB (Canada); McCartney, Leah [Department of Electrical and Computer Engineering, University of Calgary, Calgary, AB (Canada); Watkins, Cynthia B [Department of Electrical and Computer Engineering, University of Wisconsin, Madison, WI (United States); Lindstrom, Mary J [Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI (United States); Harter, Josephine [Department of Pathology, University of Wisconsin, Madison, WI (United States); Sewall, Sarah [Department of Pathology, University of Wisconsin, Madison, WI (United States); Ogilvie, Travis [Department of Pathology, University of Calgary, Calgary, AB (Canada); Magliocco, Anthony [Department of Pathology, University of Calgary, Calgary, AB (Canada); Breslin, Tara M [Department of Surgery, University of Wisconsin, Madison, WI (United States); Temple, Walley [Department of Surgery and Oncology, University of Calgary, Calgary, AB (Canada); Mew, Daphne [Department of Surgery and Oncology, University of Calgary, Calgary, AB (Canada); Booske, John H [Department of Electrical and Computer Engineering, University of Wisconsin, Madison, WI (United States); Okoniewski, Michal [Department of Electrical and Computer Engineering, University of Calgary, Calgary, AB (Canada); Hagness, Susan C [Department of Electrical and Computer Engineering, University of Wisconsin, Madison, WI (United States)

    2007-10-21

    The development of microwave breast cancer detection and treatment techniques has been driven by reports of substantial contrast in the dielectric properties of malignant and normal breast tissues. However, definitive knowledge of the dielectric properties of normal and diseased breast tissues at microwave frequencies has been limited by gaps and discrepancies across previously published studies. To address these issues, we conducted a large-scale study to experimentally determine the ultrawideband microwave dielectric properties of a variety of normal, malignant and benign breast tissues, measured from 0.5 to 20 GHz using a precision open-ended coaxial probe. Previously, we reported the dielectric properties of normal breast tissue samples obtained from reduction surgeries. Here, we report the dielectric properties of normal (adipose, glandular and fibroconnective), malignant (invasive and non-invasive ductal and lobular carcinomas) and benign (fibroadenomas and cysts) breast tissue samples obtained from cancer surgeries. We fit a one-pole Cole-Cole model to the complex permittivity data set of each characterized sample. Our analyses show that the contrast in the microwave-frequency dielectric properties between malignant and normal adipose-dominated tissues in the breast is considerable, as large as 10:1, while the contrast in the microwave-frequency dielectric properties between malignant and normal glandular/fibroconnective tissues in the breast is no more than about 10%.

  10. A large-scale study of the ultrawideband microwave dielectric properties of normal, benign and malignant breast tissues obtained from cancer surgeries

    Science.gov (United States)

    Lazebnik, Mariya; Popovic, Dijana; McCartney, Leah; Watkins, Cynthia B.; Lindstrom, Mary J.; Harter, Josephine; Sewall, Sarah; Ogilvie, Travis; Magliocco, Anthony; Breslin, Tara M.; Temple, Walley; Mew, Daphne; Booske, John H.; Okoniewski, Michal; Hagness, Susan C.

    2007-10-01

    The development of microwave breast cancer detection and treatment techniques has been driven by reports of substantial contrast in the dielectric properties of malignant and normal breast tissues. However, definitive knowledge of the dielectric properties of normal and diseased breast tissues at microwave frequencies has been limited by gaps and discrepancies across previously published studies. To address these issues, we conducted a large-scale study to experimentally determine the ultrawideband microwave dielectric properties of a variety of normal, malignant and benign breast tissues, measured from 0.5 to 20 GHz using a precision open-ended coaxial probe. Previously, we reported the dielectric properties of normal breast tissue samples obtained from reduction surgeries. Here, we report the dielectric properties of normal (adipose, glandular and fibroconnective), malignant (invasive and non-invasive ductal and lobular carcinomas) and benign (fibroadenomas and cysts) breast tissue samples obtained from cancer surgeries. We fit a one-pole Cole-Cole model to the complex permittivity data set of each characterized sample. Our analyses show that the contrast in the microwave-frequency dielectric properties between malignant and normal adipose-dominated tissues in the breast is considerable, as large as 10:1, while the contrast in the microwave-frequency dielectric properties between malignant and normal glandular/fibroconnective tissues in the breast is no more than about 10%.

  11. A large-scale study of the ultrawideband microwave dielectric properties of normal, benign and malignant breast tissues obtained from cancer surgeries

    International Nuclear Information System (INIS)

    Lazebnik, Mariya; Popovic, Dijana; McCartney, Leah; Watkins, Cynthia B; Lindstrom, Mary J; Harter, Josephine; Sewall, Sarah; Ogilvie, Travis; Magliocco, Anthony; Breslin, Tara M; Temple, Walley; Mew, Daphne; Booske, John H; Okoniewski, Michal; Hagness, Susan C

    2007-01-01

    The development of microwave breast cancer detection and treatment techniques has been driven by reports of substantial contrast in the dielectric properties of malignant and normal breast tissues. However, definitive knowledge of the dielectric properties of normal and diseased breast tissues at microwave frequencies has been limited by gaps and discrepancies across previously published studies. To address these issues, we conducted a large-scale study to experimentally determine the ultrawideband microwave dielectric properties of a variety of normal, malignant and benign breast tissues, measured from 0.5 to 20 GHz using a precision open-ended coaxial probe. Previously, we reported the dielectric properties of normal breast tissue samples obtained from reduction surgeries. Here, we report the dielectric properties of normal (adipose, glandular and fibroconnective), malignant (invasive and non-invasive ductal and lobular carcinomas) and benign (fibroadenomas and cysts) breast tissue samples obtained from cancer surgeries. We fit a one-pole Cole-Cole model to the complex permittivity data set of each characterized sample. Our analyses show that the contrast in the microwave-frequency dielectric properties between malignant and normal adipose-dominated tissues in the breast is considerable, as large as 10:1, while the contrast in the microwave-frequency dielectric properties between malignant and normal glandular/fibroconnective tissues in the breast is no more than about 10%

  12. Phenotypic transition maps of 3D breast acini obtained by imaging-guided agent-based modeling

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Jonathan; Enderling, Heiko; Becker-Weimann, Sabine; Pham, Christopher; Polyzos, Aris; Chen, Chen-Yi; Costes, Sylvain V

    2011-02-18

    We introduce an agent-based model of epithelial cell morphogenesis to explore the complex interplay between apoptosis, proliferation, and polarization. By varying the activity levels of these mechanisms we derived phenotypic transition maps of normal and aberrant morphogenesis. These maps identify homeostatic ranges and morphologic stability conditions. The agent-based model was parameterized and validated using novel high-content image analysis of mammary acini morphogenesis in vitro with focus on time-dependent cell densities, proliferation and death rates, as well as acini morphologies. Model simulations reveal apoptosis being necessary and sufficient for initiating lumen formation, but cell polarization being the pivotal mechanism for maintaining physiological epithelium morphology and acini sphericity. Furthermore, simulations highlight that acinus growth arrest in normal acini can be achieved by controlling the fraction of proliferating cells. Interestingly, our simulations reveal a synergism between polarization and apoptosis in enhancing growth arrest. After validating the model with experimental data from a normal human breast line (MCF10A), the system was challenged to predict the growth of MCF10A where AKT-1 was overexpressed, leading to reduced apoptosis. As previously reported, this led to non growth-arrested acini, with very large sizes and partially filled lumen. However, surprisingly, image analysis revealed a much lower nuclear density than observed for normal acini. The growth kinetics indicates that these acini grew faster than the cells comprising it. The in silico model could not replicate this behavior, contradicting the classic paradigm that ductal carcinoma in situ is only the result of high proliferation and low apoptosis. Our simulations suggest that overexpression of AKT-1 must also perturb cell-cell and cell-ECM communication, reminding us that extracellular context can dictate cellular behavior.

  13. Optical redox imaging indices discriminate human breast cancer from normal tissues

    Science.gov (United States)

    Xu, He N.; Tchou, Julia; Feng, Min; Zhao, Huaqing; Li, Lin Z.

    2016-01-01

    Abstract. Our long-term goal was to investigate the potential of incorporating redox imaging technique as a breast cancer (BC) diagnosis component to increase the positive predictive value of suspicious imaging finding and to reduce unnecessary biopsies and overdiagnosis. We previously found that precancer and cancer tissues in animal models displayed abnormal mitochondrial redox state. We also revealed abnormal mitochondrial redox state in cancerous specimens from three BC patients. Here, we extend our study to include biopsies of 16 patients. Tissue aliquots were collected from both apparently normal and cancerous tissues from the affected cancer-bearing breasts shortly after surgical resection. All specimens were snap-frozen and scanned with the Chance redox scanner, i.e., the three-dimensional cryogenic NADH/Fp (reduced nicotinamide adenine dinucleotide/oxidized flavoproteins) fluorescence imager. We found both Fp and NADH in the cancerous tissues roughly tripled that in the normal tissues (predox ratio Fp/(NADH + Fp) was ∼27% higher in the cancerous tissues (predox ratio alone could predict cancer with reasonable sensitivity and specificity. Our findings suggest that the optical redox imaging technique can provide parameters independent of clinical factors for discriminating cancer from noncancer breast tissues in human patients. PMID:27896360

  14. S1P transporter SPNS2 regulates proper postnatal retinal morphogenesis.

    Science.gov (United States)

    Fang, Chao; Bian, Ganlan; Ren, Pan; Xiang, Jie; Song, Jun; Yu, Caiyong; Zhang, Qian; Liu, Ling; Chen, Kun; Liu, Fangfang; Zhang, Kun; Wu, Chunfeng; Sun, Ruixia; Hu, Dan; Ju, Gong; Wang, Jian

    2018-02-08

    Spinster homolog 2 (SPNS2) is the membrane transporter of sphingosine-1-phosphate (S1P), and it participates in several physiologic processes by activating different S1P receptors (S1PRs). However, its functions in the nervous system remain largely unclear. We explored the important role of SPNS2 in the process of retinal morphogenesis using a spns2-deficient rat model. In the absence of the functional SPNS2 transporter, we observed progressively aggravating laminar disorganization of the epithelium at the postnatal stage of retinal development. Disrupted cell polarity, delayed cell-cycle exit of retinal progenitor cells, and insufficient migration of newborn neurons were proposed in this study as potential mechanisms accounting for this structural disorder. In addition, we analyzed the expression profiles of spns2 and s1prs, and proposed that SPNS2 regulated retinal morphogenesis by establishing the S1P level in the eye and activating S1PR3 signaling. These data indicate that SPNS2 is indispensable for normal retinal morphogenesis and provide new insights on the role of S1P in the developing retina using an established in vivo model.-Fang, C., Bian, G., Ren, P., Xiang, J., Song, J., Yu, C., Zhang, Q., Liu, L., Chen, K., Liu, F., Zhang, K., Wu, C., Sun, R., Hu, D., Ju, G., Wang, J. S1P transporter SPNS2 regulates proper postnatal retinal morphogenesis.

  15. Unraveling the microenvironmental influences on the normal mammary gland and induction and progression of breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Weigelt, Britta; Bissell, Mina J.

    2008-06-26

    The normal mammary gland and invasive breast cancer are both complex 'organs' composed of multiple cell types as well as extracellular matrix (ECM) in three-dimensional (3D) space. Conventionally, both normal and malignant breast cells are studied in vitro as two-dimensional (2D) monolayers of epithelial cells, which results in the loss of structure and tissue function. Many laboratories are now investigating regulation of signaling function in normal mammary gland using 3D cultures. However, it is important also to assay malignant breast cells ex vivo in a physiologically relevant environment to more closely mimic tumor architecture, signal transduction regulation and tumor behavior in vivo. Here we present the potential of these 3D models for drug testing, target validation and guidance of patient selection for clinical trials. We argue also that in order to get full insight into the biology of the normal and malignant breast, and to create in vivo-like models for therapeutic approaches in humans, we need to continue to create more complex heterotypic models to approach the full context the cells encounter in the human body.

  16. Subcellular localization of YKL-40 in normal and malignant epithelial cells of the breast

    DEFF Research Database (Denmark)

    Roslind, A.; Balslev, E.; Kruse, H.

    2008-01-01

    . YKL-40 protein expression was redistributed in carcinoma versus normal glandular tissue of the breast. A reduced expression of YKL-40 in relation to intermediate filaments and desmosomes was found in tumor cells. Changes in YKL-40 expression suggest that the function of YKL-40 in cells of epithelial......YKL-40 is a new prognostic biomarker in cancer. The biological function is only poorly understood. This study aimed at determining the subcellular localization of YKL-40, using immunogold labeling, in normal epithelial cells and in malignant tumor cells of the breast by immunoelectron microscopy...

  17. A large-scale study of the ultrawideband microwave dielectric properties of normal breast tissue obtained from reduction surgeries.

    Science.gov (United States)

    Lazebnik, Mariya; McCartney, Leah; Popovic, Dijana; Watkins, Cynthia B; Lindstrom, Mary J; Harter, Josephine; Sewall, Sarah; Magliocco, Anthony; Booske, John H; Okoniewski, Michal; Hagness, Susan C

    2007-05-21

    The efficacy of emerging microwave breast cancer detection and treatment techniques will depend, in part, on the dielectric properties of normal breast tissue. However, knowledge of these properties at microwave frequencies has been limited due to gaps and discrepancies in previously reported small-scale studies. To address these issues, we experimentally characterized the wideband microwave-frequency dielectric properties of a large number of normal breast tissue samples obtained from breast reduction surgeries at the University of Wisconsin and University of Calgary hospitals. The dielectric spectroscopy measurements were conducted from 0.5 to 20 GHz using a precision open-ended coaxial probe. The tissue composition within the probe's sensing region was quantified in terms of percentages of adipose, fibroconnective and glandular tissues. We fit a one-pole Cole-Cole model to the complex permittivity data set obtained for each sample and determined median Cole-Cole parameters for three groups of normal breast tissues, categorized by adipose tissue content (0-30%, 31-84% and 85-100%). Our analysis of the dielectric properties data for 354 tissue samples reveals that there is a large variation in the dielectric properties of normal breast tissue due to substantial tissue heterogeneity. We observed no statistically significant difference between the within-patient and between-patient variability in the dielectric properties.

  18. A large-scale study of the ultrawideband microwave dielectric properties of normal breast tissue obtained from reduction surgeries

    International Nuclear Information System (INIS)

    Lazebnik, Mariya; McCartney, Leah; Popovic, Dijana; Watkins, Cynthia B; Lindstrom, Mary J; Harter, Josephine; Sewall, Sarah; Magliocco, Anthony; Booske, John H; Okoniewski, Michal; Hagness, Susan C

    2007-01-01

    The efficacy of emerging microwave breast cancer detection and treatment techniques will depend, in part, on the dielectric properties of normal breast tissue. However, knowledge of these properties at microwave frequencies has been limited due to gaps and discrepancies in previously reported small-scale studies. To address these issues, we experimentally characterized the wideband microwave-frequency dielectric properties of a large number of normal breast tissue samples obtained from breast reduction surgeries at University of Wisconsin and University of Calgary hospitals. The dielectric spectroscopy measurements were conducted from 0.5 to 20 GHz using a precision open-ended coaxial probe. The tissue composition within the probe's sensing region was quantified in terms of percentages of adipose, fibroconnective and glandular tissues. We fit a one-pole Cole-Cole model to the complex permittivity data set obtained for each sample and determined median Cole-Cole parameters for three groups of normal breast tissues, categorized by adipose tissue content (0-30%, 31-84% and 85-100%). Our analysis of the dielectric properties data for 354 tissue samples reveals that there is a large variation in the dielectric properties of normal breast tissue due to substantial tissue heterogeneity. We observed no statistically significant difference between the within-patient and between-patient variability in the dielectric properties

  19. Differentiating fibroadenoma and ductal carcinoma in situ from normal breast tissue by multiphoton microscopy

    Science.gov (United States)

    Nie, Yuting; Wu, Yan; Lian, Yuane; Fu, Fangmeng; Wang, Chuan; Chen, Jianxin

    2014-09-01

    Fibroadenoma (FA) is the most common benign tumor of the female breast and several studies have reported that women with it have increased risk of breast cancer. While the ductal carcinoma in situ (DCIS) is a very early form of breast cancer. Thus, early detections of FA and DCIS are critical for improving breast tumor outcome and survival. In this paper, we use multiphoton microscopy (MPM) to obtain the high-contrast images of fresh, unfixed, unstained human breast specimens (normal breast tissue, FA and DCIS). Our results show that MPM has the ability to identify the characteristics of FA and DCIS including changes of duct architecture and collagen morphology. These results are consistent with the histological results. With the advancement of MPM, the technique has potential ability to serve as a real-time noninvasive imaging tool for early detection of breast tumor.

  20. Correlation study of trace metals in malignant and normal breast tissues by AAS technique

    International Nuclear Information System (INIS)

    Rahman, S.

    2012-01-01

    The study reports the application of atomic absorption spectrophotometry (AAS) for quantification of Fe, Cu and Zn in forty one formalin-fixed biopsy breast carcinoma tissue and adjoining fifteen normal tissue samples. These tissues samples were of category two breast carcinoma patients and of normal subjects. The qualitative comparison between the elements levels measured in the two types of specimens suggests significant elevation of these metals in the histopathological samples of carcinoma tissue. The samples were collected from women aged 19-51 years. Most of the patients belong to urban areas of Pakistan and middle to high socioeconomic status with the exception of few. Findings of study depicts that these elements have an important role in the initiation and development of carcinoma as consistent pattern of elevation for Fe, Cu and Zn was observed. The results showed the excessive accumulation of Fe (166.9 mg/L) in tissue samples of breast carcinoma patients (p < 0.01) than that in normal tissues samples (23.5 mg/L). In order to validate our method of analysis certified reference material Muscle Tissue Lyophilised (IAEA) MA-M-2/TM was analyzed for Fe, Cu and Zn. Determined concentrations were in good agreement with certified levels. The concentration distribution of trace elements Cu, Zn and Fe measured in the malignant tissues were found to be higher when compared to benign tissues, indicating the involvement of these metals in the breast malignancy. Results also indicate that excess iron may play a role in breast carcinogenesis. (Orig./A.B.)

  1. Multicolor immunofluorescence reveals that p63- and/or K5-positive progenitor cells contribute to normal breast epithelium and usual ductal hyperplasia but not to low-grade intraepithelial neoplasia of the breast.

    Science.gov (United States)

    Boecker, Werner; Stenman, Göran; Schroeder, Tina; Schumacher, Udo; Loening, Thomas; Stahnke, Lisa; Löhnert, Catharina; Siering, Robert Michael; Kuper, Arthur; Samoilova, Vera; Tiemann, Markus; Korsching, Eberhard; Buchwalow, Igor

    2017-05-01

    We contend that knowledge about the cellular composition of normal breast epithelium is a prerequisite for understanding proliferative breast disease. Against this background, we used multicolor immunofluorescence to study normal breast epithelium and two types of intraepithelial proliferative breast lesion for expression of the p63, basal keratin K5, glandular keratin K8/18, SMA, ER-alpha, and Ki67. We studied eight normal breast epithelium samples, 12 cases of usual ductal hyperplasia, and 33 cases of low-grade intraepithelial neoplasia (9 flat epithelial atypia, 14 low-grade ductal carcinoma in situ and 10 cases of lobular neoplasia). Usual ductal hyperplasia showed striking similarity to normal luminal breast epithelium including p63+ and/or K5+ luminal progenitor cells and the full spectrum of luminal progeny cells. In normal breast epithelium and usual ductal hyperplasia, expression of ER-alpha was associated with lack of expression of the proliferation antigen Ki67. In contrast, we found in both types of low-grade intraepithelial neoplasia robust expression of keratin K8/18 and a positive association between ER-alpha and Ki67 expression. However, these lesions were consistently negative for p63 and/or K5. Our observational study supports the view that usual ductal hyperplasia and low-grade intraepithelial neoplasia are different entities rather than part of a spectrum of the same disease. We propose a new operational model of cell differentiation that may serve to better understand correlations between normal breast epithelium and proliferative breast diseases. From our data we conclude that p63+ and/or K5+ progenitor cells contribute to maintenance of normal epithelium and usual ductal hyperplasia, but not to low-grade intraepithelial neoplasia of the breast.

  2. Postnatal development of the hippocampal dentate gyrus under normal and experimental conditions

    International Nuclear Information System (INIS)

    Altman, J.; Bayer, S.

    Studies on postnatal maturation of the dentate gyrus are reviewed. Some topics discussed are: normal development of the dentate gyrus, cytogenesis, morphogenesis, synaptogenesis, gleogenesis, myelogenesis, development of the gyrus under experimental conditions, and effects of x radiation on cytogenesis and morphogenesis

  3. Compton scattering spectrum as a source of information of normal and neoplastic breast tissues' composition

    Energy Technology Data Exchange (ETDEWEB)

    Antoniassi, M.; Conceicao, A.L.C. [Departamento de Fisica-Faculdade de Filosofia Ciencias e Letras de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, 14040-901 Sao Paulo (Brazil); Poletti, M.E., E-mail: poletti@ffclrp.usp.br [Departamento de Fisica-Faculdade de Filosofia Ciencias e Letras de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, 14040-901 Sao Paulo (Brazil)

    2012-07-15

    In this work we measured X-ray scatter spectra from normal and neoplastic breast tissues using photon energy of 17.44 keV and a scattering angle of 90 Degree-Sign , in order to study the shape (FWHM) of the Compton peaks. The obtained results for FWHM were discussed in terms of composition and histological characteristics of each tissue type. The statistical analysis shows that the distribution of FWHM of normal adipose breast tissue clearly differs from all other investigated tissues. Comparison between experimental values of FWHM and effective atomic number revealed a strong correlation between them, showing that the FWHM values can be used to provide information about elemental composition of the tissues. - Highlights: Black-Right-Pointing-Pointer X-ray scatter spectra from normal and neoplastic breast tissues were measured. Black-Right-Pointing-Pointer Shape (FWHM) of Compton peak was related with elemental composition and characteristics of each tissue type. Black-Right-Pointing-Pointer A statistical hypothesis test showed clear differences between normal and neoplastic breast tissues. Black-Right-Pointing-Pointer There is a strong correlation between experimental values of FWHM and effective atomic number. Black-Right-Pointing-Pointer Shape (FWHM) of Compton peak can be used to provide information about elemental composition of the tissues.

  4. Novel Molecular Markers of Malignancy in Histologically Normal and Benign Breast

    Directory of Open Access Journals (Sweden)

    Aejaz Nasir

    2011-01-01

    Full Text Available To detect the molecular changes of malignancy in histologically normal breast (HNB tissues, we recently developed a novel 117-gene-malignancy-signature. Here we report validation of our leading malignancy-risk-genes, topoisomerase-2-alpha (TOP2A, minichromosome-maintenance-protein-2 (MCM2 and “budding-uninhibited-by-benzimidazoles-1-homolog-beta” (BUB1B at the protein level. Using our 117-gene malignancy-signature, we classified 18 fresh-frozen HNB tissues from 18 adult female breast cancer patients into HNB-tissues with low-grade (HNB-LGMA; =9 and high-grade molecular abnormality (HNB-HGMA; =9. Archival sections of additional HNB tissues from these patients, and invasive ductal carcinoma (IDC tissues from six other patients were immunostained for these biomarkers. TOP2A/MCM2 expression was assessed as staining index (% and BUB1B expression as H-scores (0–300. Increasing TOP2A, MCM2, and BUB1B protein expression from HNB-LGMA to HNB-HGMA tissues to IDCs validated our microarray-based molecular classification of HNB tissues by immunohistochemistry. We also demonstrated an increasing expression of TOP2A protein on an independent test set of HNB/benign/reductionmammoplasties, atypical-ductal-hyperplasia with and without synchronous breast cancer, DCIS and IDC tissues using a custom tissue microarray (TMA. In conclusion, TOP2A, MCM2, and BUB1B proteins are potential molecular biomarkers of malignancy in histologically normal and benign breast tissues. Larger-scale clinical validation studies are needed to further evaluate the clinical utility of these molecular biomarkers.

  5. TMEM45A Is Dispensable for Epidermal Morphogenesis, Keratinization and Barrier Formation.

    Directory of Open Access Journals (Sweden)

    Aurélie Hayez

    Full Text Available TMEM45A gene encodes an initially uncharacterized predicted transmembrane protein. We previously showed that this gene is highly expressed in keratinocytes where its expression correlates with keratinization, suggesting a role in normal epidermal physiology. To test this hypothesis, we generated TMEM45A knockout mice and found that these mice develop without any evident phenotype. The morphology of the epidermis assessed by histology and by labelling differentiation markers in immunofluorescence was not altered. Toluidine blue permeability assay showed that the epidermal barrier develops normally during embryonic development. We also showed that depletion of TMEM45A in human keratinocytes does not alter their potential to form in vitro 3D-reconstructed epidermis. Indeed, epidermis with normal morphogenesis were generated from TMEM45A-silenced keratinocytes. Their expression of differentiation markers quantified by RT-qPCR and evidenced by immunofluorescence labelling as well as their barrier function estimated by Lucifer yellow permeability were similar to the control epidermis. In summary, TMEM45A gene expression is dispensable for epidermal morphogenesis, keratinization and barrier formation. If this protein plays a role in the epidermis, its experimental depletion can possibly be compensated by other proteins in the two experimental models analyzed in this study.

  6. Characterization and discrimination of human breast cancer and normal breast tissues using resonance Raman spectroscopy

    Science.gov (United States)

    Wu, Binlin; Smith, Jason; Zhang, Lin; Gao, Xin; Alfano, Robert R.

    2018-02-01

    Worldwide breast cancer incidence has increased by more than twenty percent in the past decade. It is also known that in that time, mortality due to the affliction has increased by fourteen percent. Using optical-based diagnostic techniques, such as Raman spectroscopy, has been explored in order to increase diagnostic accuracy in a more objective way along with significantly decreasing diagnostic wait-times. In this study, Raman spectroscopy with 532-nm excitation was used in order to incite resonance effects to enhance Stokes Raman scattering from unique biomolecular vibrational modes. Seventy-two Raman spectra (41 cancerous, 31 normal) were collected from nine breast tissue samples by performing a ten-spectra average using a 500-ms acquisition time at each acquisition location. The raw spectral data was subsequently prepared for analysis with background correction and normalization. The spectral data in the Raman Shift range of 750- 2000 cm-1 was used for analysis since the detector has highest sensitivity around in this range. The matrix decomposition technique nonnegative matrix factorization (NMF) was then performed on this processed data. The resulting leave-oneout cross-validation using two selective feature components resulted in sensitivity, specificity and accuracy of 92.6%, 100% and 96.0% respectively. The performance of NMF was also compared to that using principal component analysis (PCA), and NMF was shown be to be superior to PCA in this study. This study shows that coupling the resonance Raman spectroscopy technique with subsequent NMF decomposition method shows potential for high characterization accuracy in breast cancer detection.

  7. Transgenic Expression of Constitutively Active RAC1 Disrupts Mouse Rod Morphogenesis

    Science.gov (United States)

    Song, Hongman; Bush, Ronald A.; Vijayasarathy, Camasamudram; Fariss, Robert N.; Kjellstrom, Sten; Sieving, Paul A.

    2014-01-01

    Purpose. Dominant-active RAC1 rescues photoreceptor structure in Drosophila rhodopsin-null mutants, indicating an important role in morphogenesis. This report assesses the morphogenetic effect of activated RAC1 during mammalian rod photoreceptor development using transgenic mice that express constitutively active (CA) RAC1. Methods. Transgenic mice were generated by expressing CA RAC1 under control of the Rhodopsin promoter, and morphological features of the photoreceptors were evaluated by histology, immunohistochemistry, and transmission electron microscopy. Function was evaluated by electroretinography. Potential protein partners of CA RAC1 were identified by co-immunoprecipitation of retinal extracts. Results. Constitutively active RAC1 expression in differentiating rods disrupted outer retinal lamination as early as postnatal day (P)6, and many photoreceptor cell nuclei were displaced apically into the presumptive subretinal space. These photoreceptors did not develop normal inner and outer segments and had abnormal placement of synaptic elements. Some photoreceptor nuclei were also mislocalized into the inner nuclear layer. Extensive photoreceptor degeneration was subsequently observed in the adult animal. Constitutively active RAC1 formed a complex with the polarity protein PAR6 and with microtubule motor dynein in mouse retina. The normal localization of the PAR6 complex was disrupted in CA RAC1-expressing rod photoreceptors. Conclusions. Constitutively active RAC1 had a profound negative effect on mouse rod cell viability and development. Rod photoreceptors in the CA RAC1 retina exhibited a defect in polarity and migration. Constitutively active RAC1 disrupted rod morphogenesis and gave a phenotype resembling that found in the Crumbs mutant. PAR6 and dynein are two potential downstream effectors that may be involved in CA RAC1-mediated defective mouse photoreceptor morphogenesis. PMID:24651551

  8. Conjoined twins: morphogenesis of the heart and a review.

    Science.gov (United States)

    Gilbert-Barness, Enid; Debich-Spicer, Diane; Opitz, John M

    2003-08-01

    Five cases of conjoined twins have been studied. These included three thoracopagus twins, one monocephalus diprosopus (prosop = face), and one dicephalus dipus dibrachus. The thoracopagus twins were conjoined only from the upper thorax to the umbilicus with a normal foregut. These three cases shared a single complex multiventricular heart, one with a four chambered heart with one atrium and one ventricle belonging to each twin with complex venous and arterial connection; two had a seven chambered heart with four atria and three ventricles. The mono-cephalus diprosopus twins had a single heart with tetralogy of Fallot. The dicephalus twins had two separate axial skeletons to the sacrum, two separate hearts were connected between the right atria with a shared inferior vena cava. Thoracopagus twinning is associated with complex cardiac malformations. The cardiac anlagen in cephalopagus or diprosopus are diverted and divided along with the entire rostral end of the embryonic disc and result in two relatively normal shared hearts. However, in thoracopagus twins the single heart is multiventricular and suggests very early union with fusion of the cardiac anlagen before significant differentiation. Cardiac morphogenesis in conjoined twins therefore appears to depend on the site of the conjoined fusion and the temporal and spatial influence that determines morphogenesis as well as abnormally oriented embryonic axes. Copyright 2003 Wiley-Liss, Inc.

  9. Expression and function of the protein tyrosine phosphatase receptor J (PTPRJ in normal mammary epithelial cells and breast tumors.

    Directory of Open Access Journals (Sweden)

    Chanel E Smart

    Full Text Available The protein tyrosine phosphatase receptor J, PTPRJ, is a tumor suppressor gene that has been implicated in a range of cancers, including breast cancer, yet little is known about its role in normal breast physiology or in mammary gland tumorigenesis. In this paper we show that PTPRJ mRNA is expressed in normal breast tissue and reduced in corresponding tumors. Meta-analysis revealed that the gene encoding PTPRJ is frequently lost in breast tumors and that low expression of the transcript associated with poorer overall survival at 20 years. Immunohistochemistry of PTPRJ protein in normal human breast tissue revealed a distinctive apical localisation in the luminal cells of alveoli and ducts. Qualitative analysis of a cohort of invasive ductal carcinomas revealed retention of normal apical PTPRJ localization where tubule formation was maintained but that tumors mostly exhibited diffuse cytoplasmic staining, indicating that dysregulation of localisation associated with loss of tissue architecture in tumorigenesis. The murine ortholog, Ptprj, exhibited a similar localisation in normal mammary gland, and was differentially regulated throughout lactational development, and in an in vitro model of mammary epithelial differentiation. Furthermore, ectopic expression of human PTPRJ in HC11 murine mammary epithelial cells inhibited dome formation. These data indicate that PTPRJ may regulate differentiation of normal mammary epithelia and that dysregulation of protein localisation may be associated with tumorigenesis.

  10. Binding of (/sup 3/H) progesterone to normal and neoplastic tissue samples from tumour bearing breasts

    Energy Technology Data Exchange (ETDEWEB)

    Pollow, K; Sinnecker, R; Schmidt-Gollwitzer, M; Boquoi, E; Pollow, B [Institut fuer Molekularbiologie und Biochemie, Frauenklinik Charlottenburg der Freien Universitat, Berlin (G.F.R.)

    1977-01-01

    Macromolecular components of normal human mammary cytosol (obtained from 'non-malignant tissue samples' from cancer bearing breasts) which bind (/sup 3/H)progesterone in vitro were characterized by sucrose gradient centrifugation, gel filtration on Agarose, ion exchange chromatography, isoelectric focusing, competition studies and kinetic parameters. The size of the cytoplasmic binding components vary with the concentration of KCl. In the absence of KCl, the major components are characterized by sedimentation coefficients of about 4 S and 8 S. In solutions containing 0.3M KCl, the cytoplasmic components sediment at 4 S in sucrose gradient. The corticosteroid-binding component of normal human mammary cytosol both sediment at about the same rate in the presence of 0.3M KCl and chromatograph as a single component on Agarose. The isoelectric point of the progesterone-binding component of normal human mammary cytosol was located around pH 5.0. The progesterone-binding component was more thermo-labile than serum CBG. CBG was inactivated at temperatures above 45 deg C but temperature above 20 deg C destroyed specific progesterone receptor binding. Progesterone receptor concentrations in normal mammary cytosol of premenopausal women depended on the menstrual cycle. The binding of progesterone was highest around the time of ovulation. In breast tumor tissue samples the progesterone receptor concentration was lower than in the normal mammary cytosol (obtained in each case from the same tumor-bearing breast). In 5 out of 37 breast tumor samples progesterone binding activity could not be detected.

  11. [Adiponectin levels in breast milk of overweight/obese and normal weight mothers in the metropolitan area of Monterrey, México].

    Science.gov (United States)

    Galindo Gómez, Abelardo; Flores Scheufler, Pamela; Quevedo Escobar, Yamile; González Magaña, Regina; Rodríguez De Ita, Julieta

    Given the current epidemic of childhood obesity, it has become increasingly important to understand the risks and protective factors associated with this disease. Breastfeeding has been identified as a protective factor; however, the mechanism responsible has not been elucidated. One of the current theories analyzes the role of hormones in breast milk, with special emphasis on adiponectin. This study aims to compare adiponectin levels in breast milk of mothers with normal weight with those in breast milk of overweight/obese mothers as well as to correlate these levels with the infant's weight gain. Forty samples of breast milk were analyzed for adiponectin levels using ELISA, 20 from mothers with normal weight and 20 from overweight/obese mothers. Adiponectin levels were lower in breast milk obtained from overweight/obese mothers than in breast milk from mothers with normal weight (p Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

  12. JS-K, a nitric oxide-releasing prodrug, induces breast cancer cell death while sparing normal mammary epithelial cells.

    Science.gov (United States)

    McMurtry, Vanity; Saavedra, Joseph E; Nieves-Alicea, René; Simeone, Ann-Marie; Keefer, Larry K; Tari, Ana M

    2011-04-01

    Targeted therapy with reduced side effects is a major goal in cancer research. We investigated the effects of JS-K, a nitric oxide (NO) prodrug designed to release high levels of NO when suitably activated, on human breast cancer cell lines, on non-transformed human MCF-10A mammary cells, and on normal human mammary epithelial cells (HMECs). Cell viability assay, flow cytometry, electron microscopy, and Western blot analysis were used to study the effects of JS-K on breast cancer and on mammary epithelial cells. After a 3-day incubation, the IC50s of JS-K against the breast cancer cells ranged from 0.8 to 3 µM. However, JS-K decreased the viability of the MCF-10A cells by only 20% at 10-µM concentration, and HMECs were unaffected by 10 µM JS-K. Flow cytometry indicated that JS-K increased the percentages of breast cancer cells under-going apoptosis. Interestingly, flow cytometry indicated that JS-K increased acidic vesicle organelle formation in breast cancer cells, suggesting that JS-K induced autophagy in breast cancer cells. Electron microscopy confirmed that JS-K-treated breast cancer cells underwent autophagic cell death. Western blot analysis showed that JS-K induced the expression of microtubule light chain 3-II, another autophagy marker, in breast cancer cells. However, JS-K did not induce apoptosis or autophagy in normal human mammary epithelial cells. These data indicate that JS-K selectively induces programmed cell death in breast cancer cells while sparing normal mammary epithelial cells under the same conditions. The selective anti-tumor activity of JS-K warrants its further investigation in breast tumors.

  13. SU-F-I-01: Normalized Mean Glandular Dose Values for Dedicated Breast CT Using Realistic Breast-Shaped Phantoms

    Energy Technology Data Exchange (ETDEWEB)

    Hernandez, A [Department of Radiology, Biomedical Engineering Graduate Group, University of California Davis, Sacramento, CA (United States); Boone, J [Departments of Radiology and Biomedical Engineering, Biomedical Engeering Graduate Group, University of California Davis, Sacramento, CA (United States)

    2016-06-15

    Purpose: To estimate normalized mean glandular dose values for dedicated breast CT (DgN-CT) using breast CT-derived phantoms and compare to estimations using cylindrical phantoms. Methods: Segmented breast CT (bCT) volume data sets (N=219) were used to measure effective diameter profiles and were grouped into quintiles by volume. The profiles were averaged within each quintile to represent the range of breast sizes found clinically. These profiles were then used to generate five voxelized computational phantoms (V1, V2, V3, V4, V5 for the small to large phantom sizes, respectively), and loaded into the MCNP6 lattice geometry to simulate normalized mean glandular dose coefficients (DgN-CT) using the system specifications of the Doheny-prototype bCT scanner in our laboratory. The DgN-CT coefficients derived from the bCT-derived breast-shaped phantoms were compared to those generated using a simpler cylindrical phantom using a constant volume, and the following constraints: (1) Length=1.5*radius; (2) radius determined at chest wall (Rcw), and (3) radius determined at the phantom center-of-mass (Rcm). Results: The change in Dg-NCT coefficients averaged across all phantom sizes, was - 0.5%, 19.8%, and 1.3%, for constraints 1–3, respectively. This suggests that the cylindrical assumption is a good approximation if the radius is taken at the breast center-of-mass, but using the radius at the chest wall results in an underestimation of the glandular dose. Conclusion: The DgN-CT coefficients for bCT-derived phantoms were compared against the assumption of a cylindrical phantom and proved to be essentially equivalent when the cylinder radius was set to r=1.5/L or Rcm. While this suggests that for dosimetry applications a patient’s breast can be approximated as a cylinder (if the correct radius is applied), this assumes a homogenous composition of breast tissue and the results may be different if the realistic heterogeneous distribution of glandular tissue is considered

  14. Immortalization protocols used in cell culture models of human breast morphogenesis

    DEFF Research Database (Denmark)

    Gudjonsson, T; Villadsen, R; Rønnov-Jessen, L

    2004-01-01

    of the tissue of origin. In recent years, we have sought to establish immortalized primary breast cells, which retain crucial characteristics of their original in situ tissue pattern. This review discusses various approaches to immortalization of breast-derived epithelial and stromal cells and the application...

  15. Elastic moduli of normal and pathological human breast tissues: an inversion-technique-based investigation of 169 samples

    Science.gov (United States)

    Samani, Abbas; Zubovits, Judit; Plewes, Donald

    2007-03-01

    Understanding and quantifying the mechanical properties of breast tissues has been a subject of interest for the past two decades. This has been motivated in part by interest in modelling soft tissue response for surgery planning and virtual-reality-based surgical training. Interpreting elastography images for diagnostic purposes also requires a sound understanding of normal and pathological tissue mechanical properties. Reliable data on tissue elastic properties are very limited and those which are available tend to be inconsistent, in part as a result of measurement methodology. We have developed specialized techniques to measure tissue elasticity of breast normal tissues and tumour specimens and applied them to 169 fresh ex vivo breast tissue samples including fat and fibroglandular tissue as well as a range of benign and malignant breast tumour types. Results show that, under small deformation conditions, the elastic modulus of normal breast fat and fibroglandular tissues are similar while fibroadenomas were approximately twice the stiffness. Fibrocystic disease and malignant tumours exhibited a 3-6-fold increased stiffness with high-grade invasive ductal carcinoma exhibiting up to a 13-fold increase in stiffness compared to fibrogalndular tissue. A statistical analysis showed that differences between the elastic modulus of the majority of those tissues were statistically significant. Implications for the specificity advantages of elastography are reviewed.

  16. Elastic moduli of normal and pathological human breast tissues: an inversion-technique-based investigation of 169 samples

    International Nuclear Information System (INIS)

    Samani, Abbas; Zubovits, Judit; Plewes, Donald

    2007-01-01

    Understanding and quantifying the mechanical properties of breast tissues has been a subject of interest for the past two decades. This has been motivated in part by interest in modelling soft tissue response for surgery planning and virtual-reality-based surgical training. Interpreting elastography images for diagnostic purposes also requires a sound understanding of normal and pathological tissue mechanical properties. Reliable data on tissue elastic properties are very limited and those which are available tend to be inconsistent, in part as a result of measurement methodology. We have developed specialized techniques to measure tissue elasticity of breast normal tissues and tumour specimens and applied them to 169 fresh ex vivo breast tissue samples including fat and fibroglandular tissue as well as a range of benign and malignant breast tumour types. Results show that, under small deformation conditions, the elastic modulus of normal breast fat and fibroglandular tissues are similar while fibroadenomas were approximately twice the stiffness. Fibrocystic disease and malignant tumours exhibited a 3-6-fold increased stiffness with high-grade invasive ductal carcinoma exhibiting up to a 13-fold increase in stiffness compared to fibrogalndular tissue. A statistical analysis showed that differences between the elastic modulus of the majority of those tissues were statistically significant. Implications for the specificity advantages of elastography are reviewed

  17. Elastic moduli of normal and pathological human breast tissues: an inversion-technique-based investigation of 169 samples

    Energy Technology Data Exchange (ETDEWEB)

    Samani, Abbas [Department of Medical Biophysics/Electrical and Computer Engineering, University of Western Ontario, Medical Sciences Building, London, Ontario, N6A 5C1 (Canada); Zubovits, Judit [Department of Anatomic Pathology, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5 (Canada); Plewes, Donald [Department of Medical Biophysics, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5 (Canada)

    2007-03-21

    Understanding and quantifying the mechanical properties of breast tissues has been a subject of interest for the past two decades. This has been motivated in part by interest in modelling soft tissue response for surgery planning and virtual-reality-based surgical training. Interpreting elastography images for diagnostic purposes also requires a sound understanding of normal and pathological tissue mechanical properties. Reliable data on tissue elastic properties are very limited and those which are available tend to be inconsistent, in part as a result of measurement methodology. We have developed specialized techniques to measure tissue elasticity of breast normal tissues and tumour specimens and applied them to 169 fresh ex vivo breast tissue samples including fat and fibroglandular tissue as well as a range of benign and malignant breast tumour types. Results show that, under small deformation conditions, the elastic modulus of normal breast fat and fibroglandular tissues are similar while fibroadenomas were approximately twice the stiffness. Fibrocystic disease and malignant tumours exhibited a 3-6-fold increased stiffness with high-grade invasive ductal carcinoma exhibiting up to a 13-fold increase in stiffness compared to fibrogalndular tissue. A statistical analysis showed that differences between the elastic modulus of the majority of those tissues were statistically significant. Implications for the specificity advantages of elastography are reviewed.

  18. Perithecium morphogenesis in Sordaria macrospora.

    Science.gov (United States)

    Lord, Kathryn M; Read, Nick D

    2011-04-01

    The perithecium of the self-fertile ascomycete Sordaria macrospora provides an excellent model in which to analyse fungal multicellular development. This study provides a detailed analysis of perithecium morphogenesis in the wild type and eight developmental mutants of S. macrospora, using a range of correlative microscopical techniques. Fundamentally, perithecia and other complex multicellular structures produced by fungi arise by hyphal aggregation and adhesion, and these processes are followed by specialization and septation of hyphal compartments within the aggregates. Perithecial morphogenesis can be divided into the ascogonial, protoperithecial, and perithecial stages of development. At least 13 specialized, morphologically distinct cell-types are involved in perithecium morphogenesis, and these fall into three basic classes: hyphae, conglutinate cells and spores. Conglutinate cells arise from hyphal adhesion and certain perithecial hyphae develop from conglutinate cells. Various hypha-conglutinate cell transitions play important roles during the development of the perithecial wall and neck. Copyright © 2010. Published by Elsevier Inc.

  19. hmmr mediates anterior neural tube closure and morphogenesis in the frog Xenopus.

    Science.gov (United States)

    Prager, Angela; Hagenlocher, Cathrin; Ott, Tim; Schambony, Alexandra; Feistel, Kerstin

    2017-10-01

    Development of the central nervous system requires orchestration of morphogenetic processes which drive elevation and apposition of the neural folds and their fusion into a neural tube. The newly formed tube gives rise to the brain in anterior regions and continues to develop into the spinal cord posteriorly. Conspicuous differences between the anterior and posterior neural tube become visible already during neural tube closure (NTC). Planar cell polarity (PCP)-mediated convergent extension (CE) movements are restricted to the posterior neural plate, i.e. hindbrain and spinal cord, where they propagate neural fold apposition. The lack of CE in the anterior neural plate correlates with a much slower mode of neural fold apposition anteriorly. The morphogenetic processes driving anterior NTC have not been addressed in detail. Here, we report a novel role for the breast cancer susceptibility gene and microtubule (MT) binding protein Hmmr (Hyaluronan-mediated motility receptor, RHAMM) in anterior neurulation and forebrain development in Xenopus laevis. Loss of hmmr function resulted in a lack of telencephalic hemisphere separation, arising from defective roof plate formation, which in turn was caused by impaired neural tissue narrowing. hmmr regulated polarization of neural cells, a function which was dependent on the MT binding domains. hmmr cooperated with the core PCP component vangl2 in regulating cell polarity and neural morphogenesis. Disrupted cell polarization and elongation in hmmr and vangl2 morphants prevented radial intercalation (RI), a cell behavior essential for neural morphogenesis. Our results pinpoint a novel role of hmmr in anterior neural development and support the notion that RI is a major driving force for anterior neurulation and forebrain morphogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Relaxation time of normal breast tissues. Changes with age and variations during the menstrual cycle

    International Nuclear Information System (INIS)

    Dean, K.I.; Majurin, M.L.; Komu, M.

    1994-01-01

    The influence of age on the relaxation times of normal breast parenchyma and its surrounding fatty tissue were evaluated, and the variations during a normal menstrual cycle were analyzed using an ultra low field 0.02 T imager. Thirty-nine healthy volunteers aged 21 to 59 years were examined to determine T1 and T2 relaxation times, and 8 of these volunteers were studied once weekly during one menstrual cycle. The only significant trend was an increase in the T2 of breast parenchyma with increasing age. During the menstrual cycle there was a slight but insignificant (p=0.10) increase in T1 of the breast parenchyma values during the latter half of the menstrual cycle, and a corresponding increase in T2 values between the 2nd and 3rd weeks of the menstrual cycle, which was significant. (orig.)

  1. Relaxation time of normal breast tissues. Changes with age and variations during the menstrual cycle

    Energy Technology Data Exchange (ETDEWEB)

    Dean, K.I. (University Central Hospital, Turku (Finland). Dept. of Diagnostic Radiology); Majurin, M.L. (University Central Hospital, Turku (Finland). Dept. of Diagnostic Radiology); Komu, M. (University Central Hospital, Turku (Finland). Dept. of Diagnostic Radiology)

    1994-05-01

    The influence of age on the relaxation times of normal breast parenchyma and its surrounding fatty tissue were evaluated, and the variations during a normal menstrual cycle were analyzed using an ultra low field 0.02 T imager. Thirty-nine healthy volunteers aged 21 to 59 years were examined to determine T1 and T2 relaxation times, and 8 of these volunteers were studied once weekly during one menstrual cycle. The only significant trend was an increase in the T2 of breast parenchyma with increasing age. During the menstrual cycle there was a slight but insignificant (p=0.10) increase in T1 of the breast parenchyma values during the latter half of the menstrual cycle, and a corresponding increase in T2 values between the 2nd and 3rd weeks of the menstrual cycle, which was significant. (orig.).

  2. The Immunoexpression of Glucocorticoid Receptors in Breast Carcinomas, Lactational Change, and Normal Breast Epithelium and Its Possible Role in Mammary Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Raja Alyusuf

    2017-01-01

    Full Text Available The role of estrogen and progesterone receptors in breast cancer biology is well established. In contrast, other steroid hormones are less well studied. Glucocorticoids (GCs are known to play a role in mammary development and differentiation; thus, it is of interest to attempt to delineate their immunoexpression across a spectrum of mammary epithelia. Aim. To delineate the distribution pattern of glucocorticoid receptors (GRs in malignant versus nonmalignant epithelium with particular emphasis on lactational epithelium. Materials and Methods. Immunohistochemistry (IHC for GRs was performed on archival formalin-fixed paraffin-embedded tissue blocks of 96 cases comprising 52 invasive carcinomas, 21 cases with lactational change, and 23 cases showing normal mammary tissue histology. Results. Results reveal an overexpression of GRs in mammary malignant epithelium as compared to both normal and lactational groups individually and combined. GR overexpression is significantly more pronounced in HER-2-negative cancers. Discussion. This is the first study to compare GR expression in human lactating epithelium versus malignant and normal epithelium. The article discusses the literature related to the pathobiology of GCs in the breast with special emphasis on breast cancer. Conclusion. The lactational epithelium did not show overexpression of GR, while GR was overexpressed in mammary NST (ductal carcinoma, particularly HER-2-negative cancers.

  3. MicroRNA miR-328 regulates zonation morphogenesis by targeting CD44 expression.

    Science.gov (United States)

    Wang, Chia-Hui; Lee, Daniel Y; Deng, Zhaoqun; Jeyapalan, Zina; Lee, Shao-Chen; Kahai, Shireen; Lu, Wei-Yang; Zhang, Yaou; Yang, Burton B

    2008-06-18

    Morphogenesis is crucial to initiate physiological development and tumor invasion. Here we show that a microRNA controls zonation morphogenesis by targeting hyaluronan receptor CD44. We have developed a novel system to study microRNA functions by generating constructs expressing pre-miRNAs and mature miRNAs. Using this system, we have demonstrated that expression of miR-328 reduced cell adhesion, aggregation, and migration, and regulated formation of capillary structure. Protein analysis indicated that miR-328 repressed CD44 expression. Activities of luciferase constructs harboring the target site in CD44, but not the one containing mutation, were repressed by miR-328. Zonation morphogenesis appeared in cells transfected by miR-328: miR-328-transfected cells were present on the surface of zonating structures while the control cells stayed in the middle. MiR-328-mediated CD44 actions was validated by anti-CD44 antibody, hyaluronidase, CD44 siRNA, and CD44 expression constructs. In vivo experiments showed that CD44-silencing cells appeared as layers on the surfaces of nodules or zonating structures. Immuno-histochemistry also exhibited CD44-negative cells on the surface layers of normal rat livers and the internal zones of Portal veins. Our results demonstrate that miR-328 targets CD44, which is essential in regulating zonation morphogenesis: silencing of CD44 expression is essential in sealing the zonation structures to facilitate their extension and to inhibit complex expansion.

  4. MicroRNA miR-328 regulates zonation morphogenesis by targeting CD44 expression.

    Directory of Open Access Journals (Sweden)

    Chia-Hui Wang

    Full Text Available Morphogenesis is crucial to initiate physiological development and tumor invasion. Here we show that a microRNA controls zonation morphogenesis by targeting hyaluronan receptor CD44. We have developed a novel system to study microRNA functions by generating constructs expressing pre-miRNAs and mature miRNAs. Using this system, we have demonstrated that expression of miR-328 reduced cell adhesion, aggregation, and migration, and regulated formation of capillary structure. Protein analysis indicated that miR-328 repressed CD44 expression. Activities of luciferase constructs harboring the target site in CD44, but not the one containing mutation, were repressed by miR-328. Zonation morphogenesis appeared in cells transfected by miR-328: miR-328-transfected cells were present on the surface of zonating structures while the control cells stayed in the middle. MiR-328-mediated CD44 actions was validated by anti-CD44 antibody, hyaluronidase, CD44 siRNA, and CD44 expression constructs. In vivo experiments showed that CD44-silencing cells appeared as layers on the surfaces of nodules or zonating structures. Immuno-histochemistry also exhibited CD44-negative cells on the surface layers of normal rat livers and the internal zones of Portal veins. Our results demonstrate that miR-328 targets CD44, which is essential in regulating zonation morphogenesis: silencing of CD44 expression is essential in sealing the zonation structures to facilitate their extension and to inhibit complex expansion.

  5. A global sensitivity analysis approach for morphogenesis models

    KAUST Repository

    Boas, Sonja E. M.; Navarro, Marí a; Merks, Roeland M. H.; Blom, Joke G.

    2015-01-01

    Morphogenesis is a developmental process in which cells organize into shapes and patterns. Complex, non-linear and multi-factorial models with images as output are commonly used to study morphogenesis. It is difficult to understand

  6. Proof of region-specific multipotent progenitors in human breast epithelia

    DEFF Research Database (Denmark)

    Fridriksdottir, Agla J; Villadsen, René; Morsing, Mikkel

    2017-01-01

    in luminal progenitors to interrogate the differentiation repertoire of candidate stem cells in TDLUs. We show that stem-like activity in serial passage culture and in vivo breast morphogenesis relies on the preservation of a myoepithelial phenotype. By enrichment for region-specific progenitors, we identify...

  7. Antiandrogenic actions of medroxyprogesterone acetate on epithelial cells within normal human breast tissues cultured ex vivo.

    Science.gov (United States)

    Ochnik, Aleksandra M; Moore, Nicole L; Jankovic-Karasoulos, Tanja; Bianco-Miotto, Tina; Ryan, Natalie K; Thomas, Mervyn R; Birrell, Stephen N; Butler, Lisa M; Tilley, Wayne D; Hickey, Theresa E

    2014-01-01

    Medroxyprogesterone acetate (MPA), a component of combined estrogen-progestin therapy (EPT), has been associated with increased breast cancer risk in EPT users. MPA can bind to the androgen receptor (AR), and AR signaling inhibits cell growth in breast tissues. Therefore, the aim of this study was to investigate the potential of MPA to disrupt AR signaling in an ex vivo culture model of normal human breast tissue. Histologically normal breast tissues from women undergoing breast surgical operation were cultured in the presence or in the absence of the native AR ligand 5α-dihydrotestosterone (DHT), MPA, or the AR antagonist bicalutamide. Ki67, bromodeoxyuridine, B-cell CLL/lymphoma 2 (BCL2), AR, estrogen receptor α, and progesterone receptor were detected by immunohistochemistry. DHT inhibited the proliferation of breast epithelial cells in an AR-dependent manner within tissues from postmenopausal women, and MPA significantly antagonized this androgenic effect. These hormonal responses were not commonly observed in cultured tissues from premenopausal women. In tissues from postmenopausal women, DHT either induced or repressed BCL2 expression, and the antiandrogenic effect of MPA on BCL2 was variable. MPA significantly opposed the positive effect of DHT on AR stabilization, but these hormones had no significant effect on estrogen receptor α or progesterone receptor levels. In a subset of postmenopausal women, MPA exerts an antiandrogenic effect on breast epithelial cells that is associated with increased proliferation and destabilization of AR protein. This activity may contribute mechanistically to the increased risk of breast cancer in women taking MPA-containing EPT.

  8. Rap1 integrates tissue polarity, lumen formation, and tumorigenicpotential in human breast epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Itoh, Masahiko; Nelson, Celeste M.; Myers, Connie A.; Bissell,Mina J.

    2006-09-29

    Maintenance of apico-basal polarity in normal breast epithelial acini requires a balance between cell proliferation, cell death, and proper cell-cell and cell-extracellular matrix signaling. Aberrations in any of these processes can disrupt tissue architecture and initiate tumor formation. Here we show that the small GTPase Rap1 is a crucial element in organizing acinar structure and inducing lumen formation. Rap1 activity in malignant HMT-3522 T4-2 cells is appreciably higher than in S1 cells, their non-malignant counterparts. Expression of dominant-negative Rap1 resulted in phenotypic reversion of T4-2 cells, led to formation of acinar structures with correct apico-basal polarity, and dramatically reduced tumor incidence despite the persistence of genomic abnormalities. The resulting acini contained prominent central lumina not observed when other reverting agents were used. Conversely, expression of dominant-active Rap1 in T4-2 cells inhibited phenotypic reversion and led to increased invasiveness and tumorigenicity. Thus, Rap1 acts as a central regulator of breast architecture, with normal levels of activation instructing apical polarity during acinar morphogenesis, and increased activation inducing tumor formation and progression to malignancy.

  9. Normal physiologic and Benign foci with F-18 FDG avidity on PET/CT in patients with breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Park, Soon Ah; Lee, Kwang Man; Choi, Un Jong; Kim, Hun Soo; Kim, Hye Won; Song, Jeong Hoon [College of Medicine, Wonkwnag University, Iksan (Korea, Republic of)

    2010-12-15

    The aim of this study was to evaluate the physiologic and benign F-18 fluorodeoxyglucose (FDG) avid foci in patients with breast cancer. On 309 F-18 FDG PET/CT scans of 241 women with breast cancer, the hypermetabolic lesions compared with the surrounding normal region were evaluated retrospectively. Available reports of other relevant radiological imaging medical records, and follow-up PET/CT were reviewed for explanations of the abnormal uptake. Among the 70 physiologic foci, muscular uptake of the lower neck following the surgical and/or radiation therapy of ipsilateral breast (29%), hypermetabolic ovaries (16%) and uterine (10%) uptake during the ovulatory and menstrual phases during the normal menstrual cycle were identified, and also hypermetabolic brown fat in cold-induced thermogenesis (7%), non-specific bowel uptake (35%) were observed. Among the 147 benign lesions, sequelae of the chest wall and breasts following surgical and/or radiation therapy, were often observed (27%). Hypermetabolic thyroid glands were noted as adenomas and chronic thyroiditis (18%). Reactive hyperplasia of cervical or mediastinal lymph nodes (32%), degenerative osteoarthritis and healed fractures (15%), hypermetabolic benign lung lesions (6%) were observed. Altered physiologic and benign F-18 FDG uptake in the cervical muscle and chest wall following ipsilateral breast surgery or radiotherapy were common, and also normal physiologic uptake in ovary and uterus, brown fat, thyroid were considered as predominant findings in women patients with breast cancer. Knowledge of these findings might aid in the interpretation of FDG PET/CT in patients with breast cancer

  10. Channeling Nanoparticles for Detection and Targeted Treatment of Breast Cancerous Lesions

    Science.gov (United States)

    2011-10-01

    branched ducts from non-neoplastic breast epithelial MCF10A cells on a collagen I basis and/or silk protein scaffold and co-cultures with other cell...vapors for 30 min. PDMS elastomer and curing agent (Dow Corning Sylgard 184, Ellsworth Adhesives, Germantown, WI) were mixed in a 10 : 1 ratio and...tissue culture system based on mammary stromal cells and silk scaffolds for modeling breast morphogenesis and function, Biomaterials, 2010, 31, 3920–3929

  11. The PCP genes Celsr1 and Vangl2 are required for normal lung branching morphogenesis

    Science.gov (United States)

    Yates, Laura L.; Schnatwinkel, Carsten; Murdoch, Jennifer N.; Bogani, Debora; Formstone, Caroline J.; Townsend, Stuart; Greenfield, Andy; Niswander, Lee A.; Dean, Charlotte H.

    2010-01-01

    The lungs are generated by branching morphogenesis as a result of reciprocal signalling interactions between the epithelium and mesenchyme during development. Mutations that disrupt formation of either the correct number or shape of epithelial branches affect lung function. This, in turn, can lead to congenital abnormalities such as cystadenomatoid malformations, pulmonary hypertension or lung hypoplasia. Defects in lung architecture are also associated with adult lung disease, particularly in cases of idiopathic lung fibrosis. Identifying the signalling pathways which drive epithelial tube formation will likely shed light on both congenital and adult lung disease. Here we show that mutations in the planar cell polarity (PCP) genes Celsr1 and Vangl2 lead to disrupted lung development and defects in lung architecture. Lungs from Celsr1Crsh and Vangl2Lp mouse mutants are small and misshapen with fewer branches, and by late gestation exhibit thickened interstitial mesenchyme and defective saccular formation. We observe a recapitulation of these branching defects following inhibition of Rho kinase, an important downstream effector of the PCP signalling pathway. Moreover, epithelial integrity is disrupted, cytoskeletal remodelling perturbed and mutant endoderm does not branch normally in response to the chemoattractant FGF10. We further show that Celsr1 and Vangl2 proteins are present in restricted spatial domains within lung epithelium. Our data show that the PCP genes Celsr1 and Vangl2 are required for foetal lung development thereby revealing a novel signalling pathway critical for this process that will enhance our understanding of congenital and adult lung diseases and may in future lead to novel therapeutic strategies. PMID:20223754

  12. Sarcoglycans in the normal and pathological breast tissue of humans: an immunohistochemical and molecular study.

    Science.gov (United States)

    Arco, Alba; Favaloro, Angelo; Gioffrè, Mara; Santoro, Giuseppe; Speciale, Francesco; Vermiglio, Giovanna; Cutroneo, Giuseppina

    2012-01-01

    The sarcoglycan complex, consisting of α-, β-, γ-, δ- and ε-sarcoglycans, is a multimember transmembrane system providing a mechanosignaling connection from the cytoskeleton to the extracellular matrix. Whereas the expression of α- and γ-sarcoglycan is restricted to striated muscle, other sarcoglycans are widely expressed. Although many studies have investigated sarcoglycans in all muscle types, insufficient data are available on the distribution of the sarcoglycan complex in nonmuscle tissue. On this basis, we used immunohistochemical and RT-PCR techniques to study preliminarily the sarcoglycans in normal glandular breast tissue (which has never been studied in the literature on these proteins) to verify the effective wider distribution of this complex. Moreover, to understand the role of sarcoglycans, we also tested samples obtained from patients affected by fibrocystic mastopathy and breast fibroadenoma. Our data showed, for the first time, that all sarcoglycans are always detectable in all normal samples both in epithelial and myoepithelial cells; in pathological breast tissue, all sarcoglycans appeared severely reduced. These data demonstrated that all sarcoglycans, not only β-, δ-, and ε-sarcoglycans, have a wider distribution, implying a new unknown role for these proteins. Moreover, in breast diseases, sarcoglycans containing cadherin domain homologs could provoke a loss of strong adhesion between epithelial cells, permitting and facilitating the degeneration of these benign breast tumors into malignant tumors. Consequently, sarcoglycans could play an important and intriguing role in many breast diseases and in particular in tumor progression from benign to malignant. Copyright © 2011 S. Karger AG, Basel.

  13. A global sensitivity analysis approach for morphogenesis models

    NARCIS (Netherlands)

    S.E.M. Boas (Sonja); M.I. Navarro Jimenez (Maria); R.M.H. Merks (Roeland); J.G. Blom (Joke)

    2015-01-01

    textabstract{\\bf Background} %if any Morphogenesis is a developmental process in which cells organize into shapes and patterns. Complex, non-linear and multi-factorial models with images as output are commonly used to study morphogenesis. It is difficult to understand the relation between the

  14. Association of reproductive history with breast tissue characteristics and receptor status in the normal breast.

    Science.gov (United States)

    Gabrielson, Marike; Chiesa, Flaminia; Behmer, Catharina; Rönnow, Katarina; Czene, Kamila; Hall, Per

    2018-03-30

    Reproductive history has been associated with breast cancer risk, but more knowledge of the underlying biological mechanisms is needed. Because of limited data on normal breast tissue from healthy women, we examined associations of reproductive history and established breast cancer risk factors with breast tissue composition and markers of hormone receptors and proliferation in a nested study within the Karolinska Mammography project for risk prediction for breast cancer (Karma). Tissues from 153 women were obtained by ultrasound-guided core needle biopsy as part of the Karma project. Immunohistochemical staining was used to assessed histological composition of epithelial, stromal and adipose tissue, epithelial and stromal oestrogen receptor (ER) and progesterone receptor (PR) status, and Ki-67 proliferation status. An individualised reproductive score including parity, number of pregnancies without birth, number of births, age at first birth, and duration of breastfeeding, was calculated based on self-reported reproductive history at the time of the Karma study entry. All analyses were adjusted for age and BMI. Cumulated reproductive score was associated with increased total epithelial content and greater expression of epithelial ER. Parity was associated with greater epithelial area, increased epithelial-stromal ratio, greater epithelial ER expression and a lower extent of stromal proliferation. Increasing numbers of pregnancies and births were associated with a greater epithelial area in the entire study set, which remained significant among postmenopausal women. Increasing numbers of pregnancies and births were also associated with a greater expression of epithelial ER among postmenopausal women. Longer duration of breastfeeding was associated with greater epithelial area and greater expression of epithelial PR both in the entire study set and among postmenopausal women. Breastfeeding was also positively associated with greater epithelial ER expression among

  15. The Role of Myoepithelial Maspin in Breast Carcinoma Progression Diagnosis and Screening

    Science.gov (United States)

    2003-08-01

    myoepithelial tumors occurring within the sali- vary glands of the head and neck . In order to study the cell and molecular biology of myoepithelial cells...inhibitors, including maspin, are thought to regulate branching morphogenesis that occurs in the developing breast and salivary gland during embryological

  16. Apparent diffusion coefficient of breast cancer and normal fibroglandular tissue in diffusion-weighted imaging: the effects of menstrual cycle and menopausal status.

    Science.gov (United States)

    Kim, Jin You; Suh, Hie Bum; Kang, Hyun Jung; Shin, Jong Ki; Choo, Ki Seok; Nam, Kyung Jin; Lee, Seok Won; Jung, Young Lae; Bae, Young Tae

    2016-05-01

    The purpose of this study was to investigate prospectively whether the apparent diffusion coefficients (ADCs) of both breast cancer and normal fibroglandular tissue vary with the menstrual cycle and menopausal status. Institutional review board approval was obtained, and informed consent was obtained from each participant. Fifty-seven women (29 premenopausal, 28 postmenopausal) with newly diagnosed breast cancer underwent diffusion-weighted imaging twice (interval 12-20 days) before surgery. Two radiologists independently measured ADC of breast cancer and normal contralateral breast tissue, and we quantified the differences according to the phases of menstrual cycle and menopausal status. With normal fibroglandular tissue, ADC was significantly lower in postmenopausal than in premenopausal women (P = 0.035). In premenopausal women, ADC did not differ significantly between proliferative and secretory phases in either breast cancer or normal fibroglandular tissue (P = 0.969 and P = 0.519, respectively). In postmenopausal women, no significant differences were found between ADCs measured at different time intervals in either breast cancer or normal fibroglandular tissue (P = 0.948 and P = 0.961, respectively). The within-subject variability of the ADC measurements was quantified using the coefficient of variation (CV) and was small: the mean CVs of tumor ADC were 2.90 % (premenopausal) and 3.43 % (postmenopausal), and those of fibroglandular tissue ADC were 4.37 % (premenopausal) and 2.55 % (postmenopausal). Both intra- and interobserver agreements were excellent for ADC measurements, with intraclass correlation coefficients in the range of 0.834-0.974. In conclusion, the measured ADCs of breast cancer and normal fibroglandular tissue were not affected significantly by menstrual cycle, and the measurements were highly reproducible both within and between observers.

  17. A global sensitivity analysis approach for morphogenesis models

    KAUST Repository

    Boas, Sonja E. M.

    2015-11-21

    Background Morphogenesis is a developmental process in which cells organize into shapes and patterns. Complex, non-linear and multi-factorial models with images as output are commonly used to study morphogenesis. It is difficult to understand the relation between the uncertainty in the input and the output of such ‘black-box’ models, giving rise to the need for sensitivity analysis tools. In this paper, we introduce a workflow for a global sensitivity analysis approach to study the impact of single parameters and the interactions between them on the output of morphogenesis models. Results To demonstrate the workflow, we used a published, well-studied model of vascular morphogenesis. The parameters of this cellular Potts model (CPM) represent cell properties and behaviors that drive the mechanisms of angiogenic sprouting. The global sensitivity analysis correctly identified the dominant parameters in the model, consistent with previous studies. Additionally, the analysis provided information on the relative impact of single parameters and of interactions between them. This is very relevant because interactions of parameters impede the experimental verification of the predicted effect of single parameters. The parameter interactions, although of low impact, provided also new insights in the mechanisms of in silico sprouting. Finally, the analysis indicated that the model could be reduced by one parameter. Conclusions We propose global sensitivity analysis as an alternative approach to study the mechanisms of morphogenesis. Comparison of the ranking of the impact of the model parameters to knowledge derived from experimental data and from manipulation experiments can help to falsify models and to find the operand mechanisms in morphogenesis. The workflow is applicable to all ‘black-box’ models, including high-throughput in vitro models in which output measures are affected by a set of experimental perturbations.

  18. A global sensitivity analysis approach for morphogenesis models.

    Science.gov (United States)

    Boas, Sonja E M; Navarro Jimenez, Maria I; Merks, Roeland M H; Blom, Joke G

    2015-11-21

    Morphogenesis is a developmental process in which cells organize into shapes and patterns. Complex, non-linear and multi-factorial models with images as output are commonly used to study morphogenesis. It is difficult to understand the relation between the uncertainty in the input and the output of such 'black-box' models, giving rise to the need for sensitivity analysis tools. In this paper, we introduce a workflow for a global sensitivity analysis approach to study the impact of single parameters and the interactions between them on the output of morphogenesis models. To demonstrate the workflow, we used a published, well-studied model of vascular morphogenesis. The parameters of this cellular Potts model (CPM) represent cell properties and behaviors that drive the mechanisms of angiogenic sprouting. The global sensitivity analysis correctly identified the dominant parameters in the model, consistent with previous studies. Additionally, the analysis provided information on the relative impact of single parameters and of interactions between them. This is very relevant because interactions of parameters impede the experimental verification of the predicted effect of single parameters. The parameter interactions, although of low impact, provided also new insights in the mechanisms of in silico sprouting. Finally, the analysis indicated that the model could be reduced by one parameter. We propose global sensitivity analysis as an alternative approach to study the mechanisms of morphogenesis. Comparison of the ranking of the impact of the model parameters to knowledge derived from experimental data and from manipulation experiments can help to falsify models and to find the operand mechanisms in morphogenesis. The workflow is applicable to all 'black-box' models, including high-throughput in vitro models in which output measures are affected by a set of experimental perturbations.

  19. Sea Urchin Morphogenesis.

    Science.gov (United States)

    McClay, David R

    2016-01-01

    In the sea urchin morphogenesis follows extensive molecular specification. The specification controls the many morphogenetic events and these, in turn, precede patterning steps that establish the larval body plan. To understand how the embryo is built it was necessary to understand those series of molecular steps. Here an example of the historical sequence of those discoveries is presented as it unfolded over the last 50 years, the years during which major progress in understanding development of many animals and plants was documented by CTDB. In sea urchin development a rich series of experimental studies first established many of the phenomenological components of skeletal morphogenesis and patterning without knowledge of the molecular components. The many discoveries of transcription factors, signals, and structural proteins that contribute to the shape of the endoskeleton of the sea urchin larva then followed as molecular tools became available. A number of transcription factors and signals were discovered that were necessary for specification, morphogenesis, and patterning. Perturbation of the transcription factors and signals provided the means for assembling models of the gene regulatory networks used for specification and controlled the subsequent morphogenetic events. The earlier experimental information informed perturbation experiments that asked how patterning worked. As a consequence it was learned that ectoderm provides a series of patterning signals to the skeletogenic cells and as a consequence the skeletogenic cells secrete a highly patterned skeleton based on their ability to genotypically decode the localized reception of several signals. We still do not understand the complexity of the signals received by the skeletogenic cells, nor do we understand in detail how the genotypic information shapes the secreted skeletal biomineral, but the current knowledge at least outlines the sequence of events and provides a useful template for future

  20. Lower polyamine levels in breast milk of obese mothers compared to mothers with normal body weight.

    Science.gov (United States)

    Ali, M Atiya; Strandvik, B; Palme-Kilander, C; Yngve, A

    2013-07-01

    Obesity is associated with risks for mother and infant, and the mothers' dietary habits influence breast milk composition. Polyamines are secreted in breast milk and are essential for the regulation of intestinal and immune function in newborns and infants. The present study aimed to investigate the level of polyamines in human milk obtained from obese and normal weight mothers at different times of lactation. Breast milk from 50 mothers was obtained at day 3, and at 1 and 2 months after delivery. The mothers had normal body weight [body mass index (BMI) obese (BMI > 30 kg/m(2) ). A subgroup of obese mothers participated in a weight reduction programme during pregnancy. Polyamines were analysed using high-performance liquid chromatography. The total polyamine content was significantly lower at all times in breast milk from obese mothers compared to milk from controls. Spermine levels did not differ between groups at any time in contrast to the levels of putrescine and spermidine. Putrescine concentrations were highest on day 3 and spermidine and spermine were highest at 1 month of lactation. The obese mothers, who received dietary advice during pregnancy based on the Nordic Nutrition Recommendations, had higher concentrations of putrescine and spermidine in their milk than the obese mothers without any intervention. Polyamine concentrations were lower in breast milk from obese mothers compared to mothers with a normal weight. General dietary intervention in obese mothers increased the polyamine levels, suggesting that the low levels in obesity were at least partly associated with food habits. However, the consistency of spermine suggests a special metabolic function of this polyamine. © 2013 The Authors Journal of Human Nutrition and Dietetics © 2013 The British Dietetic Association Ltd.

  1. Hanging on for the ride: adhesion to the extracellular matrix mediates cellular responses in skeletal muscle morphogenesis and disease.

    Science.gov (United States)

    Goody, Michelle F; Sher, Roger B; Henry, Clarissa A

    2015-05-01

    Skeletal muscle specification and morphogenesis during early development are critical for normal physiology. In addition to mediating locomotion, skeletal muscle is a secretory organ that contributes to metabolic homeostasis. Muscle is a highly adaptable tissue, as evidenced by the ability to increase muscle cell size and/or number in response to weight bearing exercise. Conversely, muscle wasting can occur during aging (sarcopenia), cancer (cancer cachexia), extended hospital stays (disuse atrophy), and in many genetic diseases collectively known as the muscular dystrophies and myopathies. It is therefore of great interest to understand the cellular and molecular mechanisms that mediate skeletal muscle development and adaptation. Muscle morphogenesis transforms short muscle precursor cells into long, multinucleate myotubes that anchor to tendons via the myotendinous junction. This process requires carefully orchestrated interactions between cells and their extracellular matrix microenvironment. These interactions are dynamic, allowing muscle cells to sense biophysical, structural, organizational, and/or signaling changes within their microenvironment and respond appropriately. In many musculoskeletal diseases, these cell adhesion interactions are disrupted to such a degree that normal cellular adaptive responses are not sufficient to compensate for accumulating damage. Thus, one major focus of current research is to identify the cell adhesion mechanisms that drive muscle morphogenesis, with the hope that understanding how muscle cell adhesion promotes the intrinsic adaptability of muscle tissue during development may provide insight into potential therapeutic approaches for muscle diseases. Our objectives in this review are to highlight recent studies suggesting conserved roles for cell-extracellular matrix adhesion in vertebrate muscle morphogenesis and cellular adaptive responses in animal models of muscle diseases. Copyright © 2015 Elsevier Inc. All rights

  2. Immunohistochemical analysis of oxidative stress and DNA repair proteins in normal mammary and breast cancer tissues

    International Nuclear Information System (INIS)

    Curtis, Carol D; Thorngren, Daniel L; Nardulli, Ann M

    2010-01-01

    During the course of normal cellular metabolism, oxygen is consumed and reactive oxygen species (ROS) are produced. If not effectively dissipated, ROS can accumulate and damage resident proteins, lipids, and DNA. Enzymes involved in redox regulation and DNA repair dissipate ROS and repair the resulting damage in order to preserve a functional cellular environment. Because increased ROS accumulation and/or unrepaired DNA damage can lead to initiation and progression of cancer and we had identified a number of oxidative stress and DNA repair proteins that influence estrogen responsiveness of MCF-7 breast cancer cells, it seemed possible that these proteins might be differentially expressed in normal mammary tissue, benign hyperplasia (BH), ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC). Immunohistochemistry was used to examine the expression of a number of oxidative stress proteins, DNA repair proteins, and damage markers in 60 human mammary tissues which were classified as BH, DCIS or IBC. The relative mean intensity was determined for each tissue section and ANOVA was used to detect statistical differences in the relative expression of BH, DCIS and IBC compared to normal mammary tissue. We found that a number of these proteins were overexpressed and that the cellular localization was altered in human breast cancer tissue. Our studies suggest that oxidative stress and DNA repair proteins not only protect normal cells from the damaging effects of ROS, but may also promote survival of mammary tumor cells

  3. Phospholipid Homeostasis Regulates Dendrite Morphogenesis in Drosophila Sensory Neurons

    Directory of Open Access Journals (Sweden)

    Shan Meltzer

    2017-10-01

    Full Text Available Disruptions in lipid homeostasis have been observed in many neurodevelopmental disorders that are associated with dendrite morphogenesis defects. However, the molecular mechanisms of how lipid homeostasis affects dendrite morphogenesis are unclear. We find that easily shocked (eas, which encodes a kinase with a critical role in phospholipid phosphatidylethanolamine (PE synthesis, and two other enzymes in this synthesis pathway are required cell autonomously in sensory neurons for dendrite growth and stability. Furthermore, we show that the level of Sterol Regulatory Element-Binding Protein (SREBP activity is important for dendrite development. SREBP activity increases in eas mutants, and decreasing the level of SREBP and its transcriptional targets in eas mutants largely suppresses the dendrite growth defects. Furthermore, reducing Ca2+ influx in neurons of eas mutants ameliorates the dendrite morphogenesis defects. Our study uncovers a role for EAS kinase and reveals the in vivo function of phospholipid homeostasis in dendrite morphogenesis.

  4. Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing.

    Science.gov (United States)

    Radovich, Milan; Clare, Susan E; Atale, Rutuja; Pardo, Ivanesa; Hancock, Bradley A; Solzak, Jeffrey P; Kassem, Nawal; Mathieson, Theresa; Storniolo, Anna Maria V; Rufenbarger, Connie; Lillemoe, Heather A; Blosser, Rachel J; Choi, Mi Ran; Sauder, Candice A; Doxey, Diane; Henry, Jill E; Hilligoss, Eric E; Sakarya, Onur; Hyland, Fiona C; Hickenbotham, Matthew; Zhu, Jin; Glasscock, Jarret; Badve, Sunil; Ivan, Mircea; Liu, Yunlong; Sledge, George W; Schneider, Bryan P

    2014-01-01

    Triple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of actionable therapeutic targets (ER, PR, and HER-2). Microdissected normal ductal epithelium from healthy volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular signatures. Differential gene expression of TNBC compared with normal comparators demonstrated important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for negative studies and over-expression in studies with drug activity. Next, by comparing each individual TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes dysregulated in >90 % of TNBCs revealing an over-expressed central network. In conclusion, use of microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos.

  5. Markers of fibrosis and epithelial to mesenchymal transition demonstrate field cancerization in histologically normal tissue adjacent to breast tumors

    Science.gov (United States)

    Trujillo, Kristina A.; Heaphy, Christopher M.; Mai, Minh; Vargas, Keith M.; Jones, Anna C.; Vo, Phung; Butler, Kimberly S.; Joste, Nancy E.; Bisoffi, Marco; Griffith, Jeffrey K

    2011-01-01

    Previous studies have shown that a field of genetically altered but histologically normal tissue extends 1 cm or more from the margins of human breast tumors. The extent, composition and biological significance of this field are only partially understood, but the molecular alterations in affected cells could provide mechanisms for limitless replicative capacity, genomic instability and a microenvironment that supports tumor initiation and progression. We demonstrate by microarray, qRT-PCR and immunohistochemistry a signature of differential gene expression that discriminates between patient-matched, tumor-adjacent histologically normal breast tissues located 1 cm and 5 cm from the margins of breast adenocarcinomas (TAHN-1 and TAHN-5, respectively). The signature includes genes involved in extracellular matrix remodeling, wound healing, fibrosis and epithelial to mesenchymal transition (EMT). Myofibroblasts, which are mediators of wound healing and fibrosis, and intra-lobular fibroblasts expressing MMP2, SPARC, TGF-β3, which are inducers of EMT, were both prevalent in TAHN-1 tissues, sparse in TAHN-5 tissues, and absent in normal tissues from reduction mammoplasty. Accordingly, EMT markers S100A4 and vimentin were elevated in both luminal and myoepithelial cells, and EMT markers α-smooth muscle actin and SNAIL were elevated in luminal epithelial cells of TAHN-1 tissues. These results identify cellular processes that are differentially activated between TAHN-1 and TAHN-5 breast tissues, implicate myofibroblasts as likely mediators of these processes, provide evidence that EMT is occurring in histologically normal tissues within the affected field and identify candidate biomarkers to investigate whether or how field cancerization contributes to the development of primary or recurrent breast tumors. PMID:21105047

  6. Drosophila sosie functions with βH-Spectrin and actin organizers in cell migration, epithelial morphogenesis and cortical stability

    Science.gov (United States)

    Urwyler, Olivier; Cortinas-Elizondo, Fabiola; Suter, Beat

    2012-01-01

    Summary Morphogenesis in multicellular organisms requires the careful coordination of cytoskeletal elements, dynamic regulation of cell adhesion and extensive cell migration. sosie (sie) is a novel gene required in various morphogenesis processes in Drosophila oogenesis. Lack of sie interferes with normal egg chamber packaging, maintenance of epithelial integrity and control of follicle cell migration, indicating that sie is involved in controlling epithelial integrity and cell migration. For these functions sie is required both in the germ line and in the soma. Consistent with this, Sosie localizes to plasma membranes in the germ line and in the somatic follicle cells and is predicted to present an EGF-like domain on the extracellular side. Two positively charged residues, C-terminal to the predicted transmembrane domain (on the cytoplasmic side), are required for normal plasma membrane localization of Sosie. Because sie also contributes to normal cortical localization of βH-Spectrin, it appears that cortical βH-Spectrin mediates some of the functions of sosie. sie also interacts with the genes coding for the actin organizers Filamin and Profilin and, in the absence of sie function, F-actin is less well organized and nurse cells frequently fuse. PMID:23213377

  7. Drosophila sosie functions with β(H)-Spectrin and actin organizers in cell migration, epithelial morphogenesis and cortical stability.

    Science.gov (United States)

    Urwyler, Olivier; Cortinas-Elizondo, Fabiola; Suter, Beat

    2012-10-15

    Morphogenesis in multicellular organisms requires the careful coordination of cytoskeletal elements, dynamic regulation of cell adhesion and extensive cell migration. sosie (sie) is a novel gene required in various morphogenesis processes in Drosophila oogenesis. Lack of sie interferes with normal egg chamber packaging, maintenance of epithelial integrity and control of follicle cell migration, indicating that sie is involved in controlling epithelial integrity and cell migration. For these functions sie is required both in the germ line and in the soma. Consistent with this, Sosie localizes to plasma membranes in the germ line and in the somatic follicle cells and is predicted to present an EGF-like domain on the extracellular side. Two positively charged residues, C-terminal to the predicted transmembrane domain (on the cytoplasmic side), are required for normal plasma membrane localization of Sosie. Because sie also contributes to normal cortical localization of β(H)-Spectrin, it appears that cortical β(H)-Spectrin mediates some of the functions of sosie. sie also interacts with the genes coding for the actin organizers Filamin and Profilin and, in the absence of sie function, F-actin is less well organized and nurse cells frequently fuse.

  8. Physics and the canalization of morphogenesis: a grand challenge in organismal biology

    International Nuclear Information System (INIS)

    Von Dassow, Michelangelo; Davidson, Lance A

    2011-01-01

    Morphogenesis takes place against a background of organism-to-organism and environmental variation. Therefore, fundamental questions in the study of morphogenesis include: How are the mechanical processes of tissue movement and deformation affected by that variability, and in turn, how do the mechanic of the system modulate phenotypic variation? We highlight a few key factors, including environmental temperature, embryo size and environmental chemistry that might perturb the mechanics of morphogenesis in natural populations. Then we discuss several ways in which mechanics—including feedback from mechanical cues—might influence intra-specific variation in morphogenesis. To understand morphogenesis it will be necessary to consider whole-organism, environment and evolutionary scales because these larger scales present the challenges that developmental mechanisms have evolved to cope with. Studying the variation organisms express and the variation organisms experience will aid in deciphering the causes of birth defects

  9. Mechanical influences on morphogenesis of the knee joint revealed through morphological, molecular and computational analysis of immobilised embryos.

    Directory of Open Access Journals (Sweden)

    Karen A Roddy

    2011-02-01

    Full Text Available Very little is known about the regulation of morphogenesis in synovial joints. Mechanical forces generated from muscle contractions are required for normal development of several aspects of normal skeletogenesis. Here we show that biophysical stimuli generated by muscle contractions impact multiple events during chick knee joint morphogenesis influencing differential growth of the skeletal rudiment epiphyses and patterning of the emerging tissues in the joint interzone. Immobilisation of chick embryos was achieved through treatment with the neuromuscular blocking agent Decamethonium Bromide. The effects on development of the knee joint were examined using a combination of computational modelling to predict alterations in biophysical stimuli, detailed morphometric analysis of 3D digital representations, cell proliferation assays and in situ hybridisation to examine the expression of a selected panel of genes known to regulate joint development. This work revealed the precise changes to shape, particularly in the distal femur, that occur in an altered mechanical environment, corresponding to predicted changes in the spatial and dynamic patterns of mechanical stimuli and region specific changes in cell proliferation rates. In addition, we show altered patterning of the emerging tissues of the joint interzone with the loss of clearly defined and organised cell territories revealed by loss of characteristic interzone gene expression and abnormal expression of cartilage markers. This work shows that local dynamic patterns of biophysical stimuli generated from muscle contractions in the embryo act as a source of positional information guiding patterning and morphogenesis of the developing knee joint.

  10. Mechanical Influences on Morphogenesis of the Knee Joint Revealed through Morphological, Molecular and Computational Analysis of Immobilised Embryos

    Science.gov (United States)

    Roddy, Karen A.; Prendergast, Patrick J.; Murphy, Paula

    2011-01-01

    Very little is known about the regulation of morphogenesis in synovial joints. Mechanical forces generated from muscle contractions are required for normal development of several aspects of normal skeletogenesis. Here we show that biophysical stimuli generated by muscle contractions impact multiple events during chick knee joint morphogenesis influencing differential growth of the skeletal rudiment epiphyses and patterning of the emerging tissues in the joint interzone. Immobilisation of chick embryos was achieved through treatment with the neuromuscular blocking agent Decamethonium Bromide. The effects on development of the knee joint were examined using a combination of computational modelling to predict alterations in biophysical stimuli, detailed morphometric analysis of 3D digital representations, cell proliferation assays and in situ hybridisation to examine the expression of a selected panel of genes known to regulate joint development. This work revealed the precise changes to shape, particularly in the distal femur, that occur in an altered mechanical environment, corresponding to predicted changes in the spatial and dynamic patterns of mechanical stimuli and region specific changes in cell proliferation rates. In addition, we show altered patterning of the emerging tissues of the joint interzone with the loss of clearly defined and organised cell territories revealed by loss of characteristic interzone gene expression and abnormal expression of cartilage markers. This work shows that local dynamic patterns of biophysical stimuli generated from muscle contractions in the embryo act as a source of positional information guiding patterning and morphogenesis of the developing knee joint. PMID:21386908

  11. Interference by 2,3,7,8-tetrachlorodibenzo-p-dioxin with cultured mouse submandibular gland branching morphogenesis involves reduced epidermal growth factor receptor signaling

    International Nuclear Information System (INIS)

    Kiukkonen, Anu; Sahlberg, Carin; Partanen, Anna-Maija; Alaluusua, Satu; Pohjanvirta, Raimo; Tuomisto, Jouko; Lukinmaa, Pirjo-Liisa

    2006-01-01

    Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to mouse embryonic teeth, sharing features of early development with salivary glands in common, involves enhanced apoptosis and depends on the expression of epidermal growth factor (EGF) receptor. EGF receptor signaling, on the other hand, is essential for salivary gland branching morphogenesis. To see if TCDD impairs salivary gland morphogenesis and if the impairment is associated with EGF receptor signaling, we cultured mouse (NMRI) E13 submandibular glands with TCDD or TCDD in combination with EGF or fibronectin (FN), both previously found to enhance branching morphogenesis. Explants were examined stereomicroscopically and processed to paraffin sections. TCDD exposure impaired epithelial branching and cleft formation, resulting in enlarged buds. The glands were smaller than normal. EGF and FN alone concentration-dependently stimulated or inhibited branching morphogenesis but when co-administered with TCDD, failed to compensate for its effect. TCDD induced cytochrome P4501A1 expression in the glandular epithelium, indicating activation of the aryl hydrocarbon receptor. TCDD somewhat increased epithelial apoptosis as observed by terminal deoxynucleotidyl transferase (TdT)-mediated nick end-labeling method but the increase could not be correlated with morphological changes. The frequency of proliferating cells was not altered. Corresponding to the reduced cleft sites in TCDD-exposed explants, FN immunoreactivity in the epithelium was reduced. The results show that TCDD, comparably with EGF and FN at morphogenesis-inhibiting concentrations, impaired salivary gland branching morphogenesis in vitro. Together with the failure of EGF and FN at morphogenesis-stimulating concentrations to compensate for the effect of TCDD this implies that TCDD toxicity to developing salivary gland involves reduced EGF receptor signaling

  12. Programming Morphogenesis through Systems and Synthetic Biology.

    Science.gov (United States)

    Velazquez, Jeremy J; Su, Emily; Cahan, Patrick; Ebrahimkhani, Mo R

    2018-04-01

    Mammalian tissue development is an intricate, spatiotemporal process of self-organization that emerges from gene regulatory networks of differentiating stem cells. A major goal in stem cell biology is to gain a sufficient understanding of gene regulatory networks and cell-cell interactions to enable the reliable and robust engineering of morphogenesis. Here, we review advances in synthetic biology, single cell genomics, and multiscale modeling, which, when synthesized, provide a framework to achieve the ambitious goal of programming morphogenesis in complex tissues and organoids. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. LMW-E/CDK2 Deregulates Acinar Morphogenesis, Induces Tumorigenesis, and Associates with the Activated b-Raf-ERK1/2-mTOR Pathway in Breast Cancer Patients

    Science.gov (United States)

    Duong, MyLinh T.; Akli, Said; Wei, Caimiao; Wingate, Hannah F.; Liu, Wenbin; Lu, Yiling; Yi, Min; Mills, Gordon B.; Hunt, Kelly K.; Keyomarsi, Khandan

    2012-01-01

    Elastase-mediated cleavage of cyclin E generates low molecular weight cyclin E (LMW-E) isoforms exhibiting enhanced CDK2–associated kinase activity and resistance to inhibition by CDK inhibitors p21 and p27. Approximately 27% of breast cancers express high LMW-E protein levels, which significantly correlates with poor survival. The objective of this study was to identify the signaling pathway(s) deregulated by LMW-E expression in breast cancer patients and to identify pharmaceutical agents to effectively target this pathway. Ectopic LMW-E expression in nontumorigenic human mammary epithelial cells (hMECs) was sufficient to generate xenografts with greater tumorigenic potential than full-length cyclin E, and the tumorigenicity was augmented by in vivo passaging. However, cyclin E mutants unable to interact with CDK2 protected hMECs from tumor development. When hMECs were cultured on Matrigel, LMW-E mediated aberrant acinar morphogenesis, including enlargement of acinar structures and formation of multi-acinar complexes, as denoted by reduced BIM and elevated Ki67 expression. Similarly, inducible expression of LMW-E in transgenic mice generated hyper-proliferative terminal end buds resulting in enhanced mammary tumor development. Reverse-phase protein array assay of 276 breast tumor patient samples and cells cultured on monolayer and in three-dimensional Matrigel demonstrated that, in terms of protein expression profile, hMECs cultured in Matrigel more closely resembled patient tissues than did cells cultured on monolayer. Additionally, the b-Raf-ERK1/2-mTOR pathway was activated in LMW-E–expressing patient samples, and activation of this pathway was associated with poor disease-specific survival. Combination treatment using roscovitine (CDK inhibitor) plus either rapamycin (mTOR inhibitor) or sorafenib (a pan kinase inhibitor targeting b-Raf) effectively prevented aberrant acinar formation in LMW-E–expressing cells by inducing G1/S cell cycle arrest. LMW

  14. Human adipose tissue from normal and tumoral breast regulates the behavior of mammary epithelial cells.

    Science.gov (United States)

    Pistone Creydt, Virginia; Fletcher, Sabrina Johanna; Giudice, Jimena; Bruzzone, Ariana; Chasseing, Norma Alejandra; Gonzalez, Eduardo Gustavo; Sacca, Paula Alejandra; Calvo, Juan Carlos

    2013-02-01

    Stromal-epithelial interactions mediate both breast development and breast cancer progression. In the present work, we evaluated the effects of conditioned media (CMs) of human adipose tissue explants from normal (hATN) and tumor (hATT) breast on proliferation, adhesion, migration and metalloproteases activity on tumor (MCF-7 and IBH-7) and non-tumor (MCF-10A) human breast epithelial cell lines. Human adipose tissues were obtained from patients and the conditioned medium from hATN and hATT collected after 24 h of incubation. MCF-10A, MCF-7 and IBH-7 cells were grown and incubated with CMs and proliferation and adhesion, as well as migration ability and metalloprotease activity, of epithelial cells after exposing cell cultures to hATN- or hATT-CMs were quantified. The statistical significance between different experimental conditions was evaluated by one-way ANOVA. Tukey's post hoc tests were performed. Tumor and non-tumor breast epithelial cells significantly increased their proliferation activity after 24 h of treatment with hATT-CMs compared to control-CMs. Furthermore, cellular adhesion of these two tumor cell lines was significantly lower with hATT-CMs than with hATN-CMs. Therefore, hATT-CMs seem to induce significantly lower expression or less activity of the components involved in cellular adhesion than hATN-CMs. In addition, hATT-CMs induced pro-MMP-9 and MMP-9 activity and increased the migration of MCF-7 and IBH-7 cells compared to hATN-CMs. We conclude that the microenvironment of the tumor interacts in a dynamic way with the mutated epithelium. This evidence leads to the possibility to modify the tumor behavior/phenotype through the regulation or modification of its microenvironment. We developed a model in which we obtained CMs from adipose tissue explants completely, either from normal or tumor breast. In this way, we studied the contribution of soluble factors independently of the possible effects of direct cell contact.

  15. Airway branching morphogenesis in three dimensional culture

    Directory of Open Access Journals (Sweden)

    Gudjonsson Thorarinn

    2010-11-01

    Full Text Available Abstract Background Lungs develop from the fetal digestive tract where epithelium invades the vascular rich stroma in a process called branching morphogenesis. In organogenesis, endothelial cells have been shown to be important for morphogenesis and the maintenance of organ structure. The aim of this study was to recapitulate human lung morphogenesis in vitro by establishing a three dimensional (3D co-culture model where lung epithelial cells were cultured in endothelial-rich stroma. Methods We used a human bronchial epithelial cell line (VA10 recently developed in our laboratory. This cell line cell line maintains a predominant basal cell phenotype, expressing p63 and other basal markers such as cytokeratin-5 and -14. Here, we cultured VA10 with human umbilical vein endothelial cells (HUVECs, to mimic the close interaction between these cell types during lung development. Morphogenesis and differentiation was monitored by phase contrast microscopy, immunostainings and confocal imaging. Results We found that in co-culture with endothelial cells, the VA10 cells generated bronchioalveolar like structures, suggesting that lung epithelial branching is facilitated by the presence of endothelial cells. The VA10 derived epithelial structures display various complex patterns of branching and show partial alveolar type-II differentiation with pro-Surfactant-C expression. The epithelial origin of the branching VA10 colonies was confirmed by immunostaining. These bronchioalveolar-like structures were polarized with respect to integrin expression at the cell-matrix interface. The endothelial-induced branching was mediated by soluble factors. Furthermore, fibroblast growth factor receptor-2 (FGFR-2 and sprouty-2 were expressed at the growing tips of the branching structures and the branching was inhibited by the FGFR-small molecule inhibitor SU5402. Discussion In this study we show that a human lung epithelial cell line can be induced by endothelial cells to

  16. Discriminant analysis of normal and malignant breast tissue based upon INAA investigation of elemental concentration

    International Nuclear Information System (INIS)

    Kwanhoong Ng; Senghuat Ong; Bradley, D.A.; Laimeng Looi

    1997-01-01

    Discriminant analysis of six trace element concentrations measured by instrumental neutron activation analysis (INAA) in 26 paired-samples of malignant and histologically normal human breast tissues shows the technique to be a potentially valuable clinical tool for making malignant-normal classification. Nonparametric discriminant analysis is performed for the data obtained. Linear and quadratic discriminant analyses are also carried out for comparison. For this data set a formal analysis shows that the elements which may be useful in distinguishing between malignant and normal tissues are Ca, Rb and Br, providing correct classification for 24 out of 26 normal samples and 22 out of 26 malignant samples. (Author)

  17. Hormonal enzymatic systems in normal and cancerous human breast: control, prognostic factors, and clinical applications.

    Science.gov (United States)

    Pasqualini, Jorge R; Chetrite, Gérard S

    2012-04-01

    The bioformation and transformation of estrogens and other hormones in the breast tissue as a result of the activity of the various enzymes involved attract particular attention for the role they play in the development and pathogenesis of hormone-dependent breast cancer. The enzymatic process concerns the aromatase, which transforms androgens into estrogens; the sulfatase, which hydrolyzes the biologically inactive sulfates to the active hormone; the 17β-hydroxysteroid dehydrogenases, which are involved in the interconversion estradiol/estrone or testosterone/androstenedione; hydroxylases, which transform estrogens into mitotic and antimitotic derivatives; and sulfotransferases and glucuronidases, which, respectively convert into the biologically inactive sulfates and glucuronides. These enzymatic activities are more intense in the carcinoma than in the normal tissue. Concerning aromatase, the application of antiaromatase agents has been largely developed in the treatment of breast cancer patients, with very positive results. Various studies have shown that the activity levels of these enzymes and their mRNA can be involved as interesting prognostic factors for breast cancer. In conclusion, the application of new antienzymatic molecules can open attractive perspectives in the treatment of hormone-dependent breast cancer.

  18. CDDO-Me protects normal lung and breast epithelial cells but not cancer cells from radiation.

    Directory of Open Access Journals (Sweden)

    Mariam El-Ashmawy

    Full Text Available Although radiation therapy is commonly used for treatment for many human diseases including cancer, ionizing radiation produces reactive oxygen species that can damage both cancer and healthy cells. Synthetic triterpenoids, including CDDO-Me, act as anti-inflammatory and antioxidant modulators primarily by inducing the transcription factor Nrf2 to activate downstream genes containing antioxidant response elements (AREs. In the present series of experiments, we determined if CDDO-Me can be used as a radioprotector in normal non-cancerous human lung and breast epithelial cells, in comparison to lung and breast cancer cell lines. A panel of normal non-cancerous, partially cancer progressed, and cancer cell lines from both lung and breast tissue was exposed to gamma radiation with and without pre-treatment with CDDO-Me. CDDO-Me was an effective radioprotector when given ∼18 hours before radiation in epithelial cells (average dose modifying factor (DMF = 1.3, and Nrf2 function was necessary for CDDO-Me to exert these radioprotective effects. CDDO-Me did not protect cancer lines tested from radiation-induced cytotoxicity, nor did it protect experimentally transformed human bronchial epithelial cells (HBECs with progressive oncogenic manipulations. CDDO-Me also protected human lymphocytes against radiation-induced DNA damage. A therapeutic window exists in which CDDO-Me protects normal cells from radiation by activating the Nrf2 pathway, but does not protect experimentally transformed or cancer cell lines. This suggests that use of this oral available, non-toxic class of drug can protect non-cancerous healthy cells during radiotherapy, resulting in better outcomes and less toxicity for patients.

  19. New castanospermine glycoside analogues inhibit breast cancer cell proliferation and induce apoptosis without affecting normal cells.

    Directory of Open Access Journals (Sweden)

    Ghada Allan

    Full Text Available sp²-Iminosugar-type castanospermine analogues have been shown to exhibit anti-tumor activity. However, their effects on cell proliferation and apoptosis and the molecular mechanism at play are not fully understood. Here, we investigated the effect of two representatives, namely the pseudo-S- and C-octyl glycoside 2-oxa-3-oxocastanospermine derivatives SO-OCS and CO-OCS, on MCF-7 and MDA-MB-231 breast cancer and MCF-10A mammary normal cell lines. We found that SO-OCS and CO-OCS inhibited breast cancer cell viability in a concentration- and time-dependent manner. This effect is specific to breast cancer cells as both molecules had no impact on normal MCF-10A cell proliferation. Both drugs induced a cell cycle arrest. CO-OCS arrested cell cycle at G1 and G2/M in MCF-7 and MDA-MB-231 cells respectively. In MCF-7 cells, the G1 arrest is associated with a reduction of CDK4 (cyclin-dependent kinase 4, cyclin D1 and cyclin E expression, pRb phosphorylation, and an overexpression of p21(Waf1/Cip1. In MDA-MB-231 cells, CO-OCS reduced CDK1 but not cyclin B1 expression. SO-OCS accumulated cells in G2/M in both cell lines and this blockade was accompanied by a decrease of CDK1, but not cyclin B1 expression. Furthermore, both drugs induced apoptosis as demonstrated by the increased percentage of annexin V positive cells and Bax/Bcl-2 ratio. Interestingly, in normal MCF-10A cells the two drugs failed to modify cell proliferation, cell cycle progression, cyclins, or CDKs expression. These results demonstrate that the effect of CO-OCS and SO-OCS is triggered by both cell cycle arrest and apoptosis, suggesting that these castanospermine analogues may constitute potential anti-cancer agents against breast cancer.

  20. Baby Poop: What's Normal?

    Science.gov (United States)

    ... I'm breast-feeding my newborn and her bowel movements are yellow and mushy. Is this normal for baby poop? Answers from Jay L. Hoecker, M.D. Yellow, mushy bowel movements are perfectly normal for breast-fed babies. Still, ...

  1. Epithelial morphogenesis: the mouse eye as a model system.

    Science.gov (United States)

    Chauhan, Bharesh; Plageman, Timothy; Lou, Ming; Lang, Richard

    2015-01-01

    Morphogenesis is the developmental process by which tissues and organs acquire the shape that is critical to their function. Here, we review recent advances in our understanding of the mechanisms that drive morphogenesis in the developing eye. These investigations have shown that regulation of the actin cytoskeleton is central to shaping the presumptive lens and retinal epithelia that are the major components of the eye. Regulation of the actin cytoskeleton is mediated by Rho family GTPases, by signaling pathways and indirectly, by transcription factors that govern the expression of critical genes. Changes in the actin cytoskeleton can shape cells through the generation of filopodia (that, in the eye, connect adjacent epithelia) or through apical constriction, a process that produces a wedge-shaped cell. We have also learned that one tissue can influence the shape of an adjacent one, probably by direct force transmission, in a process we term inductive morphogenesis. Though these mechanisms of morphogenesis have been identified using the eye as a model system, they are likely to apply broadly where epithelia influence the shape of organs during development. © 2015 Elsevier Inc. All rights reserved.

  2. Epithelial-mesenchymal Transition---A Hallmark of Breast Cancer Metastasis.

    Science.gov (United States)

    Wang, Yifan; Zhou, Binhua P

    2013-03-01

    Epithelial-mesenchymal transition (EMT) is a highly conserved cellular program that converts polarized, immotile epithelial cells to migratory mesenchymal cells. In addition, EMT was initially recognized as a key step for morphogenesis during embryonic development. Emerging evidences indicate that this important developmental program promotes metastasis, drug resistance, and tumor recurrence, features that are associated with a poor clinical outcome for patients with breast cancer. Therefore, better understanding of regulation and signaling pathways in EMT is essential to develop novel targeted therapeutics. In this review, we present updated developments underlying EMT in tumor progression and metastasis, and discuss the challenges remaining in breast cancer research.

  3. Ascidian notochord morphogenesis

    OpenAIRE

    Jiang, Di; Smith, William C.

    2007-01-01

    The development of the notochord involves a complex set of cellular behaviors. While these morphogenic behaviors are common to all chordates, the ascidian provides a particularly attractive experimental model because of its relative simplicity. In particular, all notochord morphogenesis in ascidians takes place with only 40 cells, as opposed to the hundreds of cells in vertebrate models systems. Initial steps in ascidian notochord development convert a monolayer of epithelial-like cells in th...

  4. Circulating sex hormones and terminal duct lobular unit involution of the normal breast.

    Science.gov (United States)

    Khodr, Zeina G; Sherman, Mark E; Pfeiffer, Ruth M; Gierach, Gretchen L; Brinton, Louise A; Falk, Roni T; Patel, Deesha A; Linville, Laura M; Papathomas, Daphne; Clare, Susan E; Visscher, Daniel W; Mies, Carolyn; Hewitt, Stephen M; Storniolo, Anna Maria V; Rosebrock, Adrian; Caban, Jesus J; Figueroa, Jonine D

    2014-12-01

    Terminal duct lobular units (TDLU) are the predominant source of breast cancers. Lesser degrees of age-related TDLU involution have been associated with increased breast cancer risk, but factors that influence involution are largely unknown. We assessed whether circulating hormones, implicated in breast cancer risk, are associated with levels of TDLU involution using data from the Susan G. Komen Tissue Bank (KTB) at the Indiana University Simon Cancer Center (2009-2011). We evaluated three highly reproducible measures of TDLU involution, using normal breast tissue samples from the KTB (n = 390): TDLU counts, median TDLU span, and median acini counts per TDLU. RRs (for continuous measures), ORs (for categorical measures), 95% confidence intervals (95% CI), and Ptrends were calculated to assess the association between tertiles of estradiol, testosterone, sex hormone-binding globulin (SHBG), progesterone, and prolactin with TDLU measures. All models were stratified by menopausal status and adjusted for confounders. Among premenopausal women, higher prolactin levels were associated with higher TDLU counts (RRT3vsT1:1.18; 95% CI: 1.07-1.31; Ptrend = 0.0005), but higher progesterone was associated with lower TDLU counts (RRT3vsT1: 0.80; 95% CI: 0.72-0.89; Ptrend < 0.0001). Among postmenopausal women, higher levels of estradiol (RRT3vsT1:1.61; 95% CI: 1.32-1.97; Ptrend < 0.0001) and testosterone (RRT3vsT1: 1.32; 95% CI: 1.09-1.59; Ptrend = 0.0043) were associated with higher TDLU counts. These data suggest that select hormones may influence breast cancer risk potentially through delaying TDLU involution. Increased understanding of the relationship between circulating markers and TDLU involution may offer new insights into breast carcinogenesis. Cancer Epidemiol Biomarkers Prev; 23(12); 2765-73. ©2014 AACR. ©2014 American Association for Cancer Research.

  5. Computational models of airway branching morphogenesis.

    Science.gov (United States)

    Varner, Victor D; Nelson, Celeste M

    2017-07-01

    The bronchial network of the mammalian lung consists of millions of dichotomous branches arranged in a highly complex, space-filling tree. Recent computational models of branching morphogenesis in the lung have helped uncover the biological mechanisms that construct this ramified architecture. In this review, we focus on three different theoretical approaches - geometric modeling, reaction-diffusion modeling, and continuum mechanical modeling - and discuss how, taken together, these models have identified the geometric principles necessary to build an efficient bronchial network, as well as the patterning mechanisms that specify airway geometry in the developing embryo. We emphasize models that are integrated with biological experiments and suggest how recent progress in computational modeling has advanced our understanding of airway branching morphogenesis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Determination and correlation of spatial distribution of trace elements in normal and neoplastic breast tissues evaluated by μ-XRF

    International Nuclear Information System (INIS)

    Silva, M.P.; Oliveira, M.A.; Poletti, M.E.

    2012-01-01

    Full text: Some trace elements, naturally present in breast tissues, participate in a large number of biological processes, which include among others, activation or inhibition of enzymatic reactions and changes on cell membranes permeability, suggesting that these elements may influence carcinogenic processes. Thus, knowledge of the amounts of these elements and their spatial distribution in normal and neoplastic tissues may help in understanding the role of these elements in the carcinogenic process and tumor progression of breast cancers. Concentrations of trace elements like Ca, Fe, Cu and Zn, previously studied at LNLS using TXRF and conventional XRF, were elevated in neoplastic breast tissues compared to normal tissues. In this study we determined the spatial distribution of these elements in normal and neoplastic breast tissues using μ-XRF technique. We analyzed 22 samples of normal and neoplastic breast tissues (malignant and benign) obtained from paraffin blocks available for study at the Department of Pathology HC-FMRP/USP. From the blocks, a small fraction of material was removed and subjected to histological sections of 60 μm thick made with a microtome. The slices where placed in holder samples and covered with ultralen film. Tissue samples were irradiated with a white beam of synchrotron radiation. The samples were positioned at 45 degrees with respect to the incident beam on a table with 3 freedom degrees (x, y and z), allowing independent positioning of the sample in these directions. The white beam was collimated by a 20 μm microcapillary and samples were fully scanned. At each step, a spectrum was detected for 10 s. The fluorescence emitted by elements present in the sample was detected by a Si (Li) detector with 165 eV at 5.9 keV energy resolution, placed at 90 deg with respect to the incident beam. Results reveal that trace elements Ca-Zn and Fe-Cu could to be correlated in malignant breast tissues. Quantitative results, achieved by Spearman

  7. BMI and breast cancer prognosis benefit: mammography screening reveals differences between normal weight and overweight women.

    Science.gov (United States)

    Crispo, Anna; Grimaldi, Maria; D'Aiuto, Massimiliano; Rinaldo, Massimo; Capasso, Immacolata; Amore, Alfonso; D'Aiuto, Giuseppe; Giudice, Aldo; Ciliberto, Gennaro; Montella, Maurizio

    2015-02-01

    Few studies are available on the potential impact of body weight on breast cancer prognosis in screen-detected patients. Moreover, it is not known whether body mass index (BMI) could have a different prognostic impact in screen-detected versus symptomatic breast cancer patients. To investigate these unsolved issues, we carried out a retrospective study evaluating the effect of BMI on breast cancer prognosis in screen-detected vs symptomatic breast cancer patients. We conducted a follow-up study on 448 women diagnosed with incident, histologically-confirmed breast cancer. Patients were categorized according to their BMI as normal weight, overweight and obese. Disease free survival (DFS), overall survival (OS), and BMI curves were compared according to mode of cancer detection. Among screen-detected patients, higher BMI was associated with a significant lower DFS, whereas no significant difference was observed among symptomatic patients. OS showed similar results. In the multivariate analysis adjusting for age, education, tumor size, nodal status, estrogen receptor (ER), progesterone receptor (PR) and menopausal status, the risk for high level of BMI among screen-detected patients did not reach the statistical significance for either recurrence or survival. Our study highlights the potential impact of high bodyweight in breast cancer prognosis, the findings confirm that obesity plays a role in women breast cancer prognosis independently from diagnosis mode. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Morphogenesis and pattern formation in biological systems experiments and models

    CERN Document Server

    Noji, Sumihare; Ueno, Naoto; Maini, Philip

    2003-01-01

    A central goal of current biology is to decode the mechanisms that underlie the processes of morphogenesis and pattern formation. Concerned with the analysis of those phenomena, this book covers a broad range of research fields, including developmental biology, molecular biology, plant morphogenesis, ecology, epidemiology, medicine, paleontology, evolutionary biology, mathematical biology, and computational biology. In Morphogenesis and Pattern Formation in Biological Systems: Experiments and Models, experimental and theoretical aspects of biology are integrated for the construction and investigation of models of complex processes. This collection of articles on the latest advances by leading researchers not only brings together work from a wide spectrum of disciplines, but also provides a stepping-stone to the creation of new areas of discovery.

  9. A comparative study of functional properties of normal and wooden breast broiler chicken meat with NaCl addition.

    Science.gov (United States)

    Xing, Tong; Zhao, Xue; Han, Minyi; Cai, Linlin; Deng, Shaolin; Zhou, Guanghong; Xu, Xinglian

    2017-09-01

    The selection of broilers for augmented growth rate and breast has brought about wooden-breast (WB) muscle abnormalities, which caused substantial economic losses. The objective of this study was to compare water holding capacity, water mobility and distribution, salt-soluble protein (SSP) content, and protein profiles of normal and WB chicken meat with different additions of NaCl. Thirty WB and 30 normal chicken breasts were selected from a deboning line of a major Chinese processing plant at 2 to 3 h post mortem. Two different meat batters were formulated to 150 mg/g meat protein and different NaCl contents (0%, 1%, 2%, 3%, and 4%). Results indicated that as NaCl contents increased, the cooking loss of meat batters decreased (P meat showed different protein profiles, with myosin heavy chain exhibiting a higher intensity at ≥3% salt level. Low-field nuclear magnetic resonance (LF-NMR)revealed an increased T22 and higher P22 in raw WB meat compared to normal meat (P meat batters, WB meat batters had reduced T21 and lower immobilized water proportions at low NaCl contents (meat gels. Meat gels prepared from WB had a lower proportion of water within the myofibrillar protein matrix and a greater proportion of exuded bulk water at NaCl contents meat, meat batters and gels, water distribution and mobility of WB exhibited significant differences compared to normal meat. The addition of NaCl affected water mobility and distributions in meat batters, with a level of 3% NaCl eliminating the differences between processed normal and WB meat products. © 2017 Poultry Science Association Inc.

  10. Engineering strategies to recapitulate epithelial morphogenesis within synthetic three-dimensional extracellular matrix with tunable mechanical properties

    International Nuclear Information System (INIS)

    Miroshnikova, Y A; Sarang-Sieminski, A L; Jorgens, D M; Auer, M; Spirio, L; Weaver, V M

    2011-01-01

    The mechanical properties (e.g. stiffness) of the extracellular matrix (ECM) influence cell fate and tissue morphogenesis and contribute to disease progression. Nevertheless, our understanding of the mechanisms by which ECM rigidity modulates cell behavior and fate remains rudimentary. To address this issue, a number of two and three-dimensional (3D) hydrogel systems have been used to explore the effects of the mechanical properties of the ECM on cell behavior. Unfortunately, many of these systems have limited application because fiber architecture, adhesiveness and/or pore size often change in parallel when gel elasticity is varied. Here we describe the use of ECM-adsorbed, synthetic, self-assembling peptide (SAP) gels that are able to recapitulate normal epithelial acini morphogenesis and gene expression in a 3D context. By exploiting the range of viscoelasticity attainable with these SAP gels, and their ability to recreate native-like ECM fibril topology with minimal variability in ligand density and pore size, we were able to reconstitute normal and tumor-like phenotypes and gene expression patterns in nonmalignant mammary epithelial cells. Accordingly, this SAP hydrogel system presents the first tunable system capable of independently assessing the interplay between ECM stiffness and multi-cellular epithelial phenotype in a 3D context

  11. Myoepithelial cells: their origin and function in breast morphogenesis and neoplasia

    DEFF Research Database (Denmark)

    Gudjonsson, Thorarinn; Adriance, Melissa C; Sternlicht, Mark D

    2005-01-01

    The human breast epithelium is a branching ductal system composed of an inner layer of polarized luminal epithelial cells and an outer layer of myoepithelial cells that terminate in distally located terminal duct lobular units (TDLUs). While the luminal epithelial cell has received the most atten...

  12. Imaging morphogenesis: technological advances and biological insights.

    Science.gov (United States)

    Keller, Philipp J

    2013-06-07

    Morphogenesis, the development of the shape of an organism, is a dynamic process on a multitude of scales, from fast subcellular rearrangements and cell movements to slow structural changes at the whole-organism level. Live-imaging approaches based on light microscopy reveal the intricate dynamics of this process and are thus indispensable for investigating the underlying mechanisms. This Review discusses emerging imaging techniques that can record morphogenesis at temporal scales from seconds to days and at spatial scales from hundreds of nanometers to several millimeters. To unlock their full potential, these methods need to be matched with new computational approaches and physical models that help convert highly complex image data sets into biological insights.

  13. Nuclear location of tumor suppressor protein maspin inhibits proliferation of breast cancer cells without affecting proliferation of normal epithelial cells

    International Nuclear Information System (INIS)

    Machowska, Magdalena; Wachowicz, Katarzyna; Sopel, Mirosław; Rzepecki, Ryszard

    2014-01-01

    Maspin, which is classified as a tumor suppressor protein, is downregulated in many types of cancer. Several studies have suggested potential anti-proliferative activity of maspin as well as sensitizing activity of maspin for therapeutic cytotoxic agents in breast cancer tissue culture and animal models. All of the experimental data gathered so far have been based on studies with maspin localized cytoplasmically, while maspin in breast cancer tumor cells may be located in the cytoplasm, nucleus or both. In this study, the effect of maspin cytoplasmic and nuclear location and expression level on breast cancer proliferation and patient survival was studied. Tissue sections from 166 patients with invasive ductal breast cancer were stained by immunohistochemistry for maspin and Ki-67 protein. The localization and expression level of maspin were correlated with estimated patient overall survival and percent of Ki-67-positive cells. In further studies, we created constructs for transient transfection of maspin into breast cancer cells with targeted cytoplasmic and nuclear location. We analyzed the effect of maspin location in normal epithelial cell line MCF10A and three breast cancer cell lines - MCF-7, MDA-MB-231 and SKBR-3 - by immunofluorescence and proliferation assay. We observed a strong positive correlation between moderate and high nuclear maspin level and survival of patients. Moreover, a statistically significant negative relationship was observed between nuclear maspin and Ki-67 expression in patients with invasive ductal breast cancer. Spearman’s correlation analysis showed a negative correlation between level of maspin localized in nucleus and percentage of Ki-67 positive cells. No such differences were observed in cells with cytoplasmic maspin. We found a strong correlation between nuclear maspin and loss of Ki-67 protein in breast cancer cell lines, while there was no effect in normal epithelial cells from breast. The anti-proliferative effect of nuclear

  14. Nuclear location of tumor suppressor protein maspin inhibits proliferation of breast cancer cells without affecting proliferation of normal epithelial cells

    Science.gov (United States)

    2014-01-01

    Background Maspin, which is classified as a tumor suppressor protein, is downregulated in many types of cancer. Several studies have suggested potential anti-proliferative activity of maspin as well as sensitizing activity of maspin for therapeutic cytotoxic agents in breast cancer tissue culture and animal models. All of the experimental data gathered so far have been based on studies with maspin localized cytoplasmically, while maspin in breast cancer tumor cells may be located in the cytoplasm, nucleus or both. In this study, the effect of maspin cytoplasmic and nuclear location and expression level on breast cancer proliferation and patient survival was studied. Methods Tissue sections from 166 patients with invasive ductal breast cancer were stained by immunohistochemistry for maspin and Ki-67 protein. The localization and expression level of maspin were correlated with estimated patient overall survival and percent of Ki-67-positive cells. In further studies, we created constructs for transient transfection of maspin into breast cancer cells with targeted cytoplasmic and nuclear location. We analyzed the effect of maspin location in normal epithelial cell line MCF10A and three breast cancer cell lines - MCF-7, MDA-MB-231 and SKBR-3 - by immunofluorescence and proliferation assay. Results We observed a strong positive correlation between moderate and high nuclear maspin level and survival of patients. Moreover, a statistically significant negative relationship was observed between nuclear maspin and Ki-67 expression in patients with invasive ductal breast cancer. Spearman’s correlation analysis showed a negative correlation between level of maspin localized in nucleus and percentage of Ki-67 positive cells. No such differences were observed in cells with cytoplasmic maspin. We found a strong correlation between nuclear maspin and loss of Ki-67 protein in breast cancer cell lines, while there was no effect in normal epithelial cells from breast. The anti

  15. Estrogen Receptor and Progesterone Receptor Expression in Normal Terminal Duct Lobular Units Surrounding Invasive Breast Cancer

    Science.gov (United States)

    Yang, Xiaohong R.; Figueroa, Jonine D.; Hewitt, Stephen M.; Falk, Roni T.; Pfeiffer, Ruth M.; Lissowska, Jolanta; Peplonska, Beata; Brinton, Louise A.; Garcia-Closas, Montserrat; Sherman, Mark E.

    2014-01-01

    Introduction Molecular and morphological alterations related to carcinogenesis have been found in terminal duct lobular units (TDLUs), the microscopic structures from which most breast cancer precursors and cancers develop, and therefore, analysis of these structures may reveal early changes in breast carcinogenesis and etiologic heterogeneity. Accordingly, we evaluated relationships of breast cancer risk factors and tumor pathology to estrogen receptor (ER) and progesterone receptor (PR) expression in TDLUs surrounding breast cancers. Methods We analyzed 270 breast cancer cases included in a population-based breast cancer case-control study conducted in Poland. TDLUs were mapped in relation to breast cancer: within the same block as the tumor (TDLU-T), proximal to tumor (TDLU-PT), or distant from (TDLU-DT). ER/PR was quantitated using image analysis of immunohistochemically stained TDLUs prepared as tissue microarrays. Results In surgical specimens containing ER-positive breast cancers, ER and PR levels were significantly higher in breast cancer cells than in normal TDLUs, and higher in TDLU-T than in TDLU-DT or TDLU-PT, which showed similar results. Analyses combining DT-/PT TDLUs within subjects demonstrated that ER levels were significantly lower in premenopausal women vs. postmenopausal women (odds ratio [OR]=0.38, 95% confidence interval [CI]=0.19, 0.76, P=0.0064) and among recent or current menopausal hormone therapy users compared with never users (OR=0.14, 95% CI=0.046–0.43, Ptrend=0.0006). Compared with premenopausal women, TDLUs of postmenopausal women showed lower levels of PR (OR=0.90, 95% CI=0.83–0.97, Ptrend=0.007). ER and PR expression in TDLUs was associated with epidermal growth factor receptor (EGFR) expression in invasive tumors (P=0.019 for ER and P=0.03 for PR), but not with other tumor features. Conclusions Our data suggest that TDLUs near breast cancers reflect field effects, whereas those at a distance demonstrate influences of breast

  16. Exploring bacteria-induced growth and morphogenesis in the green macroalga order Ulvales (Chlorophyta

    Directory of Open Access Journals (Sweden)

    Thomas eWichard

    2015-03-01

    Full Text Available Green macroalgae, such as Ulvales, lose their typical morphology completely when grown under axenic conditions or in the absence of the appropriate microbiome. As a result, slow growing aberrant phenotypes or even callus-like morphotypes are observed in Ulvales. The cross-kingdom interactions between marine algae and microorganisms are hence not only restricted by the exchange of macronutrients, including vitamins and nutrients, but also by infochemicals such as bacterial morphogenetic compounds. The latter are a fundamental trait mediating the mutualism within the chemosphere where the organisms interact with each other via compounds in their surroundings.Approximately 60 years ago, pilot studies demonstrated that certain bacteria promote growth, whereas other bacteria induce morphogenesis; this is particularly true for the order of Ulvales. However, only slow progress was made towards the underlying mechanism due to the complexity of, for example, algal cultivation techniques, and the lack of standardized experiments in the laboratory.A breakthrough in this research was the discovery of the morphogenetic compound thallusin, which was isolated from an epiphytic bacterium and induces normal germination and restores the foliaceous morphotypes of Monostroma. Owing to the low concentration, the purification and structure elucidation of highly biologically active morphogenetic compounds is still challenging. Recently, it was found that only the combination of two specific bacteria from the Rhodobacteraceae and Flavobacteriaceae can completely recover the growth and morphogenesis of axenic Ulva mutabilis cultures forming a symbiotic tripartite community by chemical communication.This review combines literature detailing evidence of bacteria-induced morphogenesis in Ulvales. A set of standardized experimental approaches is further proposed for the preparation of axenic algal tissues, bacteria isolation, co-cultivation experiments, and the analysis of

  17. Exploring bacteria-induced growth and morphogenesis in the green macroalga order Ulvales (Chlorophyta)

    Science.gov (United States)

    Wichard, Thomas

    2015-01-01

    Green macroalgae, such as Ulvales, lose their typical morphology completely when grown under axenic conditions or in the absence of the appropriate microbiome. As a result, slow growing aberrant phenotypes or even callus-like morphotypes are observed in Ulvales. The cross-kingdom interactions between marine algae and microorganisms are hence not only restricted by the exchange of macronutrients, including vitamins and nutrients, but also by infochemicals such as bacterial morphogenetic compounds. The latter are a fundamental trait mediating the mutualism within the chemosphere where the organisms interact with each other via compounds in their surroundings. Approximately 60 years ago, pilot studies demonstrated that certain bacteria promote growth, whereas other bacteria induce morphogenesis; this is particularly true for the order of Ulvales. However, only slow progress was made towards the underlying mechanism due to the complexity of, for example, algal cultivation techniques, and the lack of standardized experiments in the laboratory. A breakthrough in this research was the discovery of the morphogenetic compound thallusin, which was isolated from an epiphytic bacterium and induces normal germination restoring the foliaceous morphotypes of Monostroma. Owing to the low concentration, the purification and structure elucidation of highly biologically active morphogenetic compounds are still challenging. Recently, it was found that only the combination of two specific bacteria from the Rhodobacteraceae and Flavobacteriaceae can completely recover the growth and morphogenesis of axenic Ulva mutabilis cultures forming a symbiotic tripartite community by chemical communication. This review combines literature detailing evidences of bacteria-induced morphogenesis in Ulvales. A set of standardized experimental approaches is further proposed for the preparation of axenic algal tissues, bacteria isolation, co-cultivation experiments, and the analysis of the chemosphere

  18. Supplementary Material for: A global sensitivity analysis approach for morphogenesis models

    KAUST Repository

    Boas, Sonja

    2015-01-01

    Abstract Background Morphogenesis is a developmental process in which cells organize into shapes and patterns. Complex, non-linear and multi-factorial models with images as output are commonly used to study morphogenesis. It is difficult to understand the relation between the uncertainty in the input and the output of such ‘black-box’ models, giving rise to the need for sensitivity analysis tools. In this paper, we introduce a workflow for a global sensitivity analysis approach to study the impact of single parameters and the interactions between them on the output of morphogenesis models. Results To demonstrate the workflow, we used a published, well-studied model of vascular morphogenesis. The parameters of this cellular Potts model (CPM) represent cell properties and behaviors that drive the mechanisms of angiogenic sprouting. The global sensitivity analysis correctly identified the dominant parameters in the model, consistent with previous studies. Additionally, the analysis provided information on the relative impact of single parameters and of interactions between them. This is very relevant because interactions of parameters impede the experimental verification of the predicted effect of single parameters. The parameter interactions, although of low impact, provided also new insights in the mechanisms of in silico sprouting. Finally, the analysis indicated that the model could be reduced by one parameter. Conclusions We propose global sensitivity analysis as an alternative approach to study the mechanisms of morphogenesis. Comparison of the ranking of the impact of the model parameters to knowledge derived from experimental data and from manipulation experiments can help to falsify models and to find the operand mechanisms in morphogenesis. The workflow is applicable to all ‘black-box’ models, including high-throughput in vitro models in which output measures are affected by a set of experimental perturbations.

  19. The Fog signaling pathway: Insights into signaling in morphogenesis

    Science.gov (United States)

    Manning, Alyssa J.; Rogers, Stephen L.

    2014-01-01

    Epithelia form the building blocks of many tissue and organ types. Epithelial cells often form a contiguous 2-dimensional sheet that is held together by strong adhesions. The mechanical properties conferred by these adhesions allow the cells to undergo dramatic three-dimensional morphogenetic movements while maintaining cell–cell contacts during embryogenesis and post-embryonic development. The Drosophila Folded gastrulation pathway triggers epithelial cell shape changes that drive gastrulation and tissue folding and is one of the most extensively studied examples of epithelial morphogenesis. This pathway has yielded key insights into the signaling mechanisms and cellular machinery involved in epithelial remodeling. In this review, we discuss principles of morphogenesis and signaling that have been discovered through genetic and cell biological examination of this pathway. We also consider various regulatory mechanisms and the system's relevance to mammalian development. We propose future directions that will continue to broaden our knowledge of morphogenesis across taxa. PMID:25127992

  20. Contrast enhancement kinetics of normal breast parenchyma in dynamic MR mammography: effects of menopausal status, oral contraceptives, and postmenopausal hormone therapy

    International Nuclear Information System (INIS)

    Hegenscheid, Katrin; Seipel, Rebecca; Laqua, Rene; Hosten, Norbert; Puls, Ralf; Schmidt, Carsten O.; Ohlinger, Ralf

    2012-01-01

    To investigate effects of menopausal status, oral contraceptives (OC), and postmenopausal hormone therapy (HT) on normal breast parenchymal contrast enhancement (CE) and non-mass-like enhancing areas in magnetic resonance mammography (MRM). A total of 459 female volunteers (mean age 49.1 ± 12.5 years) underwent T1-weighted 3D MRM 1-5 min after bolus injection of gadobutrol. Quantitative analysis was performed in normal breast parenchyma by manually tracing regions of interest and calculating percentage CE. Semiquantitative analysis was performed in non-mass-like enhancing areas, and signal intensity changes were characterised by five predefined kinetic curve types. The influence of OC (n = 69) and HT (n = 24) on CE was studied using random effects models. Breast parenchymal enhancement was significantly higher in premenopausal than in postmenopausal women (P < 0.001). CE decreased significantly with the use of OC (P = 0.01), while HT had negligible effects (P = 0.52). Prevalence of kinetic curve types of non-mass-like enhancement differed strongly between pre- and postmenopausal women (P < 0.0001), but was similar in OC users and non-OC users (P = 0.61) as well as HT users and non-HT users (P = 0.77). Normal breast parenchymal enhancement and non-mass-like enhancing areas were strongly affected by menopausal status, while they were not affected by HT use and only moderately by OC use. (orig.)

  1. Contrast enhancement kinetics of normal breast parenchyma in dynamic MR mammography: effects of menopausal status, oral contraceptives, and postmenopausal hormone therapy

    Energy Technology Data Exchange (ETDEWEB)

    Hegenscheid, Katrin; Seipel, Rebecca; Laqua, Rene; Hosten, Norbert; Puls, Ralf [Ernst-Moritz-Arndt University Medical Center Greifswald, Department of Diagnostic Radiology and Neuroradiology, Greifswald (Germany); Schmidt, Carsten O. [Ernst-Moritz-Arndt University Medical Center Greifswald, Institute for Community Medicine, Greifswald (Germany); Ohlinger, Ralf [Ernst-Moritz-Arndt University Medical Center Greifswald, Department of Gynecology and Obstetrics, Greifswald (Germany)

    2012-12-15

    To investigate effects of menopausal status, oral contraceptives (OC), and postmenopausal hormone therapy (HT) on normal breast parenchymal contrast enhancement (CE) and non-mass-like enhancing areas in magnetic resonance mammography (MRM). A total of 459 female volunteers (mean age 49.1 {+-} 12.5 years) underwent T1-weighted 3D MRM 1-5 min after bolus injection of gadobutrol. Quantitative analysis was performed in normal breast parenchyma by manually tracing regions of interest and calculating percentage CE. Semiquantitative analysis was performed in non-mass-like enhancing areas, and signal intensity changes were characterised by five predefined kinetic curve types. The influence of OC (n = 69) and HT (n = 24) on CE was studied using random effects models. Breast parenchymal enhancement was significantly higher in premenopausal than in postmenopausal women (P < 0.001). CE decreased significantly with the use of OC (P = 0.01), while HT had negligible effects (P = 0.52). Prevalence of kinetic curve types of non-mass-like enhancement differed strongly between pre- and postmenopausal women (P < 0.0001), but was similar in OC users and non-OC users (P = 0.61) as well as HT users and non-HT users (P = 0.77). Normal breast parenchymal enhancement and non-mass-like enhancing areas were strongly affected by menopausal status, while they were not affected by HT use and only moderately by OC use. (orig.)

  2. Hierarchical clustering of breast cancer methylomes revealed differentially methylated and expressed breast cancer genes.

    Directory of Open Access Journals (Sweden)

    I-Hsuan Lin

    Full Text Available Oncogenic transformation of normal cells often involves epigenetic alterations, including histone modification and DNA methylation. We conducted whole-genome bisulfite sequencing to determine the DNA methylomes of normal breast, fibroadenoma, invasive ductal carcinomas and MCF7. The emergence, disappearance, expansion and contraction of kilobase-sized hypomethylated regions (HMRs and the hypomethylation of the megabase-sized partially methylated domains (PMDs are the major forms of methylation changes observed in breast tumor samples. Hierarchical clustering of HMR revealed tumor-specific hypermethylated clusters and differential methylated enhancers specific to normal or breast cancer cell lines. Joint analysis of gene expression and DNA methylation data of normal breast and breast cancer cells identified differentially methylated and expressed genes associated with breast and/or ovarian cancers in cancer-specific HMR clusters. Furthermore, aberrant patterns of X-chromosome inactivation (XCI was found in breast cancer cell lines as well as breast tumor samples in the TCGA BRCA (breast invasive carcinoma dataset. They were characterized with differentially hypermethylated XIST promoter, reduced expression of XIST, and over-expression of hypomethylated X-linked genes. High expressions of these genes were significantly associated with lower survival rates in breast cancer patients. Comprehensive analysis of the normal and breast tumor methylomes suggests selective targeting of DNA methylation changes during breast cancer progression. The weak causal relationship between DNA methylation and gene expression observed in this study is evident of more complex role of DNA methylation in the regulation of gene expression in human epigenetics that deserves further investigation.

  3. Analysis and Diagnosis of Breast Cancer

    OpenAIRE

    Poulami Das; Debnath Bhattacharyya; Samir K. Bandyopadhyay; Tai-hoon Kim

    2009-01-01

    In this paper, we propose a method to identify abnormal growth of cells in breast tissue and suggest further pathological test, if necessary. We compare normal breast tissue with malignant invasive breast tissue by a series of image processing steps. Normal ductalepithelial cells and ductal / lobular invasive carcinogenic cells also consider for comparison here in this paper. In fact, features of cancerous breast tissue (invasive) are extracted and analyses with normal breast tissue. We also ...

  4. Relative expression of rRNA transcripts and 45S rDNA promoter methylation status are dysregulated in tumors in comparison with matched-normal tissues in breast cancer.

    Science.gov (United States)

    Karahan, Gurbet; Sayar, Nilufer; Gozum, Gokcen; Bozkurt, Betul; Konu, Ozlen; Yulug, Isik G

    2015-06-01

    Ribosomal RNA (rRNA) expression, one of the most important factors regulating ribosome production, is primarily controlled by a CG-rich 45 S rDNA promoter. However, the DNA methylation state of the 45 S rDNA promoter, as well as its effect on rRNA gene expression in types of human cancers is controversial. In the present study we analyzed the methylation status of the rDNA promoter (-380 to +53 bp) as well as associated rRNA expression levels in breast cancer cell lines and breast tumor-normal tissue pairs. We found that the aforementioned regulatory region was extensively methylated (74-96%) in all cell lines and in 68% (13/19 tumor-normal pairs) of the tumors. Expression levels of rRNA transcripts 18 S, 28 S, 5.8 S and 45 S external transcribed spacer (45 S ETS) greatly varied in the breast cancer cell lines regardless of their methylation status. Analyses of rRNA transcript expression levels in the breast tumor and normal matched tissues showed no significant difference when normalized with TBP. On the other hand, using the geometric mean of the rRNA expression values (GM-rRNA) as reference enabled us to identify significant changes in the relative expression of rRNAs in the tissue samples. We propose GM-rRNA normalization as a novel strategy to analyze expression differences between rRNA transcripts. Accordingly, the 18S rRNA/GM-rRNA ratio was significantly higher whereas the 5.8S rRNA/GM-rRNA ratio was significantly lower in breast tumor samples than this ratio in the matched normal samples. Moreover, the 18S rRNA/GM-rRNA ratio was negatively correlated with the 45 S rDNA promoter methylation level in the normal breast tissue samples, yet not in the breast tumors. Significant correlations observed between the expression levels of rRNA transcripts in the normal samples were lost in the tumor samples. We showed that the expression of rRNA transcripts may not be based solely on promoter methylation. Carcinogenesis may cause dysregulation of the correlation

  5. Microgravity simulation activates Cdc42 via Rap1GDS1 to promote vascular branch morphogenesis during vasculogenesis

    Directory of Open Access Journals (Sweden)

    Shouli Wang

    2017-12-01

    Full Text Available Gravity plays an important role in normal tissue maintenance. The ability of stem cells to repair tissue loss in space through regeneration and differentiation remains largely unknown. To investigate the impact of microgravity on blood vessel formation from pluripotent stem cells, we employed the embryoid body (EB model for vasculogenesis and simulated microgravity by clinorotation. We first differentiated mouse embryonic stem cells into cystic EBs containing two germ layers and then analyzed vessel formation under clinorotation. We observed that endothelial cell differentiation was slightly reduced under clinorotation, whereas vascular branch morphogenesis was markedly enhanced. EB-derived endothelial cells migrated faster, displayed multiple cellular processes, and had higher Cdc42 and Rac1 activity when subjected to clinorotation. Genetic analysis and rescue experiments demonstrated that Cdc42 but not Rac1 is required for microgravity-induced vascular branch morphogenesis. Furthermore, affinity pull-down assay and mass spectrometry identified Rap1GDS1 to be a Cdc42 guanine nucleotide exchange factor, which was upregulated by clinorotation. shRNA-mediated knockdown of Rap1GDS1 selectively suppressed Cdc42 activation and inhibited both baseline and microgravity-induced vasculogenesis. This was rescued by ectopic expression of constitutively active Cdc42. Taken together, these results support the notion that simulated microgravity activates Cdc42 via Rap1GDS1 to promote vascular branch morphogenesis.

  6. Feedback, Lineages and Self-Organizing Morphogenesis.

    Directory of Open Access Journals (Sweden)

    Sameeran Kunche

    2016-03-01

    Full Text Available Feedback regulation of cell lineage progression plays an important role in tissue size homeostasis, but whether such feedback also plays an important role in tissue morphogenesis has yet to be explored. Here we use mathematical modeling to show that a particular feedback architecture in which both positive and negative diffusible signals act on stem and/or progenitor cells leads to the appearance of bistable or bi-modal growth behaviors, ultrasensitivity to external growth cues, local growth-driven budding, self-sustaining elongation, and the triggering of self-organization in the form of lamellar fingers. Such behaviors arise not through regulation of cell cycle speeds, but through the control of stem or progenitor self-renewal. Even though the spatial patterns that arise in this setting are the result of interactions between diffusible factors with antagonistic effects, morphogenesis is not the consequence of Turing-type instabilities.

  7. Feedback, Lineages and Self-Organizing Morphogenesis

    Science.gov (United States)

    Calof, Anne L.; Lowengrub, John S.; Lander, Arthur D.

    2016-01-01

    Feedback regulation of cell lineage progression plays an important role in tissue size homeostasis, but whether such feedback also plays an important role in tissue morphogenesis has yet to be explored. Here we use mathematical modeling to show that a particular feedback architecture in which both positive and negative diffusible signals act on stem and/or progenitor cells leads to the appearance of bistable or bi-modal growth behaviors, ultrasensitivity to external growth cues, local growth-driven budding, self-sustaining elongation, and the triggering of self-organization in the form of lamellar fingers. Such behaviors arise not through regulation of cell cycle speeds, but through the control of stem or progenitor self-renewal. Even though the spatial patterns that arise in this setting are the result of interactions between diffusible factors with antagonistic effects, morphogenesis is not the consequence of Turing-type instabilities. PMID:26989903

  8. Enhanced effect of geldanamycin nanocomposite against breast cancer cells growing in vitro and as xenograft with vanquished normal cell toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Prabhu, Suma [Department of Radiation Biology and Toxicology, School of Life Sciences, Manipal University, Manipal 576 104, Karnataka (India); Ananthanarayanan, Preeta; Aziz, Sajida Kannangar [Department of Biotechnology, School of Life Sciences, Manipal University, Manipal 576 104, Karnataka (India); Rai, Sharada [Department of Pathology, Kasturba Medical College, Mangalore Campus, Manipal University, Mangalore 575 001, Karnataka (India); Mutalik, Srinivas [Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576 104, Karnataka (India); Sadashiva, Satish Rao Bola, E-mail: rao.satish@manipal.edu [Department of Radiation Biology and Toxicology, School of Life Sciences, Manipal University, Manipal 576 104, Karnataka (India)

    2017-04-01

    Despite enormous advances in remedies developed for breast cancer, an effective therapeutic strategy by targeting malignant cells with the least normal tissue toxicity is yet to be developed. Hsp90 is considered to be an important therapeutic target to inhibit cell proliferation. Geldanamycin (GDM), a potent inhibitor of Hsp90 was withdrawn from clinical trials due to its undesirable hepatotoxicity. We report a superparamagnetic iron oxide (SPION) based polymeric nanocomposite of GDM augmenting anticancer competence with decreased hepatic toxicity. The particle size of nanocomposite was ascertained to be 76 ± 10 nm with acceptable stability. A comparative dose dependent in vitro validation of cytotoxicity showed an enhanced cellular damage and necrosis in breast cancer (MCF-7) cell line at a low dose of 5.49 nM (in GDM nanocomposite) in contrast to 20 nM of pure GDM, while normal breast epithelial cells (MCF-10A) were least affected. Besides, in vivo study (in breast cancer xenografts) substantiated 2.7 fold delay in tumor progression mediated by redundancy in the downstream functions of p-Akt and MAPK-Erk leading to apoptosis with negligible hepatotoxicity. Pure GDM disrupted the function and morphology of liver with lesser therapeutic efficacy than the GDM nanocomposite. These findings deduce that GDM based polymeric magnetite nanocomposite play a vital role in efficacious therapy while vanquishing normal cells and hepatic toxicity and thereby promising it to be reinstated in clinics. - Highlights: • GDM nanocomposite shows selective cell kill of cancerous breast cells. • Nanocomposite delays the growth of tumor in comparison to pure GDM treatment. • GDM promotes apoptosis by down-regulation of p-Akt and MAPK-Erk. • GDM nanocomposite nullifies the hepatotoxicity generally exhibited by pure GDM.

  9. Identification of genes for normalization of real-time RT-PCR data in breast carcinomas

    DEFF Research Database (Denmark)

    Lyng, Maria B; Laenkholm, Anne-Vibeke; Pallisgaard, Niels

    2008-01-01

    BACKGROUND: Quantitative real-time RT-PCR (RT-qPCR) has become a valuable molecular technique in basic and translational biomedical research, and is emerging as an equally valuable clinical tool. Correlation of inter-sample values requires data normalization, which can be accomplished by various...... means, the most common of which is normalization to internal, stably expressed, reference genes. Recently, such traditionally utilized reference genes as GAPDH and B2M have been found to be regulated in various circumstances in different tissues, emphasizing the need to identify genes independent...... of factors influencing the tissue, and that are stably expressed within the experimental milieu. In this study, we identified genes for normalization of RT-qPCR data for invasive breast cancer (IBC), with special emphasis on estrogen receptor positive (ER+) IBC, but also examined their applicability to ER...

  10. Educating Normal Breast Mucosa to Prevent Breast Cancer

    Science.gov (United States)

    2016-12-01

    immune system to maintain epithelial integrity. In this study our goal was to study the immune subsets associated with breast mucosa and develop the...into the mammary gland. Specific Aim 3: Determine an optimal oral vaccine approach able to minimize hyperplasia . 5 287 288 289 290 291 292...colonization, but also regulating homeostasis of the epithelial layer. As a part of the mucosal immune system, the mammary gland may have characteristic

  11. Conserved RNA-Binding Proteins Required for Dendrite Morphogenesis in Caenorhabditis elegans Sensory Neurons

    Science.gov (United States)

    Antonacci, Simona; Forand, Daniel; Wolf, Margaret; Tyus, Courtney; Barney, Julia; Kellogg, Leah; Simon, Margo A.; Kerr, Genevieve; Wells, Kristen L.; Younes, Serena; Mortimer, Nathan T.; Olesnicky, Eugenia C.; Killian, Darrell J.

    2015-01-01

    The regulation of dendritic branching is critical for sensory reception, cell−cell communication within the nervous system, learning, memory, and behavior. Defects in dendrite morphology are associated with several neurologic disorders; thus, an understanding of the molecular mechanisms that govern dendrite morphogenesis is important. Recent investigations of dendrite morphogenesis have highlighted the importance of gene regulation at the posttranscriptional level. Because RNA-binding proteins mediate many posttranscriptional mechanisms, we decided to investigate the extent to which conserved RNA-binding proteins contribute to dendrite morphogenesis across phyla. Here we identify a core set of RNA-binding proteins that are important for dendrite morphogenesis in the PVD multidendritic sensory neuron in Caenorhabditis elegans. Homologs of each of these genes were previously identified as important in the Drosophila melanogaster dendritic arborization sensory neurons. Our results suggest that RNA processing, mRNA localization, mRNA stability, and translational control are all important mechanisms that contribute to dendrite morphogenesis, and we present a conserved set of RNA-binding proteins that regulate these processes in diverse animal species. Furthermore, homologs of these genes are expressed in the human brain, suggesting that these RNA-binding proteins are candidate regulators of dendrite development in humans. PMID:25673135

  12. Comparison of normal tissue pharmacokinetics with 111In/9Y monoclonal antibody m170 for breast and prostate cancer

    International Nuclear Information System (INIS)

    Lehmann, Joerg; DeNardo, Gerald L.; Yuan, Aina; Shen Sui; O'Donnell, Robert T.; Richman, Carol M.; De Nardo, Sally J.

    2006-01-01

    Purpose: Radioactivity deposition in normal tissues limits the dose deliverable by radiopharmaceuticals (RP) in radioimmunotherapy (RIT). This study investigated the absorbed radiation dose in normal tissues for prostate cancer patients in comparison to breast cancer patients for 2 RPs using the monoclonal antibody (MAb) m170. Methods and Materials: 111 In-DOTA-glycylglycylglycyl-L-p-isothiocyanatophenylalanine amide (GGGF)-m170 and 111 In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) 2-iminothiolane (2IT)-m170, representing the same MAb and chelate with and without a cleavable linkage, were studied in 13 breast cancer and 26 prostate cancer patients. Dosimetry for 9 Y was calculated using 111 In MAb pharmacokinetics from the initial imaging study for each patient, using reference man- and patient-specific masses. Results: The reference man-specific radiation doses (cGy/MBq) were not significantly different for the breast and the prostate cancer patients for both RPs in all but one tissue-RP combination (liver, DOTA-2IT). The patient-specific doses had differences between the groups most of which can be related to weight differences. Conclusions: Similar normal tissue doses were calculated for two groups of patients having different cancers and genders. This similarity combined with continued careful analysis of the imaging data might allow the use of higher starting doses in early phase RIT studies

  13. Gene expression profiling of histologically normal breast tissue in females with human epidermal growth factor receptor 2‑positive breast cancer.

    Science.gov (United States)

    Zubor, Pavol; Hatok, Jozef; Moricova, Petra; Kapustova, Ivana; Kajo, Karol; Mendelova, Andrea; Sivonova, Monika Kmetova; Danko, Jan

    2015-02-01

    Gene expression profile‑based taxonomy of breast cancer (BC) has been described as a significant breakthrough in comprehending the differences in the origin and behavior of cancer to allow individually tailored therapeutic approaches. In line with this, we hypothesized that the gene expression profile of histologically normal epithelium (HNEpi) could harbor certain genetic abnormalities predisposing breast tissue cells to develop human epidermal growth factor receptor 2 (HER2)‑positive BC. Thus, the aim of the present study was to assess gene expression in normal and BC tissue (BCTis) from patients with BC in order to establish its value as a potential diagnostic marker for cancer development. An array study evaluating a panel of 84 pathway‑ and disease‑specific genes in HER2‑positive BC and tumor‑adjacent HNEpi was performed using quantitative polymerase chain reaction in 12 patients using microdissected samples from frozen tissue. Common prognostic and predictive parameters of BC were assessed by immunohistochemistry and in situ hybridization. In the BCTis and HNEpi samples of 12 HER2‑positive subjects with BC, the expression of 2,016 genes was assessed. A total of 39.3% of genes were deregulated at a minimal two‑fold deregulation rate and 10.7% at a five‑fold deregulation rate in samples of HNEpi or BCTis. Significant differences in gene expression between BCTis and HNEpi samples were revealed for BCL2L2, CD44, CTSD, EGFR, ERBB2, ITGA6, NGFB, RPL27, SCBG2A1 and SCGB1D2 genes (Pbreast tissue revealed gene expression abnormalities that may represent potential markers of increased risk for HER2‑positive malignant transformation of breast tissue, and may be able to be employed as predictors of prognosis.

  14. Study of electron densities of normal and neoplastic human breast tissues by Compton scattering using synchrotron radiation

    Energy Technology Data Exchange (ETDEWEB)

    Antoniassi, M.; Conceicao, A.L.C. [Departamento de Fisica-Faculdade de Filosofia Ciencias e Letras de Ribeirao Preto-Universidade de Sao Paulo, Ribeirao Preto, Sao Paulo (Brazil); Poletti, M.E., E-mail: poletti@ffclrp.usp.br [Departamento de Fisica-Faculdade de Filosofia Ciencias e Letras de Ribeirao Preto-Universidade de Sao Paulo, Ribeirao Preto, Sao Paulo (Brazil)

    2012-07-15

    Electron densities of 33 samples of normal (adipose and fibroglangular) and neoplastic (benign and malignant) human breast tissues were determined through Compton scattering data using a monochromatic synchrotron radiation source and an energy dispersive detector. The area of Compton peaks was used to determine the electron densities of the samples. Adipose tissue exhibits the lowest values of electron density whereas malignant tissue the highest. The relationship with their histology was discussed. Comparison with previous results showed differences smaller than 4%. - Highlights: Black-Right-Pointing-Pointer Electron density of normal and neoplastic breast tissues was measured using Compton scattering. Black-Right-Pointing-Pointer Monochromatic synchrotron radiation was used to obtain the Compton scattering data. Black-Right-Pointing-Pointer The area of Compton peaks was used to determine the electron densities of samples. Black-Right-Pointing-Pointer Adipose tissue shows the lowest electron density values whereas the malignant tissue the highest. Black-Right-Pointing-Pointer Comparison with previous results showed differences smaller than 4%.

  15. Study of electron densities of normal and neoplastic human breast tissues by Compton scattering using synchrotron radiation

    International Nuclear Information System (INIS)

    Antoniassi, M.; Conceição, A.L.C.; Poletti, M.E.

    2012-01-01

    Electron densities of 33 samples of normal (adipose and fibroglangular) and neoplastic (benign and malignant) human breast tissues were determined through Compton scattering data using a monochromatic synchrotron radiation source and an energy dispersive detector. The area of Compton peaks was used to determine the electron densities of the samples. Adipose tissue exhibits the lowest values of electron density whereas malignant tissue the highest. The relationship with their histology was discussed. Comparison with previous results showed differences smaller than 4%. - Highlights: ► Electron density of normal and neoplastic breast tissues was measured using Compton scattering. ► Monochromatic synchrotron radiation was used to obtain the Compton scattering data. ► The area of Compton peaks was used to determine the electron densities of samples. ► Adipose tissue shows the lowest electron density values whereas the malignant tissue the highest. ► Comparison with previous results showed differences smaller than 4%.

  16. The APC tumor suppressor is required for epithelial cell polarization and three-dimensional morphogenesis

    Science.gov (United States)

    Lesko, Alyssa C.; Goss, Kathleen H.; Yang, Frank F.; Schwertner, Adam; Hulur, Imge; Onel, Kenan; Prosperi, Jenifer R.

    2015-01-01

    The Adenomatous Polyposis Coli (APC) tumor suppressor has been previously implicated in the control of apical-basal polarity; yet, the consequence of APC loss-of-function in epithelial polarization and morphogenesis has not been characterized. To test the hypothesis that APC is required for the establishment of normal epithelial polarity and morphogenesis programs, we generated APC-knockdown epithelial cell lines. APC depletion resulted in loss of polarity and multi-layering on permeable supports, and enlarged, filled spheroids with disrupted polarity in 3D culture. Importantly, these effects of APC knockdown were independent of Wnt/β-catenin signaling, but were rescued with either full-length or a carboxy (c)-terminal segment of APC. Moreover, we identified a gene expression signature associated with APC knockdown that points to several candidates known to regulate cell-cell and cell-matrix communication. Analysis of epithelial tissues from mice and humans carrying heterozygous APC mutations further support the importance of APC as a regulator of epithelial behavior and tissue architecture. These data also suggest that the initiation of epithelial-derived tumors as a result of APC mutation or gene silencing may be driven by loss of polarity and dysmorphogenesis. PMID:25578398

  17. [Fibrocystic breast disease--breast cancer sequence].

    Science.gov (United States)

    Habor, V; Habor, A; Copotoiu, C; Panţîru, A

    2010-01-01

    Fibrocystic breast disease has developed a major issue: the breast cancer sequence. Its involvement regarding the increse of breast cancer risk has 2 aspects: it may be either the marker of a prone tissue or a premalignant hystological deffect. Difficult differential diagnosis of benign proliferative breast lession and carcinoma led to the idea of sequency between the two: cancer does not initiate on normal mammary epithelia; it takes several proliferative stages for it to occur. In our series we analized a number of 677 breast surgical procedures where the pathologic examination reveals 115 cases (17%) of coexistence between cancer and fibrocystic breast disease. This aspect has proved to be related to earlier debut of breast cancer, suggesting that epithelial hyperplasia is a risk factor for breast cancer.

  18. Morphogenesis in bat wings: linking development, evolution and ecology.

    Science.gov (United States)

    Adams, Rick A

    2008-01-01

    The evolution of powered flight in mammals required specific developmental shifts from an ancestral limb morphology to one adapted for flight. Through studies of comparative morphogenesis, investigators have quantified points and rates of divergence providing important insights into how wings evolved in mammals. Herein I compare growth,development and skeletogenesis of forelimbs between bats and the more ancestral state provided by the rat (Rattus norvegicus)and quantify growth trajectories that illustrate morphological divergence both developmentally and evolutionarily. In addition, I discuss how wing shape is controlled during morphogenesis by applying multivariate analyses of wing bones and wing membranes and discuss how flight dynamics are stabilized during flight ontogeny. Further, I discuss the development of flight in bats in relation to the ontogenetic niche and how juveniles effect populational foraging patterns. In addition, I provide a hypothetical ontogenetic landscape model that predicts how and when selection is most intense during juvenile morphogenesis and test this model with data from a population of the little brown bat, Myotis lucifugus. (c) 2007 S. Karger AG, Basel

  19. Ret and Etv4 Promote Directed Movements of Progenitor Cells during Renal Branching Morphogenesis.

    Directory of Open Access Journals (Sweden)

    Paul Riccio

    2016-02-01

    Full Text Available Branching morphogenesis of the epithelial ureteric bud forms the renal collecting duct system and is critical for normal nephron number, while low nephron number is implicated in hypertension and renal disease. Ureteric bud growth and branching requires GDNF signaling from the surrounding mesenchyme to cells at the ureteric bud tips, via the Ret receptor tyrosine kinase and coreceptor Gfrα1; Ret signaling up-regulates transcription factors Etv4 and Etv5, which are also critical for branching. Despite extensive knowledge of the genetic control of these events, it is not understood, at the cellular level, how renal branching morphogenesis is achieved or how Ret signaling influences epithelial cell behaviors to promote this process. Analysis of chimeric embryos previously suggested a role for Ret signaling in promoting cell rearrangements in the nephric duct, but this method was unsuited to study individual cell behaviors during ureteric bud branching. Here, we use Mosaic Analysis with Double Markers (MADM, combined with organ culture and time-lapse imaging, to trace the movements and divisions of individual ureteric bud tip cells. We first examine wild-type clones and then Ret or Etv4 mutant/wild-type clones in which the mutant and wild-type sister cells are differentially and heritably marked by green and red fluorescent proteins. We find that, in normal kidneys, most individual tip cells behave as self-renewing progenitors, some of whose progeny remain at the tips while others populate the growing UB trunks. In Ret or Etv4 MADM clones, the wild-type cells generated at a UB tip are much more likely to remain at, or move to, the new tips during branching and elongation, while their Ret-/- or Etv4-/- sister cells tend to lag behind and contribute only to the trunks. By tracking successive mitoses in a cell lineage, we find that Ret signaling has little effect on proliferation, in contrast to its effects on cell movement. Our results show that Ret

  20. The Differential Expression of Aqueous Soluble Proteins in Breast Normal and Cancerous Tissues in Relation to Ethnicity of the Patients; Chinese, Malay and Indian

    Directory of Open Access Journals (Sweden)

    Seng Liang

    2010-01-01

    Full Text Available Female breast cancer is one of the leading causes of female mortality worldwide. In Malaysia, breast cancer is the most commonly diagnosed cancer in women. Of the women in Malaysia, the Chinese have the highest number of breast cancer cases, followed by the Indian and the Malay. The most common type of breast cancer is infiltrating ductal carcinoma (IDC. A proteomic approach was applied in this study to identify changes in the protein profile of cancerous tissues compared with normal tissues from 18 patients; 8 Chinese, 6 Malay and 4 Indian were analysed. Twenty-four differentially expressed hydrophilic proteins were identified. We evaluated the potential of these proteins as biomarkers for infiltrating ductal carcinoma based on their ethnic-specific expressions. Three of the upregulated proteins, calreticulin, 14-3-3 protein zeta and 14-3-3 protein eta, were found to be expressed at a significantly higher level in the cancerous breast tissues when compared with the normal tissues in cases of infiltrating ductal carcinoma. The upregulation in expression was particularly dominant in the Malay cohort.

  1. Normal Axillary Lymph Node Variability Between White and Black Women on Breast MRI.

    Science.gov (United States)

    Grimm, Lars J; Viradia, Neal K; Johnson, Karen S

    2018-03-01

    This study aimed to determine if there were differences in the imaging features of normal lymph nodes between white and black women using magnetic resonance imaging. Following institutional review board approval, we identified white and black women who underwent breast magnetic resonance imaging from November 1, 2008 to December 31, 2013 at our institution. To identify normal lymph nodes for measurement, patients with any benign or malignant causes for lymph node enlargement and patients with any subsequent breast cancer in the following 2 years were excluded. Black and white women were age matched at a 1:2 ratio. The largest lymph node in each axilla was measured for the long-axis length and maximal cortical thickness. Comparisons were made between white and black women using a conditional logistic regression to control for matching. There were 55 black women and 110 white women for analysis. The mean lymph node long-axis length was 14.7 ± 5.3 mm for black women and 14.4 ± 6.4 mm for white women (P = .678). The mean maximum cortical thickness was 3.3 ± 1.6 mm for black women and 2.6 ± 1.4 mm for Caucasian women (P < .001). A significantly higher percentage of black than white women had cortical thicknesses greater than threshold values of 3, 4, 5, 6, and 7 mm (P < .01 for all). The normal lymph node cortical thickness in black women is significantly greater than in white women, which should be considered when deciding to recommend a lymph node biopsy. Copyright © 2018 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

  2. The physiology of the normal human breast: an exploratory study.

    Science.gov (United States)

    Mills, Dixie; Gordon, Eva J; Casano, Ashley; Lahti, Sarah Michelle; Nguyen, Tinh; Preston, Alex; Tondre, Julie; Wu, Kuan; Yanase, Tiffany; Chan, Henry; Chia, David; Esfandiari, Mahtash; Himmel, Tiffany; Love, Susan M

    2011-12-01

    The physiology of the nonlactating human breast likely plays a key role in factors that contribute to the etiology of breast cancer and other breast conditions. Although there has been extensive research into the physiology of lactation, few reports explore the physiology of the resting mammary gland, including mechanisms by which compounds such as hormones, drugs, and potential carcinogens enter the breast ducts. The purpose of this study was to explore transport of exogenous drugs into ductal fluid in nonlactating women and determine if their concentrations in the fluid are similar to those observed in the breast milk of lactating women. We selected two compounds that have been well characterized during lactation, caffeine and cimetidine. Caffeine passively diffuses into breast milk, but cimetidine is actively transported and concentrated in breast milk. After ingestion of caffeine and cimetidine, 14 nonlactating subjects had blood drawn and underwent ductal lavage at five time points over 12 h to measure drug levels in the fluid and blood. The concentrations of both caffeine and cimetidine in lavage fluid were substantially less than those observed in breast milk. Our results support recent evidence that the cimetidine transporter is not expressed in the nonlactating mammary gland, and highlight intriguing differences in the physiology and molecular transport of the lactating and nonlactating breast. The findings of this exploratory study warrant further exploration into the physiology of the nonlactating mammary gland to elucidate factors involved in disease initiation and progression.

  3. TU-F-12A-09: GLCM Texture Analysis for Normal-Tissue Toxicity: A Prospective Ultrasound Study of Acute Toxicity in Breast-Cancer Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Liu, T; Yang, X; Curran, W; Torres, M [Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GA (United States)

    2014-06-15

    Purpose: To evaluate the morphologic and structural integrity of the breast glands using sonographic textural analysis, and identify potential early imaging signatures for radiation toxicity following breast-cancer radiotherapy (RT). Methods: Thirty-eight patients receiving breast RT participated in a prospective ultrasound imaging study. Each participant received 3 ultrasound scans: 1 week before RT (baseline), and at 6-week and 3-month follow-ups. Patients were imaged with a 10-MHz ultrasound on the four quadrant of the breast. A second order statistical method of texture analysis, called gray level co-occurrence matrix (GLCM), was employed to assess RT-induced breast-tissue toxicity. The region of interest (ROI) was 28 mm × 10 mm in size at a 10 mm depth under the skin. Twenty GLCM sonographic features, ratios of the irradiated breast and the contralateral breast, were used to quantify breast-tissue toxicity. Clinical assessment of acute toxicity was conducted using the RTOG toxicity scheme. Results: Ninety-seven ultrasound studies (776 images) were analyzed; and 5 out of 20 sonographic features showed significant differences (p < 0.05) among the baseline scans, the acute toxicity grade 1 and 2 groups. These sonographic features quantified the degree of tissue damage through homogeneity, heterogeneity, randomness, and symmetry. Energy ratio value decreased from 108±0.05 (normal) to 0.99±0.05 (Grade 1) and 0.84±0.04 (Grade 2); Entropy ratio value increased from 1.01±0.01 to 1.02±0.01 and 1.04±0.01; Contrast ratio value increased from 1.03±0.03 to 1.07±0.06 and 1.21±0.09; Variance ratio value increased from 1.06±0.03 to 1.20±0.04 and 1.42±0.10; Cluster Prominence ratio value increased from 0.98±0.02 to 1.01±0.04 and 1.25±0.07. Conclusion: This work has demonstrated that the sonographic features may serve as imaging signatures to assess radiation-induced normal tissue damage. While these findings need to be validated in a larger cohort, they suggest

  4. Study on the abnormal morphogenesis of the arterial end of the heart induced by neutron irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Hidaka, N [Hiroshima Univ. (Japan). Research Inst. for Nuclear Medicine and Biology

    1980-02-01

    Transposition complexes of the great arteries were frequently produced in rat embryonic hearts whose mothers were exposed to a single whole-body dose of 130 rad 14.1 MeV fast neutron radiation on 8 day after conception. To clarify the morphogenesis of transposition complexes, especially double outlet right ventricle (DORV), embryonic rat hearts were serially sectioned and were reconstructed photographically 13 to 16 days after conception, when truncal swelling, intercalated valve swelling, and conical ridges appeared. In the control group, all the hearts had a normal D (dextral) loop. In the experimental group, 82.6% of the hearts had a D loop, 11.3% had an L (levo) loop, and 5.9% had an A (anterior) loop. In this group, the D loop hearts were divided into normal, retarded, and abnormal. Most of the retarded hearts developed into abnormal hearts. The positional relationships between experimentally produced swelling and ridges are classified. Morphologic anomalies are formed in the truncoconal region and correspond to the site of and the quantitative changes of the swelling and ridges. Abnormality in the position and extent of the swelling and ridges is the most important characteristic in the morphogenesis of transposition complexes. The second most important characteristic is abnormality in the time of appearance and the extent and site of cell death in the conical septum. DORV is embryologically divided into two types: a type in which the great arteries are normally related and a type in which they are inversely related. The developmental process of the DORV is entirely different from that of the complete transposition of the great arteries.

  5. The Expression of the Zonula Adhaerens Protein PLEKHA7 Is Strongly Decreased in High Grade Ductal and Lobular Breast Carcinomas.

    Directory of Open Access Journals (Sweden)

    Jean-Christophe Tille

    Full Text Available PLEKHA7 is a junctional protein, which participates in a complex that stabilizes E-cadherin at the zonula adhaerens. Since E-cadherin is involved in epithelial morphogenesis, signaling, and tumor progression, we explored PLEKHA7 expression in cancer. PLEKHA7 expression was assessed in invasive ductal and lobular carcinomas of the breast by immunohistochemistry, immunofluorescence and quantitative RT-PCR. PLEKHA7 was detected at epithelial junctions of normal mammary ducts and lobules, and of tubular and micropapillary structures within G1 and G2 ductal carcinomas. At these junctions, the localization of PLEKHA7 was along the circumferential belt (zonula adhaerens, and only partially overlapping with that of E-cadherin, p120ctn and ZO-1, as shown previously in rodent tissues. PLEKHA7 immunolabeling was strongly decreased in G3 ductal carcinomas and undetectable in lobular carcinomas. PLEKHA7 mRNA was detected in both ductal and lobular carcinomas, with no observed correlation between mRNA levels and tumor type or grade. In summary, PLEKHA7 is a junctional marker of epithelial cells within tubular structures both in normal breast tissue and ductal carcinomas, and since PLEKHA7 protein but not mRNA expression is strongly decreased or lost in high grade ductal carcinomas and in lobular carcinomas, loss of PLEKHA7 is a newly characterized feature of these carcinomas.

  6. Comparative measurement of ghrelin, leptin, adiponectin, EGF and IGF-1 in breast milk of mothers with overweight/obese and normal-weight infants.

    Science.gov (United States)

    Khodabakhshi, A; Ghayour-Mobarhan, M; Rooki, H; Vakili, R; Hashemy, S-I; Mirhafez, S R; Shakeri, M-T; Kashanifar, R; Pourbafarani, R; Mirzaei, H; Dahri, M; Mazidi, M; Ferns, G; Safarian, M

    2015-05-01

    Obese infants are more susceptible to develop adulthood obesity and its related comorbidities. Previous studies have shown the presence of hormones and growth factors in maternal breast milk that may influence infant adiposity. The aim of this study was to investigate differences in concentrations of three hormones and two growth factors in the breast milk of mothers with obese and non-obese infants. In this cross-sectional study, 40 mothers with overweight or obese infants (weight for length percentile >97) and 40 age-matched mothers with normal-weight infant (-10 milk concentrations of ghrelin and adiponectin, leptin, epithelial growth factor (EGF) and insulin-like growth factor-1 (IGF-1) were measured using enzyme-linked immunosorbent assay methods. The mean breast milk concentration of ghrelin was higher in mothers with normal-weight infants, 137.50 pg/ml, than in mothers with obese infants, 132.00 pg/ml (P=0.001). This was also true regarding the concentration of EGF in mothers with (0/04 ng/ml) and without (0/038 ng/ml) normal-weight infants (P=0.01). No significant differences were observed in concentrations of leptin, adiponectin and IGF-1 between two groups (P > 0.05). There was also a significant positive correlation between EGF and ghrelin in both groups. This study revealed that there was a correlation between ghrelin and EGF level in breast milk of mothers with obese and non-obese infants, suggesting a possible regulatory effect of these two hormones on weight in infants.

  7. Expression of BMI-1 and Mel-18 in breast tissue--a diagnostic marker in patients with breast cancer.

    Science.gov (United States)

    Riis, Margit L H; Lüders, Torben; Nesbakken, Anne-Jorunn; Vollan, Hilde S; Kristensen, Vessela; Bukholm, Ida R K

    2010-12-16

    Polycomb Group (PcG) proteins are epigenetic silencers involved in maintaining cellular identity, and their deregulation can result in cancer. Expression of Mel-18 and Bmi-1 has been studied in tumor tissue, but not in adjacent non-cancerous breast epithelium. Our study compares the expression of the two genes in normal breast epithelium of cancer patients and relates it to the level of expression in the corresponding tumors as well as in breast epithelium of healthy women. A total of 79 tumors, of which 71 malignant tumors of the breast, 6 fibroadenomas, and 2 DCIS were studied and compared to the reduction mammoplastic specimens of 11 healthy women. In addition there was available adjacent cancer free tissue for 23 of the malignant tumors. The tissue samples were stored in RNAlater, RNA was isolated to create expression microarray profile. These two genes were then studied more closely first on mRNA transcription level by microarrays (Agilent 44 K) and quantitative RT-PCR (TaqMan) and then on protein expression level using immunohistochemistry. Bmi-1 mRNA is significantly up-regulated in adjacent normal breast tissue in breast cancer patients compared to normal breast tissue from noncancerous patients. Conversely, mRNA transcription level of Mel-18 is lower in normal breast from patients operated for breast cancer compared to breast tissue from mammoplasty. When protein expression of these two genes was evaluated, we observed that most of the epithelial cells were positive for Bmi-1 in both groups of tissue samples, although the expression intensity was stronger in normal tissue from cancer patients compared to mammoplasty tissue samples. Protein expression of Mel-18 showed inversely stronger intensity in tissue samples from mammoplasty compared to normal breast tissue from patients operated for breast cancer. Bmi-1 mRNA level is consistently increased and Mel-18 mRNA level is consistently decreased in adjacent normal breast tissue of cancer patients as compared

  8. Isotropic 3D nuclear morphometry of normal, fibrocystic and malignant breast epithelial cells reveals new structural alterations.

    Science.gov (United States)

    Nandakumar, Vivek; Kelbauskas, Laimonas; Hernandez, Kathryn F; Lintecum, Kelly M; Senechal, Patti; Bussey, Kimberly J; Davies, Paul C W; Johnson, Roger H; Meldrum, Deirdre R

    2012-01-01

    Grading schemes for breast cancer diagnosis are predominantly based on pathologists' qualitative assessment of altered nuclear structure from 2D brightfield microscopy images. However, cells are three-dimensional (3D) objects with features that are inherently 3D and thus poorly characterized in 2D. Our goal is to quantitatively characterize nuclear structure in 3D, assess its variation with malignancy, and investigate whether such variation correlates with standard nuclear grading criteria. We applied micro-optical computed tomographic imaging and automated 3D nuclear morphometry to quantify and compare morphological variations between human cell lines derived from normal, benign fibrocystic or malignant breast epithelium. To reproduce the appearance and contrast in clinical cytopathology images, we stained cells with hematoxylin and eosin and obtained 3D images of 150 individual stained cells of each cell type at sub-micron, isotropic resolution. Applying volumetric image analyses, we computed 42 3D morphological and textural descriptors of cellular and nuclear structure. We observed four distinct nuclear shape categories, the predominant being a mushroom cap shape. Cell and nuclear volumes increased from normal to fibrocystic to metastatic type, but there was little difference in the volume ratio of nucleus to cytoplasm (N/C ratio) between the lines. Abnormal cell nuclei had more nucleoli, markedly higher density and clumpier chromatin organization compared to normal. Nuclei of non-tumorigenic, fibrocystic cells exhibited larger textural variations than metastatic cell nuclei. At pfibrocystic from the metastatic cell populations. Our results provide a new perspective on nuclear structure variations associated with malignancy and point to the value of automated quantitative 3D nuclear morphometry as an objective tool to enable development of sensitive and specific nuclear grade classification in breast cancer diagnosis.

  9. Diagnosis of breast cancer by tissue analysis

    Institute of Scientific and Technical Information of China (English)

    Debnath Bhattacharyya; Samir Kumar Bandyopadhyay; Tai-hoon Kim

    2013-01-01

    In this paper,we propose a technique to locate abnormal growth of cells in breast tissue and suggest further pathological test,when require.We compare normal breast tissue with malignant invasive breast tissue by a series of image processing steps.Normal ductal epithelial cells and ductal/lobular invasive carcinogenic cells also consider for comparison here in this paper.In fact,features of cancerous breast tissue (invasive) are extracted and analyses with normal breast tissue.We also suggest the breast cancer recognition technique through image processing and prevention by controlling p53 gene mutation to some extent.

  10. Study of apparent diffusion coefficient value in the normal breastq

    International Nuclear Information System (INIS)

    Cai Shifeng

    2007-01-01

    Objective: To investigate the differences of apparent diffusion coefficient (ADC) value in normal breasts and to evaluate the correlation between ADC value and corresponding histology. Methods: Sixty-two normal breasts including 42 normal breasts of 42 patients with unilateral lesions and 20 normal breasts of 10 volunteers were studied. The ADC value of all 62 normal breasts were calculated when b value was given from 1000 to 0 s/mm 2 , 1000 to 500 s/mm 2 and 500 to 0 s/mm 2 . The MRI features of 60 normal breasts were classified into 3 types (dense, lobular-speckled, degenerative types) according to Wolf's classification and histology. Results: DWI and ADC images were different in 3 types of normal breasts because of different histologic structures. The mean ADC value of the dense type breasts was (1.70 ± 0.37) x 10 -3 mm 2 /s, the lobular-speckled type was (1.93 ± 0.46) x 10 -3 mm 2 /s and the degenerative type was (1.18 ± 0.65) x 10 -3 mm 2 /s (F=12.998, P=0.000). There were no significant differences between the dense type and the lobular-speckled type (F=2.167, P=0.147), but significant differences between the dense type and the degenerative type, the lobular-speckled type and the degenerate type (F=5.593 and 19.128; P=0.029 and 0.000). When b value decreased, the ADC value of the dense type and the lobular-speckled type increased correspondingly, but the degenerative type didn't increase apparently. Conclusion: ADC value was influenced by histologic structures in normal breasts and also was influenced by b value in the dense type and lobular-speckled type breasts. (authors)

  11. Slug controls stem/progenitor cell growth dynamics during mammary gland morphogenesis.

    Directory of Open Access Journals (Sweden)

    Mayssa Nassour

    Full Text Available Morphogenesis results from the coordination of distinct cell signaling pathways controlling migration, differentiation, apoptosis, and proliferation, along stem/progenitor cell dynamics. To decipher this puzzle, we focused on epithelial-mesenchymal transition (EMT "master genes". EMT has emerged as a unifying concept, involving cell-cell adhesion, migration and apoptotic pathways. EMT also appears to mingle with stemness. However, very little is known on the physiological role and relevance of EMT master-genes. We addressed this question during mammary morphogenesis. Recently, a link between Slug/Snai2 and stemness has been described in mammary epithelial cells, but EMT master genes actual localization, role and targets during mammary gland morphogenesis are not known and we focused on this basic question.Using a Slug-lacZ transgenic model and immunolocalization, we located Slug in a distinct subpopulation covering about 10-20% basal cap and duct cells, mostly cycling cells, coexpressed with basal markers P-cadherin, CK5 and CD49f. During puberty, Slug-deficient mammary epithelium exhibited a delayed development after transplantation, contained less cycling cells, and overexpressed CK8/18, ER, GATA3 and BMI1 genes, linked to luminal lineage. Other EMT master genes were overexpressed, suggesting compensation mechanisms. Gain/loss-of-function in vitro experiments confirmed Slug control of mammary epithelial cell luminal differentiation and proliferation. In addition, they showed that Slug enhances specifically clonal mammosphere emergence and growth, cell motility, and represses apoptosis. Strikingly, Slug-deprived mammary epithelial cells lost their potential to generate secondary clonal mammospheres.We conclude that Slug pathway controls the growth dynamics of a subpopulation of cycling progenitor basal cells during mammary morphogenesis. Overall, our data better define a key mechanism coordinating cell lineage dynamics and morphogenesis, and

  12. Evaluation of factors in development of Vis/NIR spectroscopy models for discriminating PSE, DFD and normal broiler breast meat

    Science.gov (United States)

    1. To evaluate the performance of visible and near-infrared (Vis/NIR) spectroscopic models for discriminating true pale, soft and exudative (PSE), normal and dark, firm and dry (DFD) broiler breast meat in different conditions of preprocessing methods, spectral ranges, characteristic wavelength sele...

  13. Mammary stem cell and macrophage markers are enriched in normal tissue adjacent to inflammatory breast cancer.

    Science.gov (United States)

    Reddy, Jay P; Atkinson, Rachel L; Larson, Richard; Burks, Jared K; Smith, Daniel; Debeb, Bisrat G; Ruffell, Brian; Creighton, Chad J; Bambhroliya, Arvind; Reuben, James M; Van Laere, Steven J; Krishnamurthy, Savitri; Symmans, William F; Brewster, Abenaa M; Woodward, Wendy A

    2018-06-01

    We hypothesized that breast tissue not involved by tumor in inflammatory breast cancer (IBC) patients contains intrinsic differences, including increased mammary stem cells and macrophage infiltration, which may promote the IBC phenotype. Normal breast parenchyma ≥ 5 cm away from primary tumors was obtained from mastectomy specimens. This included an initial cohort of 8 IBC patients and 60 non-IBC patients followed by a validation cohort of 19 IBC patients and 25 non-IBC patients. Samples were immunostained for either CD44 + CD49f + CD133/2 + mammary stem cell markers or the CD68 macrophage marker and correlated with IBC status. Quantitation of positive cells was determined using inForm software from PerkinElmer. We also examined the association between IBC status and previously published tumorigenic stem cell and IBC tumor signatures in the validation cohort samples. 8 of 8 IBC samples expressed isolated CD44 + CD49f + CD133/2 + stem cell marked cells in the initial cohort as opposed to 0/60 non-IBC samples (p = 0.001). Similarly, the median number of CD44 + CD49f + CD133/2 + cells was significantly higher in the IBC validation cohort as opposed to the non-IBC validation cohort (25.7 vs. 14.2, p = 0.007). 7 of 8 IBC samples expressed CD68 + histologically confirmed macrophages in initial cohort as opposed to 12/48 non-IBC samples (p = 0.001). In the validation cohort, the median number of CD68 + cells in IBC was 3.7 versus 1.0 in the non-IBC cohort (p = 0.06). IBC normal tissue was positively associated with a tumorigenic stem cell signature (p = 0.02) and with a 79-gene IBC signature (p stem cell signature and IBC-specific tumor signature. Collectively, these data suggest that IBC normal tissue differs from non-IBC tissue. Whether these changes occur before the tumor develops or is induced by tumor warrants further investigation.

  14. Epimorphin mediates mammary luminal morphogenesis through control of C/EBPbeta

    International Nuclear Information System (INIS)

    Hirai, Yohei; Radisky, Derek; Boudreau, Rosanne; Simian, Marina; Stevens, Mary E.; Oka, Yumiko; Takebe, Kyoko; Niwa, Shinichiro; Bissell, Mina J.

    2002-01-01

    We have previously shown that epimorphin, a protein expressed on the surface of myoepithelial and fibroblast cells of the mammary gland, acts as a multifunctional morphogen of mammary epithelial cells. Here, we present the molecular mechanism by which epimorphin mediates luminal morphogenesis. Treatment of cells with epimorphin to induce lumen formation greatly increases the overall expression of transcription factor CCAAT/enhancer binding protein beta (C/EBPbeta) and alters the relative expression of its two principal isoforms, LIP and LAP. These alterations were shown to be essential for the morphogenetic activities, as constitutive expression of LIP was sufficient to produce lumen formation, while constitutive expression of LAP blocked epimorphin-mediated luminal morphogenesis. Furthermore, in a transgenic mouse model in which epimorphin expression was expressed in an apolar fashion on the surface of mammary epithelial cells, we found increased expression of C/EBPbeta, increased relative expression of LIP to LAP, and enlarged ductal lumina. Together, our studies demonstrate a role for epimorphin in luminal morphogenesis through control of C/EBPbeta expression

  15. Breast Reconstruction with Flap Surgery

    Science.gov (United States)

    ... augmented with a breast implant to achieve the desired breast size. Surgical methods Autologous tissue breast reconstruction ... as long as a year or two before feeling completely healed and back to normal. Future breast ...

  16. The ureteric bud epithelium: morphogenesis and roles in metanephric kidney patterning.

    Science.gov (United States)

    Nagalakshmi, Vidya K; Yu, Jing

    2015-03-01

    The mammalian metanephric kidney is composed of two epithelial components, the collecting duct system and the nephron epithelium, that differentiate from two different tissues -the ureteric bud epithelium and the nephron progenitors, respectively-of intermediate mesoderm origin. The collecting duct system is generated through reiterative ureteric bud branching morphogenesis, whereas the nephron epithelium is formed in a process termed nephrogenesis, which is initiated with the mesenchymal-epithelial transition of the nephron progenitors. Ureteric bud branching morphogenesis is regulated by nephron progenitors, and in return, the ureteric bud epithelium regulates nephrogenesis. The metanephric kidney is physiologically divided along the corticomedullary axis into subcompartments that are enriched with specific segments of these two epithelial structures. Here, we provide an overview of the major molecular and cellular processes underlying the morphogenesis and patterning of the ureteric bud epithelium and its roles in the cortico-medullary patterning of the metanephric kidney. © 2015 Wiley Periodicals, Inc.

  17. LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling

    DEFF Research Database (Denmark)

    Chang, Joan; Nicolau, Monica; Cox, Thomas R

    2013-01-01

    Lysyl oxidase-like 2 (LOXL2) is a matrix remodeling enzyme that has been shown to play a key role in invasion and metastasis of breast carcinoma cells. However, very little is known about its role in normal tissue homeostasis. Here, we investigate the effects of LOXL2 expression in normal mammary...... epithelial cells in order to gain insight into how LOXL2 mediates cancer progression....

  18. Melatonin Inhibits Embryonic Salivary Gland Branching Morphogenesis by Regulating Both Epithelial Cell Adhesion and Morphology

    Science.gov (United States)

    Miura, Jiro; Sakai, Manabu; Uchida, Hitoshi; Nakamura, Wataru; Nohara, Kanji; Maruyama, Yusuke; Hattori, Atsuhiko; Sakai, Takayoshi

    2015-01-01

    Many organs, including salivary glands, lung, and kidney, are formed by epithelial branching during embryonic development. Branching morphogenesis occurs via either local outgrowths or the formation of clefts that subdivide epithelia into buds. This process is promoted by various factors, but the mechanism of branching morphogenesis is not fully understood. Here we have defined melatonin as a potential negative regulator or “brake” of branching morphogenesis, shown that the levels of it and its receptors decline when branching morphogenesis begins, and identified the process that it regulates. Melatonin has various physiological functions, including circadian rhythm regulation, free-radical scavenging, and gonadal development. Furthermore, melatonin is present in saliva and may have an important physiological role in the oral cavity. In this study, we found that the melatonin receptor is highly expressed on the acinar epithelium of the embryonic submandibular gland. We also found that exogenous melatonin reduces salivary gland size and inhibits branching morphogenesis. We suggest that this inhibition does not depend on changes in either proliferation or apoptosis, but rather relates to changes in epithelial cell adhesion and morphology. In summary, we have demonstrated a novel function of melatonin in organ formation during embryonic development. PMID:25876057

  19. Apoptosis during budding morphogenesis of dentition

    Czech Academy of Sciences Publication Activity Database

    Peterková, Renata; Peterka, Miroslav; Viriot, L.; Lesot, H.

    2002-01-01

    Roč. 70, č. 7 (2002), s. 353 ISSN 0301-4681. [International Conference of the International Society of Differentiation /12./. Lyon, France, 14.09.2002-17.09.2002] R&D Projects: GA ČR GA304/02/0448 Institutional research plan: CEZ:AV0Z5039906 Keywords : morphogenesis of dentition Subject RIV: FF - HEENT, Dentistry Impact factor: 2.078, year: 2002

  20. Drosophila convoluted/dALS is an essential gene required for tracheal tube morphogenesis and apical matrix organization.

    Science.gov (United States)

    Swanson, Lianna E; Yu, Marcus; Nelson, Kevin S; Laprise, Patrick; Tepass, Ulrich; Beitel, Greg J

    2009-04-01

    Insulin-like growth factors (IGFs) control cell and organism growth through evolutionarily conserved signaling pathways. The mammalian acid-labile subunit (ALS) is a secreted protein that complexes with IGFs to modulate their activity. Recent work has shown that a Drosophila homolog of ALS, dALS, can also complex with and modulate the activity of a Drosophila IGF. Here we report the first mutations in the gene encoding dALS. Unexpectedly, we find that these mutations are allelic to a previously described mutation in convoluted (conv), a gene required for epithelial morphogenesis. In conv mutants, the tubes of the Drosophila tracheal system become abnormally elongated without altering tracheal cell number. conv null mutations cause larval lethality, but do not disrupt several processes required for tracheal tube size control, including septate junction formation, deposition of a lumenal/apical extracellular matrix, and lumenal secretion of Vermiform and Serpentine, two putative matrix-modifying proteins. Clearance of lumenal matrix and subcellular localization of clathrin also appear normal in conv mutants. However, we show that Conv/dALS is required for the dynamic organization of the transient lumenal matrix and normal structure of the cuticle that lines the tracheal lumen. These and other data suggest that the Conv/dALS-dependent tube size control mechanism is distinct from other known processes involved in tracheal tube size regulation. Moreover, we present evidence indicating that Conv/dALS has a novel, IGF-signaling independent function in tracheal morphogenesis.

  1. Feature Extraction and Analysis of Breast Cancer Specimen

    Science.gov (United States)

    Bhattacharyya, Debnath; Robles, Rosslin John; Kim, Tai-Hoon; Bandyopadhyay, Samir Kumar

    In this paper, we propose a method to identify abnormal growth of cells in breast tissue and suggest further pathological test, if necessary. We compare normal breast tissue with malignant invasive breast tissue by a series of image processing steps. Normal ductal epithelial cells and ductal / lobular invasive carcinogenic cells also consider for comparison here in this paper. In fact, features of cancerous breast tissue (invasive) are extracted and analyses with normal breast tissue. We also suggest the breast cancer recognition technique through image processing and prevention by controlling p53 gene mutation to some greater extent.

  2. Plasmacytoma of the Breast

    African Journals Online (AJOL)

    GB

    2015-10-04

    Oct 4, 2015 ... The clinical diagnosis of a breast plasmacytoma is ... lead to a diagnosis of breast plasmacytoma (1-3). Bone marrow ... breast cancer cases present at an advanced stage, ... pelvic ultrasonography, were normal, Bence Jones.

  3. Ectopic expression of Msx-2 in posterior limb bud mesoderm impairs limb morphogenesis while inducing BMP-4 expression, inhibiting cell proliferation, and promoting apoptosis.

    Science.gov (United States)

    Ferrari, D; Lichtler, A C; Pan, Z Z; Dealy, C N; Upholt, W B; Kosher, R A

    1998-05-01

    expression of BMP-4, a secreted signaling molecule that is coexpressed with Msx-2 during normal limb development in the anterior limb mesoderm, the posterior necrotic zone, and interdigital mesenchyme. This indicates that Msx-2 regulates BMP-4 expression and that the suppressive effects of Msx-2 on limb morphogenesis might be mediated in part by BMP-4. These studies indicate that during normal limb development Msx-2 is a key component of a regulatory network that delimits the boundaries of the progress zone by suppressing the morphogenesis of the regions of the limb mesoderm in which it is highly expressed, thus restricting the outgrowth and formation of skeletal elements and associated structures to the progress zone. We also report that rather large numbers of apoptotic cells as well as proliferating cells are present throughout the AER during all stages of normal limb development we have examined, indicating that many of the cells of the AER are continuously undergoing programmed cell death at the same time that new AER cells are being generated by cell proliferation. Thus, a balance between cell proliferation and programmed cell death may play a very important role in maintaining the activity of the AER. Copyright 1998 Academic Press.

  4. Embryo mechanics: balancing force production with elastic resistance during morphogenesis.

    Science.gov (United States)

    Davidson, Lance A

    2011-01-01

    Morphogenesis requires the spatial and temporal control of embryo mechanics, including force production and mechanical resistance to those forces, to coordinate tissue deformation and large-scale movements. Thus, biomechanical processes play a key role in directly shaping the embryo. Additional roles for embryo mechanics during development may include the patterning of positional information and to provide feedback to ensure the success of morphogenetic movements in shaping the larval body and organs. To understand the multiple roles of mechanics during development requires familiarity with engineering principles of the mechanics of structures, the viscoelastic properties of biomaterials, and the integration of force and stress within embryonic structures as morphogenesis progresses. In this chapter, we review the basic engineering principles of biomechanics as they relate to morphogenesis, introduce methods for quantifying embryo mechanics and the limitations of these methods, and outline a formalism for investigating the role of embryo mechanics in birth defects. We encourage the nascent field of embryo mechanics to adopt standard engineering terms and test methods so that studies of diverse organisms can be compared and universal biomechanical principles can be revealed. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. Inheritance of proliferative breast disease in breast cancer kindreds

    International Nuclear Information System (INIS)

    Skolnick, M.H.; Cannon-Albright, L.A.; Goldgar, D.E.; Ward, J.H.; Marshall, C.J.; Schumann, G.B.; Hogle, H.; McWhorter, W.P.; Wright, E.C.; Tran, T.D.; Bishop, D.T.; Kushner, J.P.; Eyre, H.J.

    1990-01-01

    Previous studies have emphasized that genetic susceptibility to breast cancer is rare and is expressed primarily as premenopausal breast cancer, bilateral breast cancer, or both. Proliferative breast disease (PBD) is a significant risk factor for the development of breast cancer and appears to be a precursor lesion. PBD and breast cancer were studied in 103 women from 20 kindreds that were selected for the presence of two first degree relatives with breast cancer and in 31 control women. Physical examination, screening mammography, and four-quadrant fine-needle breast aspirates were performed. Cytologic analysis of breast aspirates revealed PBD in 35% of clinically normal female first degree relatives of breast cancer cases and in 13% of controls. Genetic analysis suggests that genetic susceptibility causes both PBD and breast cancer in these kindreds. This study supports the hypothesis that this susceptibility is responsible for a considerable portion of breast cancer, including unilateral and postmenopausal breast cancer

  6. INHIBITION OF SPONTANEOUS APOPTOSIS IN HUMAN BREAST CANCER

    Institute of Scientific and Technical Information of China (English)

    邵志敏; 江明; 吴炅; 余黎民; 韩企夏; 张延璆; 沈镇宙

    1996-01-01

    Breast tumorigenesis proceeds through an accumulation of specific genetic alteration. Breast malignant transformation is dependent on not only the rate of cell production but also on apoptcsis,a genetically prograined process of autonomous ceil death. We investigated whether breast tumorigenesis involved an altered susceptibility to apoptosis and proliferation by examining normal breast epithelium and breast cancer sampies. We found there is a great inhibition of spontaneous apoptosis in breast cancer ceils compared with normal breast epithelium. The inhibition of apoptosis in breast cancer may contribute to neoplastic transformation.

  7. Isotropic 3D nuclear morphometry of normal, fibrocystic and malignant breast epithelial cells reveals new structural alterations.

    Directory of Open Access Journals (Sweden)

    Vivek Nandakumar

    Full Text Available Grading schemes for breast cancer diagnosis are predominantly based on pathologists' qualitative assessment of altered nuclear structure from 2D brightfield microscopy images. However, cells are three-dimensional (3D objects with features that are inherently 3D and thus poorly characterized in 2D. Our goal is to quantitatively characterize nuclear structure in 3D, assess its variation with malignancy, and investigate whether such variation correlates with standard nuclear grading criteria.We applied micro-optical computed tomographic imaging and automated 3D nuclear morphometry to quantify and compare morphological variations between human cell lines derived from normal, benign fibrocystic or malignant breast epithelium. To reproduce the appearance and contrast in clinical cytopathology images, we stained cells with hematoxylin and eosin and obtained 3D images of 150 individual stained cells of each cell type at sub-micron, isotropic resolution. Applying volumetric image analyses, we computed 42 3D morphological and textural descriptors of cellular and nuclear structure.We observed four distinct nuclear shape categories, the predominant being a mushroom cap shape. Cell and nuclear volumes increased from normal to fibrocystic to metastatic type, but there was little difference in the volume ratio of nucleus to cytoplasm (N/C ratio between the lines. Abnormal cell nuclei had more nucleoli, markedly higher density and clumpier chromatin organization compared to normal. Nuclei of non-tumorigenic, fibrocystic cells exhibited larger textural variations than metastatic cell nuclei. At p<0.0025 by ANOVA and Kruskal-Wallis tests, 90% of our computed descriptors statistically differentiated control from abnormal cell populations, but only 69% of these features statistically differentiated the fibrocystic from the metastatic cell populations.Our results provide a new perspective on nuclear structure variations associated with malignancy and point to the

  8. FLI1 Expression in Breast Cancer Cell Lines and Primary Breast Carcinomas is Correlated with ER, PR and HER2

    Directory of Open Access Journals (Sweden)

    Inam Jasim Lafta

    2017-12-01

    Full Text Available FLI1 is a member of ETS family of transcription factors that regulate a variety of normal biologic activities including cell proliferation, differentiation, and apoptosis. The expression of FLI1 and its correlation with well-known breast cancer prognostic markers (ER, PR and HER2 was determined in primary breast tumors as well as four breast cancer lines including: MCF-7, T47D, MDA-MB-231 and MDA-MB-468 using RT-qPCR with either 18S rRNA or ACTB (β-actin for normalization of data. FLI1 mRNA level was decreased in the breast cancer cell lines under study compared to the normal breast tissue; however, Jurkat cells, which were used as a positive control, showed overexpression compared to the normal breast. Regarding primary breast carcinomas, FLI1 is significantly under expressed in all of the stages of breast cancer upon using 18S as an internal control. This FLI1 expression was correlated with ER, PR and HER2 status. In conclusion FLI1 can be exploited as a preliminary marker that can predict the status of ER, PR and HER2 in primary breast tumors.

  9. PAR-Complex and Crumbs Function During Photoreceptor Morphogenesis and Retinal Degeneration.

    Science.gov (United States)

    Pichaud, Franck

    2018-01-01

    The fly photoreceptor has long been used as a model to study sensory neuron morphogenesis and retinal degeneration. In particular, elucidating how these cells are built continues to help further our understanding of the mechanisms of polarized cell morphogenesis, intracellular trafficking and the causes of human retinal pathologies. The conserved PAR complex, which in flies consists of Cdc42-PAR6-aPKC-Bazooka, and the transmembrane protein Crumbs (Crb) are key players during photoreceptor morphogenesis. While the PAR complex regulates polarity in many cell types, Crb function in polarity is relatively specific to epithelial cells. Together Cdc42-PAR6-aPKC-Bazooka and Crb orchestrate the differentiation of the photoreceptor apical membrane (AM) and zonula adherens (ZA) , thus allowing these cells to assemble into a neuro-epithelial lattice. In addition to its function in epithelial polarity, Crb has also been shown to protect fly photoreceptors from light-induced degeneration, a process linked to Rhodopsin expression and trafficking. Remarkably, mutations in the human Crumbs1 (CRB1) gene lead to retinal degeneration, making the fly photoreceptor a powerful disease model system.

  10. Occult Breast Cancer: Scintimammography with High-Resolution Breast-specific Gamma Camera in Women at High Risk for Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Rachel F. Brem; Jocelyn A. Rapelyea; , Gilat Zisman; Kevin Mohtashemi; Joyce Raub; Christine B. Teal; Stan Majewski; Benjamin L. Welch

    2005-08-01

    To prospectively evaluate a high-resolution breast-specific gamma camera for depicting occult breast cancer in women at high risk for breast cancer but with normal mammographic and physical examination findings. MATERIALS AND METHODS: Institutional Review Board approval and informed consent were obtained. The study was HIPAA compliant. Ninety-four high-risk women (age range, 36-78 years; mean, 55 years) with normal mammographic (Breast Imaging Reporting and Data System [BI-RADS] 1 or 2) and physical examination findings were evaluated with scintimammography. After injection with 25-30 mCi (925-1110 MBq) of technetium 99m sestamibi, patients were imaged with a high-resolution small-field-of-view breast-specific gamma camera in craniocaudal and mediolateral oblique projections. Scintimammograms were prospectively classified according to focal radiotracer uptake as normal (score of 1), with no focal or diffuse uptake; benign (score of 2), with minimal patchy uptake; probably benign (score of 3), with scattered patchy uptake; probably abnormal (score of 4), with mild focal radiotracer uptake; and abnormal (score of 5), with marked focal radiotracer uptake. Mammographic breast density was categorized according to BI-RADS criteria. Patients with normal scintimammograms (scores of 1, 2, or 3) were followed up for 1 year with an annual mammogram, physical examination, and repeat scintimammography. Patients with abnormal scintimammograms (scores of 4 or 5) underwent ultrasonography (US), and those with focal hypoechoic lesions underwent biopsy. If no lesion was found during US, patients were followed up with scintimammography. Specific pathologic findings were compared with scintimammographic findings. RESULTS: Of 94 women, 78 (83%) had normal scintimammograms (score of 1, 2, or 3) at initial examination and 16 (17%) had abnormal scintimammograms (score of 4 or 5). Fourteen (88%) of the 16 patients had either benign findings at biopsy or no focal abnormality at US; in two

  11. Occult Breast Cancer: Scintimammography with High-Resolution Breast-specific Gamma Camera in Women at High Risk for Breast Cancer

    International Nuclear Information System (INIS)

    Rachel F. Brem; Jocelyn A. Rapelyea; , Gilat Zisman; Kevin Mohtashemi; Joyce Raub; Christine B. Teal; Stan Majewski; Benjamin L. Welch

    2005-01-01

    To prospectively evaluate a high-resolution breast-specific gamma camera for depicting occult breast cancer in women at high risk for breast cancer but with normal mammographic and physical examination findings. MATERIALS AND METHODS: Institutional Review Board approval and informed consent were obtained. The study was HIPAA compliant. Ninety-four high-risk women (age range, 36-78 years; mean, 55 years) with normal mammographic (Breast Imaging Reporting and Data System [BI-RADS] 1 or 2) and physical examination findings were evaluated with scintimammography. After injection with 25-30 mCi (925-1110 MBq) of technetium 99m sestamibi, patients were imaged with a high-resolution small-field-of-view breast-specific gamma camera in craniocaudal and mediolateral oblique projections. Scintimammograms were prospectively classified according to focal radiotracer uptake as normal (score of 1), with no focal or diffuse uptake; benign (score of 2), with minimal patchy uptake; probably benign (score of 3), with scattered patchy uptake; probably abnormal (score of 4), with mild focal radiotracer uptake; and abnormal (score of 5), with marked focal radiotracer uptake. Mammographic breast density was categorized according to BI-RADS criteria. Patients with normal scintimammograms (scores of 1, 2, or 3) were followed up for 1 year with an annual mammogram, physical examination, and repeat scintimammography. Patients with abnormal scintimammograms (scores of 4 or 5) underwent ultrasonography (US), and those with focal hypoechoic lesions underwent biopsy. If no lesion was found during US, patients were followed up with scintimammography. Specific pathologic findings were compared with scintimammographic findings. RESULTS: Of 94 women, 78 (83%) had normal scintimammograms (score of 1, 2, or 3) at initial examination and 16 (17%) had abnormal scintimammograms (score of 4 or 5). Fourteen (88%) of the 16 patients had either benign findings at biopsy or no focal abnormality at US; in two

  12. Relationship between in vitro chromosomal radiosensitivity of peripheral blood lymphocytes and the expression of normal tissue damage following radiotherapy for breast cancer

    International Nuclear Information System (INIS)

    Barber, J.B.P.; Burrill, W.; Spreadborough, A.R.; Levine, E.; Warren, C.; Scott, D.; Kiltie, A.E.; Roberts, S.A.

    2000-01-01

    There is a need for rapid and reliable tests for the prediction of normal tissue responses to radiotherapy, as this could lead to individualization of patient radiotherapy schedules and thus improvements in the therapeutic ratio. Because the use of cultured fibroblasts is too slow to be practicable in a clinical setting, we evaluated the predictive role of assays of lymphocyte chromosomal radiosensitivity in patients having radiotherapy for breast cancer. Radiosensitivity was assessed using a macronucleus (MN) assay at high dose rate (HDR) and low dose rate (LDR) on lymphocytes irradiated in the G 0 phase of the cell cycle (Scott D, Barber JB, Levine EL, Burril W, Roberts SA. Radiation-induced micronucleus induction in lymphocytes identifies a frequency of radiosensitive cases among breast cancer patients: a test for predisposition? Br. J. Cancer 1998;77;614-620) and an assay of G 2 phase chromatid radiosensitivity ('G 2 assay') (Scott D, Spreadborough A, Levine E, Roberts SA. Genetic predisposition in breast cancer. Lancet 1994; 344: 1444). In a study of acute reactions, blood samples were taken from breast cancer patients before the start of radiotherapy, and the skin reaction documented. 116 patients were tested with the HDR MN assay, 73 with the LDR MN assay and 123 with the G 2 assay. In a study of late reactions, samples were taken from a series of breast cancer patients 8-14 years after radiotherapy and the patients assessed for the severity of late effects according to the 'LENT SOMA' scales. 47 were tested with the HDR assay, 26 with the LDR assay and 19 with the G 2 assay. For each clinical endpoint, patients were classified as being normal reactors or 'highly radiosensitive patients' (HR patients (Burnet NG. Johansen J, Turesson I, Nyman J. Describing patients' normal tissue reactions: Concerning the possibility of individualising radiotherapy dose prescriptions based on potential predictive assays of normal tissue radiosensitivity. Int. J. Cancer 1998

  13. Vitronectin in human breast carcinomas

    DEFF Research Database (Denmark)

    Aaboe, Mads; Offersen, Birgitte Vrou; Christensen, Anni

    2003-01-01

    We have analysed the occurrence of the extracellular glycoprotein vitronectin in carcinomas and normal tissue of human breast. Immunohistochemical analysis of carcinomas revealed a strong vitronectin accumulation in extracellular matrix (ECM) around some cancer cell clusters and in the subendothe......We have analysed the occurrence of the extracellular glycoprotein vitronectin in carcinomas and normal tissue of human breast. Immunohistochemical analysis of carcinomas revealed a strong vitronectin accumulation in extracellular matrix (ECM) around some cancer cell clusters...... and in the subendothelial area of some blood vessels. In normal tissue, vitronectin had a homogeneous periductal occurrence, with local accumulation much lower than that in the carcinomas. Using a new solid phase radioligand assay, the vitronectin concentrations of extracts of carcinomas and normal breast tissue were...... is not synthesised locally in breast tissue but derived by leakage from vessels, followed by extracellular accumulation in patterns distinctly different in carcinomas and normal tissue. The observation of a high vitronectin content in the carcinomas and its localisation in the tissue contributes to the clarification...

  14. Bmp signaling mediates endoderm pouch morphogenesis by regulating Fgf signaling in zebrafish

    Science.gov (United States)

    Swartz, Mary E.; McCarthy, Neil; Norrie, Jacqueline L.; Eberhart, Johann K.

    2016-01-01

    The endodermal pouches are a series of reiterated structures that segment the pharyngeal arches and help pattern the vertebrate face. Multiple pathways regulate the complex process of endodermal development, including the Bone morphogenetic protein (Bmp) pathway. However, the role of Bmp signaling in pouch morphogenesis is poorly understood. Using genetic and chemical inhibitor approaches, we show that pouch morphogenesis requires Bmp signaling from 10-18 h post-fertilization, immediately following gastrulation. Blocking Bmp signaling during this window results in morphological defects to the pouches and craniofacial skeleton. Using genetic chimeras we show that Bmp signals directly to the endoderm for proper morphogenesis. Time-lapse imaging and analysis of reporter transgenics show that Bmp signaling is necessary for pouch outpocketing via the Fibroblast growth factor (Fgf) pathway. Double loss-of-function analyses demonstrate that Bmp and Fgf signaling interact synergistically in craniofacial development. Collectively, our analyses shed light on the tissue and signaling interactions that regulate development of the vertebrate face. PMID:27122171

  15. Collective cell migration in morphogenesis, regeneration and cancer.

    NARCIS (Netherlands)

    Friedl, P.H.A.; Gilmour, D.

    2009-01-01

    The collective migration of cells as a cohesive group is a hallmark of the tissue remodelling events that underlie embryonic morphogenesis, wound repair and cancer invasion. In such migration, cells move as sheets, strands, clusters or ducts rather than individually, and use similar actin- and

  16. The microenvironment determines the breast cancer cells' phenotype: organization of MCF7 cells in 3D cultures

    International Nuclear Information System (INIS)

    Krause, Silva; Maffini, Maricel V; Soto, Ana M; Sonnenschein, Carlos

    2010-01-01

    Stromal-epithelial interactions mediate breast development, and the initiation and progression of breast cancer. In the present study, we developed 3-dimensional (3D) in vitro models to study breast cancer tissue organization and the role of the microenvironment in phenotypic determination. The human breast cancer MCF7 cells were grown alone or co-cultured with primary human breast fibroblasts. Cells were embedded in matrices containing either type I collagen or a combination of reconstituted basement membrane proteins and type I collagen. The cultures were carried out for up to 6 weeks. For every time point (1-6 weeks), the gels were fixed and processed for histology, and whole-mounted for confocal microscopy evaluation. The epithelial structures were characterized utilizing immunohistochemical techniques; their area and proliferation index were measured using computerized morphometric analysis. Statistical differences between groups were analyzed by ANOVA, Dunnett's T3 post-hoc test and chi-square. Most of the MCF7 cells grown alone within a collagen matrix died during the first two weeks; those that survived organized into large, round and solid clusters. The presence of fibroblasts in collagen gels reduced MCF7 cell death, induced cell polarity, and the formation of round and elongated epithelial structures containing a lumen. The addition of reconstituted basement membrane to collagen gels by itself had also survival and organizational effects on the MCF7 cells. Regardless of the presence of fibroblasts, the MCF7 cells both polarized and formed a lumen. The addition of fibroblasts to the gel containing reconstituted basement membrane and collagen induced the formation of elongated structures. Our results indicate that a matrix containing both type I collagen and reconstituted basement membrane, and the presence of normal breast fibroblasts constitute the minimal permissive microenvironment to induce near-complete tumor phenotype reversion. These human

  17. Lack of protein-tyrosine sulfation disrupts photoreceptor outer segment morphogenesis, retinal function and retinal anatomy.

    Science.gov (United States)

    Sherry, David M; Murray, Anne R; Kanan, Yogita; Arbogast, Kelsey L; Hamilton, Robert A; Fliesler, Steven J; Burns, Marie E; Moore, Kevin L; Al-Ubaidi, Muayyad R

    2010-11-01

    To investigate the role(s) of protein-tyrosine sulfation in the retina, we examined retinal function and structure in mice lacking tyrosylprotein sulfotransferases (TPST) 1 and 2. Tpst double knockout (DKO; Tpst1(-/-) /Tpst2 (-/-) ) retinas had drastically reduced electroretinographic responses, although their photoreceptors exhibited normal responses in single cell recordings. These retinas appeared normal histologically; however, the rod photoreceptors had ultrastructurally abnormal outer segments, with membrane evulsions into the extracellular space, irregular disc membrane spacing and expanded intradiscal space. Photoreceptor synaptic terminals were disorganized in Tpst DKO retinas, but established ultrastructurally normal synapses, as did bipolar and amacrine cells; however, the morphology and organization of neuronal processes in the inner retina were abnormal. These results indicate that protein-tyrosine sulfation is essential for proper outer segment morphogenesis and synaptic function, but is not critical for overall retinal structure or synapse formation, and may serve broader functions in neuronal development and maintenance. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  18. What Is Breast in the Bone?

    Science.gov (United States)

    Shemanko, Carrie S; Cong, Yingying; Forsyth, Amanda

    2016-10-22

    The normal developmental program that prolactin generates in the mammary gland is usurped in the cancerous process and can be used out of its normal cellular context at a site of secondary metastasis. Prolactin is a pleiotropic peptide hormone and cytokine that is secreted from the pituitary gland, as well as from normal and cancerous breast cells. Experimental and epidemiologic data suggest that prolactin is associated with mammary gland development, and also the increased risk of breast tumors and metastatic disease in postmenopausal women. Breast cancer spreads to the bone in approximately 70% of cases with advanced breast cancer. Despite treatment, new bone metastases will still occur in 30%-50% of patients. Only 20% of patients with bone metastases survive five years after the diagnosis of bone metastasis. The breast cancer cells in the bone microenvironment release soluble factors that engage osteoclasts and/or osteoblasts and result in bone breakdown. The breakdown of the bone matrix, in turn, enhances the proliferation of the cancer cells, creating a vicious cycle. Recently, it was shown that prolactin accelerated the breast cancer cell-mediated osteoclast differentiation and bone breakdown by the regulation of breast cancer-secreted proteins. Interestingly, prolactin has the potential to affect multiple proteins that are involved in both breast development and likely bone metastasis, as well. Prolactin has normal bone homeostatic roles and, combined with the natural "recycling" of proteins in different tissues that can be used for breast development and function, or in bone function, increases the impact of prolactin signaling in breast cancer bone metastases. Thus, this review will focus on the role of prolactin in breast development, bone homeostasis and in breast cancer to bone metastases, covering the molecular aspects of the vicious cycle.

  19. Progesterone receptors (PR) mediate STAT actions: PR and prolactin receptor signaling crosstalk in breast cancer models.

    Science.gov (United States)

    Leehy, Katherine A; Truong, Thu H; Mauro, Laura J; Lange, Carol A

    2018-02-01

    Estrogen is the major mitogenic stimulus of mammary gland development during puberty wherein ER signaling acts to induce abundant PR expression. PR signaling, in contrast, is the primary driver of mammary epithelial cell proliferation in adulthood. The high circulating levels of progesterone during pregnancy signal through PR, inducing expression of the prolactin receptor (PRLR). Cooperation between PR and prolactin (PRL) signaling, via regulation of downstream components in the PRL signaling pathway including JAKs and STATs, facilitates the alveolar morphogenesis observed during pregnancy. Indeed, these pathways are fully integrated via activation of shared signaling pathways (i.e. JAKs, MAPKs) as well as by the convergence of PRs and STATs at target genes relevant to both mammary gland biology and breast cancer progression (i.e. proliferation, stem cell outgrowth, tissue cell type heterogeneity). Thus, rather than a single mediator such as ER, transcription factor cascades (ER>PR>STATs) are responsible for rapid proliferative and developmental programming in the normal mammary gland. It is not surprising that these same mediators typify uncontrolled proliferation in a majority of breast cancers, where ER and PR are most often co-expressed and may cooperate to drive malignant tumor progression. This review will primarily focus on the integration of PR and PRL signaling in breast cancer models and the importance of this cross-talk in cancer progression in the context of mammographic density. Components of these PR/PRL signaling pathways could offer alternative drug targets and logical complements to anti-ER or anti-estrogen-based endocrine therapies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Binding of Glutathione to Enterovirus Capsids Is Essential for Virion Morphogenesis

    Science.gov (United States)

    Thibaut, Hendrik Jan; Thys, Bert; Canela, María-Dolores; Aguado, Leire; Wimmer, Eckard; Paul, Aniko; Pérez-Pérez, María-Jesús; van Kuppeveld, Frank J. M.; Neyts, Johan

    2014-01-01

    Enteroviruses (family of the Picornaviridae) cover a large group of medically important human pathogens for which no antiviral treatment is approved. Although these viruses have been extensively studied, some aspects of the viral life cycle, in particular morphogenesis, are yet poorly understood. We report the discovery of TP219 as a novel inhibitor of the replication of several enteroviruses, including coxsackievirus and poliovirus. We show that TP219 binds directly glutathione (GSH), thereby rapidly depleting intracellular GSH levels and that this interferes with virus morphogenesis without affecting viral RNA replication. The inhibitory effect on assembly was shown not to depend on an altered reducing environment. Using TP219, we show that GSH is an essential stabilizing cofactor during the transition of protomeric particles into pentameric particles. Sequential passaging of coxsackievirus B3 in the presence of low GSH-levels selected for GSH-independent mutants that harbored a surface-exposed methionine in VP1 at the interface between two protomers. In line with this observation, enteroviruses that already contained this surface-exposed methionine, such as EV71, did not rely on GSH for virus morphogenesis. Biochemical and microscopical analysis provided strong evidence for a direct interaction between GSH and wildtype VP1 and a role for this interaction in localizing assembly intermediates to replication sites. Consistently, the interaction between GSH and mutant VP1 was abolished resulting in a relocalization of the assembly intermediates to replication sites independent from GSH. This study thus reveals GSH as a novel stabilizing host factor essential for the production of infectious enterovirus progeny and provides new insights into the poorly understood process of morphogenesis. PMID:24722756

  1. Review of aragonite and calcite crystal morphogenesis in thermal spring systems

    Science.gov (United States)

    Jones, Brian

    2017-06-01

    Aragonite and calcite crystals are the fundamental building blocks of calcareous thermal spring deposits. The diverse array of crystal morphologies found in these deposits, which includes monocrystals, mesocrystals, skeletal crystals, dendrites, and spherulites, are commonly precipitated under far-from-equilibrium conditions. Such crystals form through both abiotic and biotic processes. Many crystals develop through non-classical crystal growth models that involve the arrangement of nanocrystals in a precisely controlled crystallographic register. Calcite crystal morphogenesis has commonly been linked to a ;driving force;, which is a conceptual measure of the distance of the growth conditions from equilibrium conditions. Essentially, this scheme indicates that increasing levels of supersaturation and various other parameters that produce a progressive change from monocrystals and mesocrystals to skeletal crystals to crystallographic and non-crystallographic dendrites, to dumbbells, to spherulites. Despite the vast amount of information available from laboratory experiments and natural spring systems, the precise factors that control the driving force are open to debate. The fact that calcite crystal morphogenesis is still poorly understood is largely a reflection of the complexity of the factors that influence aragonite and calcite precipitation. Available information indicates that variations in calcite crystal morphogenesis can be attributed to physical and chemical parameters of the parent water, the presence of impurities, the addition of organic or inorganic additives to the water, the rate of crystal growth, and/or the presence of microbes and their associated biofilms. The problems in trying to relate crystal morphogenesis to specific environmental parameters arise because it is generally impossible to disentangle the controlling factor(s) from the vast array of potential parameters that may act alone or in unison with each other.

  2. Tissue stiffening coordinates morphogenesis by triggering collective cell migration in vivo.

    Science.gov (United States)

    Barriga, Elias H; Franze, Kristian; Charras, Guillaume; Mayor, Roberto

    2018-02-22

    Collective cell migration is essential for morphogenesis, tissue remodelling and cancer invasion. In vivo, groups of cells move in an orchestrated way through tissues. This movement involves mechanical as well as molecular interactions between cells and their environment. While the role of molecular signals in collective cell migration is comparatively well understood, how tissue mechanics influence collective cell migration in vivo remains unknown. Here we investigated the importance of mechanical cues in the collective migration of the Xenopus laevis neural crest cells, an embryonic cell population whose migratory behaviour has been likened to cancer invasion. We found that, during morphogenesis, the head mesoderm underlying the cephalic neural crest stiffens. This stiffening initiates an epithelial-to-mesenchymal transition in neural crest cells and triggers their collective migration. To detect changes in their mechanical environment, neural crest cells use mechanosensation mediated by the integrin-vinculin-talin complex. By performing mechanical and molecular manipulations, we show that mesoderm stiffening is necessary and sufficient to trigger neural crest migration. Finally, we demonstrate that convergent extension of the mesoderm, which starts during gastrulation, leads to increased mesoderm stiffness by increasing the cell density underneath the neural crest. These results show that convergent extension of the mesoderm has a role as a mechanical coordinator of morphogenesis, and reveal a link between two apparently unconnected processes-gastrulation and neural crest migration-via changes in tissue mechanics. Overall, we demonstrate that changes in substrate stiffness can trigger collective cell migration by promoting epithelial-to-mesenchymal transition in vivo. More broadly, our results raise the idea that tissue mechanics combines with molecular effectors to coordinate morphogenesis.

  3. Binding of glutathione to enterovirus capsids is essential for virion morphogenesis.

    Directory of Open Access Journals (Sweden)

    Hendrik Jan Thibaut

    2014-04-01

    Full Text Available Enteroviruses (family of the Picornaviridae cover a large group of medically important human pathogens for which no antiviral treatment is approved. Although these viruses have been extensively studied, some aspects of the viral life cycle, in particular morphogenesis, are yet poorly understood. We report the discovery of TP219 as a novel inhibitor of the replication of several enteroviruses, including coxsackievirus and poliovirus. We show that TP219 binds directly glutathione (GSH, thereby rapidly depleting intracellular GSH levels and that this interferes with virus morphogenesis without affecting viral RNA replication. The inhibitory effect on assembly was shown not to depend on an altered reducing environment. Using TP219, we show that GSH is an essential stabilizing cofactor during the transition of protomeric particles into pentameric particles. Sequential passaging of coxsackievirus B3 in the presence of low GSH-levels selected for GSH-independent mutants that harbored a surface-exposed methionine in VP1 at the interface between two protomers. In line with this observation, enteroviruses that already contained this surface-exposed methionine, such as EV71, did not rely on GSH for virus morphogenesis. Biochemical and microscopical analysis provided strong evidence for a direct interaction between GSH and wildtype VP1 and a role for this interaction in localizing assembly intermediates to replication sites. Consistently, the interaction between GSH and mutant VP1 was abolished resulting in a relocalization of the assembly intermediates to replication sites independent from GSH. This study thus reveals GSH as a novel stabilizing host factor essential for the production of infectious enterovirus progeny and provides new insights into the poorly understood process of morphogenesis.

  4. PAR-Complex and Crumbs Function During Photoreceptor Morphogenesis and Retinal Degeneration

    Directory of Open Access Journals (Sweden)

    Franck Pichaud

    2018-03-01

    Full Text Available The fly photoreceptor has long been used as a model to study sensory neuron morphogenesis and retinal degeneration. In particular, elucidating how these cells are built continues to help further our understanding of the mechanisms of polarized cell morphogenesis, intracellular trafficking and the causes of human retinal pathologies. The conserved PAR complex, which in flies consists of Cdc42-PAR6-aPKC-Bazooka, and the transmembrane protein Crumbs (Crb are key players during photoreceptor morphogenesis. While the PAR complex regulates polarity in many cell types, Crb function in polarity is relatively specific to epithelial cells. Together Cdc42-PAR6-aPKC-Bazooka and Crb orchestrate the differentiation of the photoreceptor apical membrane (AM and zonula adherens (ZA, thus allowing these cells to assemble into a neuro-epithelial lattice. In addition to its function in epithelial polarity, Crb has also been shown to protect fly photoreceptors from light-induced degeneration, a process linked to Rhodopsin expression and trafficking. Remarkably, mutations in the human Crumbs1 (CRB1 gene lead to retinal degeneration, making the fly photoreceptor a powerful disease model system.

  5. Polarized protein transport and lumen formation during epithelial tissue morphogenesis.

    Science.gov (United States)

    Blasky, Alex J; Mangan, Anthony; Prekeris, Rytis

    2015-01-01

    One of the major challenges in biology is to explain how complex tissues and organs arise from the collective action of individual polarized cells. The best-studied model of this process is the cross talk between individual epithelial cells during their polarization to form the multicellular epithelial lumen during tissue morphogenesis. Multiple mechanisms of apical lumen formation have been proposed. Some epithelial lumens form from preexisting polarized epithelial structures. However, de novo lumen formation from nonpolarized cells has recently emerged as an important driver of epithelial tissue morphogenesis, especially during the formation of small epithelial tubule networks. In this review, we discuss the latest findings regarding the mechanisms and regulation of de novo lumen formation in vitro and in vivo.

  6. Evaluation of magnetization transfer ratios for breast tissues and breast diseases

    Energy Technology Data Exchange (ETDEWEB)

    Sasaki, Fumio; Murai, Hiroshi; Takeuchi, Thouru; Iwase, Takuji; Miura, Shigeto; Mastushima, Shigeru; Oosaki, Hikaru [Aichi Cancer Center, Nagoya (Japan). Hospital; Kinosada, Yasuomi

    1997-03-01

    To determine MTRs for normal structures and benign diseases in the breast two-dimensional magnetization transfer imaging was performed in 62 patients and in 3 young female volunteers. With regard to the MTRs of measurements in the normal breast tissues, fat tissues which is close to simple cysts in MTRs show little transfer of longitudinal magnetization. MTRs of the muscles was 15.15{+-}6.22%, which exceeded those of breast parenchyma. The breast parenchyma didn`t show the change of MTR value due to the difference of patient age and due to variable amount of fat and fibrous tissues. Breast parenchyma in the two young volunteers clearly showed biphasic change of MTR values in accordance with the menstrual cycle; little transfer value was due to hydration in the postovulatory period and high transfer value was due to dehydration in the preovulatory period. In the remaining one volunteer during lactation period, mammary parenchyma shows sever decrease in MTR, because mammary gland is loaded with massive fluid, showing a very high signal intensity on First IR and T2-weighted images. MTR values of benign breast diseases including mastopathy, fibroadenoma and phyllodes tumor had no significant difference from those of the breast parenchyma and muscle. Non-invasive ductal carcinoma was equivalent to breast parenchyma in MTR. (K.H.)

  7. Three-dimensional lithographically-defined organotypic tissue arrays for quantitative analysis of morphogenesis and neoplastic progression

    Energy Technology Data Exchange (ETDEWEB)

    Nelson, Celeste M.; Inman, Jamie L.; Bissell, Mina J.

    2008-02-13

    Here we describe a simple micromolding method to construct three-dimensional arrays of organotypic epithelial tissue structures that approximate in vivo histology. An elastomeric stamp containing an array of posts of defined geometry and spacing is used to mold microscale cavities into the surface of type I collagen gels. Epithelial cells are seeded into the cavities and covered with a second layer of collagen. The cells reorganize into hollow tissues corresponding to the geometry of the cavities. Patterned tissue arrays can be produced in 3-4 h and will undergo morphogenesis over the following one to three days. The protocol can easily be adapted to study a variety of tissues and aspects of normal and neoplastic development.

  8. Identification of valid reference genes for the normalization of RT-qPCR expression studies in human breast cancer cell lines treated with and without transient transfection.

    Directory of Open Access Journals (Sweden)

    Lin-Lin Liu

    Full Text Available Reverse transcription-quantitative polymerase chain reaction (RT-qPCR is a powerful technique for examining gene expression changes during tumorigenesis. Target gene expression is generally normalized by a stably expressed endogenous reference gene; however, reference gene expression may differ among tissues under various circumstances. Because no valid reference genes have been documented for human breast cancer cell lines containing different cancer subtypes treated with transient transfection, we identified appropriate and reliable reference genes from thirteen candidates in a panel of 10 normal and cancerous human breast cell lines under experimental conditions with/without transfection treatments with two transfection reagents. Reference gene expression stability was calculated using four algorithms (geNorm, NormFinder, BestKeeper and comparative delta Ct, and the recommended comprehensive ranking was provided using geometric means of the ranking values using the RefFinder tool. GeNorm analysis revealed that two reference genes should be sufficient for all cases in this study. A stability analysis suggests that 18S rRNA-ACTB is the best reference gene combination across all cell lines; ACTB-GAPDH is best for basal breast cancer cell lines; and HSPCB-ACTB is best for ER+ breast cancer cells. After transfection, the stability ranking of the reference gene fluctuated, especially with Lipofectamine 2000 transfection reagent in two subtypes of basal and ER+ breast cell lines. Comparisons of relative target gene (HER2 expression revealed different expressional patterns depending on the reference genes used for normalization. We suggest that identifying the most stable and suitable reference genes is critical for studying specific cell lines under certain circumstances.

  9. Pluripotency Genes and Their Functions in the Normal and Aberrant Breast and Brain

    Directory of Open Access Journals (Sweden)

    Tracy Seymour

    2015-11-01

    Full Text Available Pluripotent stem cells (PSCs attracted considerable interest with the successful isolation of embryonic stem cells (ESCs from the inner cell mass of murine, primate and human embryos. Whilst it was initially thought that the only PSCs were ESCs, in more recent years cells with similar properties have been isolated from organs of the adult, including the breast and brain. Adult PSCs in these organs have been suggested to be remnants of embryonic development that facilitate normal tissue homeostasis during repair and regeneration. They share certain characteristics with ESCs, such as an inherent capacity to self-renew and differentiate into cells of the three germ layers, properties that are regulated by master pluripotency transcription factors (TFs OCT4 (octamer-binding transcription factor 4, SOX2 (sex determining region Y-box 2, and homeobox protein NANOG. Aberrant expression of these TFs can be oncogenic resulting in heterogeneous tumours fueled by cancer stem cells (CSC, which are resistant to conventional treatments and are associated with tumour recurrence post-treatment. Further to enriching our understanding of the role of pluripotency TFs in normal tissue function, research now aims to develop optimized isolation and propagation methods for normal adult PSCs and CSCs for the purposes of regenerative medicine, developmental biology, and disease modeling aimed at targeted personalised cancer therapies.

  10. Breast development and anatomy.

    Science.gov (United States)

    Pandya, Sonali; Moore, Richard G

    2011-03-01

    In this article, the development of the female breast, as well as the functional anatomy, blood supply, innervation and lymphatic drainage are described. A thorough understanding of the breast anatomy is an important adjunct to a meticulous clinical breast examination. Breast examination is a complex skill involving key maneuvers, including careful inspection and palpation. Clinical breast examination can provide an opportunity for the clinician to educate patients about their breast and about breast cancer, its symptoms, risk factors, early detection, and normal breast composition, and specifically variability. Clinical breast examination can help to detect some cancers not found by mammography, and clinicians should not override their examination findings if imaging is not supportive of the physical findings.

  11. In vivo 31P MR spectroscopy of breast tumors: preliminary results

    International Nuclear Information System (INIS)

    Choe, Bo Young; Kim, Hak Hee; Suh, Tae Suk; Shinn, Kyung Sub; Jung, Sang Seol

    1995-01-01

    To evaluate the various phosphorus metabolism of breast tumors with use of in vivo phosphorus-31 ( 31 P) MR spectroscopy (MRS). Five patients with breast tumor (benign in two, malignant in three) and three normal healthy volunteers participated in this study. All in vivo 31 P MRS examinations were performed on 1.5T whole-body MRI/MRS system by using a Free Induction Decay (FID) pulse sequence. T1-weighted MR images were used for localization of tumors. Peak areas for each phosphorus metabolite were measured using a Marquart algorithm. Breast carcinoma had a substantially larger phosphomonoester (PME) and a smaller phosphocreatine (PCr) peak intensity than normal breast tissue. This was reflected in the relatively higher PME/PCr ratio of breast carcinomas as well as phosphodiester (PDE)/PCr, inorganic phosphate (Pi)/PCr, and adenosine triphosphate (ATP)/PCr ratios, compared with normal controls. The mean pH value of breast tumor demonstrating the alkaline nature was higher than that of normal controls. Spectral patterns between benign breast disease and normal breast tissue were quite similar, and differentiation was not established. Our preliminary study suggests that in vivo 31 P MRS is a noninvasive examination which may be useful in the early differentiation of malignant breast tumors from normal and benign conditions. However, normal control and benign conditions could not be characterized on the basis of the phosphorus metabolite ratios

  12. Regulation of Epithelial Morphogenesis by the G-Protein Coupled Receptor Mist and its Ligand Fog*

    Science.gov (United States)

    Manning, Alyssa J.; Peters, Kimberly A.; Peifer, Mark; Rogers, Stephen L.

    2014-01-01

    Epithelial morphogenesis is essential for shaping organs and tissues and for establishment of the three embryonic germ layers during gastrulation. Studies of gastrulation in Drosophila have provided insight into how epithelial morphogenesis is governed by developmental patterning mechanisms. We developed an assay to recapitulate morphogenetic shape changes in individual cultured cells, and used RNAi-based screening to identify Mist, a Drosophila G protein-coupled receptor (GPCR) that transduces signals from the secreted ligand Folded gastrulation (Fog) in cultured cells. Mist functioned in Fog-dependent embryonic morphogenesis, and the transcription factor Snail regulated expression of mist in zygotes. Our data revealed how a cell fate transcriptional program acts through a ligand-GPCR pair to stimulate epithelial morphogenetic shape changes. PMID:24222713

  13. Canonical TGF-β Signaling Negatively Regulates Neuronal Morphogenesis through TGIF/Smad Complex-Mediated CRMP2 Suppression.

    Science.gov (United States)

    Nakashima, Hideyuki; Tsujimura, Keita; Irie, Koichiro; Ishizu, Masataka; Pan, Miao; Kameda, Tomonori; Nakashima, Kinichi

    2018-05-16

    Functional neuronal connectivity requires proper neuronal morphogenesis and its dysregulation causes neurodevelopmental diseases. Transforming growth factor-β (TGF-β) family cytokines play pivotal roles in development, but little is known about their contribution to morphological development of neurons. Here we show that the Smad-dependent canonical signaling of TGF-β family cytokines negatively regulates neuronal morphogenesis during brain development. Mechanistically, activated Smads form a complex with transcriptional repressor TG-interacting factor (TGIF), and downregulate the expression of a neuronal polarity regulator, collapsin response mediator protein 2. We also demonstrate that TGF-β family signaling inhibits neurite elongation of human induced pluripotent stem cell-derived neurons. Furthermore, the expression of TGF-β receptor 1, Smad4, or TGIF, which have mutations found in patients with neurodevelopmental disorders, disrupted neuronal morphogenesis in both mouse (male and female) and human (female) neurons. Together, these findings suggest that the regulation of neuronal morphogenesis by an evolutionarily conserved function of TGF-β signaling is involved in the pathogenesis of neurodevelopmental diseases. SIGNIFICANCE STATEMENT Canonical transforming growth factor-β (TGF-β) signaling plays a crucial role in multiple organ development, including brain, and mutations in components of the signaling pathway associated with several human developmental disorders. In this study, we found that Smads/TG-interacting factor-dependent canonical TGF-β signaling regulates neuronal morphogenesis through the suppression of collapsin response mediator protein-2 (CRMP2) expression during brain development, and that function of this signaling is evolutionarily conserved in the mammalian brain. Mutations in canonical TGF-β signaling factors identified in patients with neurodevelopmental disorders disrupt the morphological development of neurons. Thus, our

  14. Breast compression in mammography: how much is enough?

    Science.gov (United States)

    Poulos, Ann; McLean, Donald; Rickard, Mary; Heard, Robert

    2003-06-01

    The amount of breast compression that is applied during mammography potentially influences image quality and the discomfort experienced. The aim of this study was to determine the relationship between applied compression force, breast thickness, reported discomfort and image quality. Participants were women attending routine breast screening by mammography at BreastScreen New South Wales Central and Eastern Sydney. During the mammographic procedure, an 'extra' craniocaudal (CC) film was taken at a reduced level of compression ranging from 10 to 30 Newtons. Breast thickness measurements were recorded for both the normal and the extra CC film. Details of discomfort experienced, cup size, menstrual status, existing breast pain and breast problems were also recorded. Radiologists were asked to compare the image quality of the normal and manipulated film. The results indicated that 24% of women did not experience a difference in thickness when the compression was reduced. This is an important new finding because the aim of breast compression is to reduce breast thickness. If breast thickness is not reduced when compression force is applied then discomfort is increased with no benefit in image quality. This has implications for mammographic practice when determining how much breast compression is sufficient. Radiologists found a decrease in contrast resolution within the fatty area of the breast between the normal and the extra CC film, confirming a decrease in image quality due to insufficient applied compression force.

  15. The Royal College of Radiologists Breast Group breast imaging classification

    International Nuclear Information System (INIS)

    Maxwell, A.J.; Ridley, N.T.; Rubin, G.; Wallis, M.G.; Gilbert, F.J.; Michell, M.J.

    2009-01-01

    Standardisation of the classification of breast imaging reports will improve communication between the referrer and the radiologist and avoid ambiguity, which may otherwise lead to mismanagement of patients. Following wide consultation, Royal College of Radiologists Breast Group has produced a scoring system for the classification of breast imaging. This will facilitate audit and the development of nationally agreed standards for the investigation of women with breast disease. This five-point system is as follows: 1, normal; 2, benign findings; 3, indeterminate/probably benign findings; 4, findings suspicious of malignancy; 5, findings highly suspicious of malignancy. It is recommended that this be used in the reporting of all breast imaging examinations in the UK.

  16. The unfolded protein response is required for dendrite morphogenesis

    Science.gov (United States)

    Wei, Xing; Howell, Audrey S; Dong, Xintong; Taylor, Caitlin A; Cooper, Roshni C; Zhang, Jianqi; Zou, Wei; Sherwood, David R; Shen, Kang

    2015-01-01

    Precise patterning of dendritic fields is essential for the formation and function of neuronal circuits. During development, dendrites acquire their morphology by exuberant branching. How neurons cope with the increased load of protein production required for this rapid growth is poorly understood. Here we show that the physiological unfolded protein response (UPR) is induced in the highly branched Caenorhabditis elegans sensory neuron PVD during dendrite morphogenesis. Perturbation of the IRE1 arm of the UPR pathway causes loss of dendritic branches, a phenotype that can be rescued by overexpression of the ER chaperone HSP-4 (a homolog of mammalian BiP/ grp78). Surprisingly, a single transmembrane leucine-rich repeat protein, DMA-1, plays a major role in the induction of the UPR and the dendritic phenotype in the UPR mutants. These findings reveal a significant role for the physiological UPR in the maintenance of ER homeostasis during morphogenesis of large dendritic arbors. DOI: http://dx.doi.org/10.7554/eLife.06963.001 PMID:26052671

  17. Intensity modulated radiotherapy and 3D conformal radiotherapy for whole breast irradiation: a comparative dosimetric study and introduction of a novel qualitative index for plan evaluation, the normal tissue index

    Energy Technology Data Exchange (ETDEWEB)

    Yim, Jackie; Suttie, Clare; Bromley, Regina; Morgia, Marita; Lamoury, Gillian [Department of Radiation Oncology, Royal North Shore Hospital, St Leonards, New South Wales (Australia)

    2015-09-15

    We report on a retrospective dosimetric study, comparing 3D conformal radiotherapy (3DCRT) and hybrid intensity modulated radiotherapy (hIMRT). We evaluated plans based on their planning target volume coverage, dose homogeneity, dose to organs at risk (OARs) and exposure of normal tissue to radiation. The Homogeneity Index (HI) was used to assess the dose homogeneity in the target region, and we describe a new index, the normal tissue index (NTI), to assess the dose in the normal tissue inside the tangent treatment portal. Plans were generated for 25 early-stage breast cancer patients, using a hIMRT technique. These were compared with the 3DCRT plans of the treatment previously received by the patients. Plan quality was evaluated using the HI, NTI and dose to OARs. The hIMRT technique was significantly more homogenous than the 3DCRT technique, while maintaining target coverage. The hIMRT technique was also superior at minimising the amount of tissue receiving D{sub 105%} and above (P < 0.0001). The ipsilateral lung and contralateral breast maximum were significantly lower in the hIMRT plans (P < 0.05 and P < 0.005), but the 3DCRT technique achieved a lower mean heart dose in left-sided breast cancer patients (P < 0.05). Hybrid intensity modulated radiotherapy plans achieved improved dose homogeneity compared to the 3DCRT plans and superior outcome with regard to dose to normal tissues. We propose that the addition of both HI and NTI in evaluating the quality of intensity modulated radiotherapy (IMRT) breast plans provides clinically relevant comparators which more accurately reflect the new paradigm of treatment goals and outcomes in the era of breast IMRT.

  18. Intensity modulated radiotherapy and 3D conformal radiotherapy for whole breast irradiation: a comparative dosimetric study and introduction of a novel qualitative index for plan evaluation, the normal tissue index

    International Nuclear Information System (INIS)

    Yim, Jackie; Suttie, Clare; Bromley, Regina; Morgia, Marita; Lamoury, Gillian

    2015-01-01

    We report on a retrospective dosimetric study, comparing 3D conformal radiotherapy (3DCRT) and hybrid intensity modulated radiotherapy (hIMRT). We evaluated plans based on their planning target volume coverage, dose homogeneity, dose to organs at risk (OARs) and exposure of normal tissue to radiation. The Homogeneity Index (HI) was used to assess the dose homogeneity in the target region, and we describe a new index, the normal tissue index (NTI), to assess the dose in the normal tissue inside the tangent treatment portal. Plans were generated for 25 early-stage breast cancer patients, using a hIMRT technique. These were compared with the 3DCRT plans of the treatment previously received by the patients. Plan quality was evaluated using the HI, NTI and dose to OARs. The hIMRT technique was significantly more homogenous than the 3DCRT technique, while maintaining target coverage. The hIMRT technique was also superior at minimising the amount of tissue receiving D 105% and above (P < 0.0001). The ipsilateral lung and contralateral breast maximum were significantly lower in the hIMRT plans (P < 0.05 and P < 0.005), but the 3DCRT technique achieved a lower mean heart dose in left-sided breast cancer patients (P < 0.05). Hybrid intensity modulated radiotherapy plans achieved improved dose homogeneity compared to the 3DCRT plans and superior outcome with regard to dose to normal tissues. We propose that the addition of both HI and NTI in evaluating the quality of intensity modulated radiotherapy (IMRT) breast plans provides clinically relevant comparators which more accurately reflect the new paradigm of treatment goals and outcomes in the era of breast IMRT

  19. Leptin: A proliferative factor for breast cancer?

    International Nuclear Information System (INIS)

    Caldefie-Chezet, F.; Damez, M.; Latour, M. de; Konska, G.; Mishellani, F.; Fusillier, C.; Guerry, M.; Penault-Llorca, F.; Guillot, J.; Vasson, M.-P.

    2005-01-01

    Mammary adipose tissue is an important source of paracrine mitogens and anti-mitogens, including insulin-like growth factor, transforming growth factors, and cytokines (especially, TNFα and IL-1β). Nevertheless, it is also an important source of the adipocytokine, leptin. Recently, leptin was reported to stimulate the proliferation of various cell types (pancreatic β cells, prostate, colorectal, lung, etc.) as a new growth factor. It was also shown to stimulate the proliferation of breast cancer cell lines. In this study, we conducted an immunohistochemical analysis of leptin expression in normal tissue and benign and malignant ductal breast cell, representing the different states of the invasion process. We determined for the first time that leptin is expressed both by ductal breast tumors and by benign lesions as atypical hyperplasia. This suggests that leptin may be taken up or synthesized by all modified ductal breast cells, and may prove a proliferative factor. Moreover, leptin is unexpressed by normal tissue in the healthy breast but is exhibited by the normal tissue in near vicinity of the malignant ductal breast lesions. We also postulated that leptin may be a prognostic or diagnostic factor for ductal breast cancer. These putative hypotheses require further study

  20. Different apoptotic effects of [Pt(O,O'-acac)(γ-acac)(DMS)] and cisplatin on normal and cancerous human epithelial breast cells in primary culture.

    Science.gov (United States)

    Vetrugno, Carla; Muscella, Antonella; Fanizzi, Francesco Paolo; Cossa, Luca Giulio; Migoni, Danilo; De Pascali, Sandra Angelica; Marsigliante, Santo

    2014-11-01

    The aim of this study was to determine whether [platinum (Pt)(O,O'-acetylacetonate (acac))(γ-acac)(dimethylsulphide (DMS))] is differentially cytotoxic in normal and cancer cells, and to measure comparative levels of cytotoxicity compared with cisplatin in the same cells. We performed experiments on cancerous and normal epithelial breast cells in primary culture obtained from the same patients. The apoptotic effects [Pt(O,O'-acac)(γ-acac)(DMS)] and cisplatin in cancerous and normal breast cells were compared. Cancer cells were more sensitive to [Pt(O,O'-acac)(γ-acac)(DMS)] (IC50 = 5.22 ± 1.2 μmol·L(-1)) than normal cells (IC50 = 116.9 ± 8.8 μmol·L(-1)). However, the difference was less strong when cisplatin was used (IC50 = 96.0 ± 6.9 and 61.9 ± 6.1 μmol·L(-1) for cancer and normal cells respectively). Both compounds caused reactive oxygen species (ROS) production with different mechanisms: [Pt(O,O'-acac)(γ-acac)(DMS)] quickly activated NAD(P)H oxidase while cisplatin caused a slower formation of mitochondrial ROS. Cisplatin and [Pt(O,O'-acac)(γ-acac)(DMS)] caused activation of caspases, proteolysis of PARP and modulation of Bcl-2, Bax and Bid. [Pt(O,O'-acac)(γ-acac)(DMS)] also caused leakage of cytochrome c from the mitochondria. Overall, these processes proceeded more quickly in cells treated with [Pt(O,O'-acac)(γ-acac)(DMS)] compared with cisplatin. [Pt(O,O'-acac)(γ-acac)(DMS)] effects were faster and quantitatively greater in cancer than in normal cells. [Pt(O,O'-acac)(γ-acac)(DMS)] caused a fast decrease of mitochondrial membrane potential, especially in cancer cells. [Pt(O,O'-acac)(γ-acac)(DMS)] was specific to breast cancer cells in primary culture, and this observation makes this compound potentially more interesting than cisplatin. © 2014 The British Pharmacological Society.

  1. Different apoptotic effects of [Pt(O,O′-acac)(γ-acac)(DMS)] and cisplatin on normal and cancerous human epithelial breast cells in primary culture

    Science.gov (United States)

    Vetrugno, Carla; Muscella, Antonella; Fanizzi, Francesco Paolo; Cossa, Luca Giulio; Migoni, Danilo; De Pascali, Sandra Angelica; Marsigliante, Santo

    2014-01-01

    Background and Purpose The aim of this study was to determine whether [platinum (Pt)(O,O′-acetylacetonate (acac))(γ-acac)(dimethylsulphide (DMS))] is differentially cytotoxic in normal and cancer cells, and to measure comparative levels of cytotoxicity compared with cisplatin in the same cells. Experimental Approach We performed experiments on cancerous and normal epithelial breast cells in primary culture obtained from the same patients. The apoptotic effects [Pt(O,O′-acac)(γ-acac)(DMS)] and cisplatin in cancerous and normal breast cells were compared. Key Results Cancer cells were more sensitive to [Pt(O,O′-acac)(γ-acac)(DMS)] (IC50 = 5.22 ± 1.2 μmol·L−1) than normal cells (IC50 = 116.9 ± 8.8 μmol·L−1). However, the difference was less strong when cisplatin was used (IC50 = 96.0 ± 6.9 and 61.9 ± 6.1 μmol·L−1 for cancer and normal cells respectively). Both compounds caused reactive oxygen species (ROS) production with different mechanisms: [Pt(O,O′-acac)(γ-acac)(DMS)] quickly activated NAD(P)H oxidase while cisplatin caused a slower formation of mitochondrial ROS. Cisplatin and [Pt(O,O′-acac)(γ-acac)(DMS)] caused activation of caspases, proteolysis of PARP and modulation of Bcl-2, Bax and Bid. [Pt(O,O′-acac)(γ-acac)(DMS)] also caused leakage of cytochrome c from the mitochondria. Overall, these processes proceeded more quickly in cells treated with [Pt(O,O′-acac)(γ-acac)(DMS)] compared with cisplatin. [Pt(O,O′-acac)(γ-acac)(DMS)] effects were faster and quantitatively greater in cancer than in normal cells. [Pt(O,O′-acac)(γ-acac)(DMS)] caused a fast decrease of mitochondrial membrane potential, especially in cancer cells. Conclusions and Implications [Pt(O,O′-acac)(γ-acac)(DMS)] was specific to breast cancer cells in primary culture, and this observation makes this compound potentially more interesting than cisplatin. PMID:24990093

  2. Analysis of breast thermograms using Gabor wavelet anisotropy index.

    Science.gov (United States)

    Suganthi, S S; Ramakrishnan, S

    2014-09-01

    In this study, an attempt is made to distinguish the normal and abnormal tissues in breast thermal images using Gabor wavelet transform. Thermograms having normal, benign and malignant tissues are considered in this study and are obtained from public online database. Segmentation of breast tissues is performed by multiplying raw image and ground truth mask. Left and right breast regions are separated after removing the non-breast regions from the segmented image. Based on the pathological conditions, the separated breast regions are grouped as normal and abnormal tissues. Gabor features such as energy and amplitude in different scales and orientations are extracted. Anisotropy and orientation measures are calculated from the extracted features and analyzed. A distinctive variation is observed among different orientations of the extracted features. It is found that the anisotropy measure is capable of differentiating the structural changes due to varied metabolic conditions. Further, the Gabor features also showed relative variations among different pathological conditions. It appears that these features can be used efficiently to identify normal and abnormal tissues and hence, improve the relevance of breast thermography in early detection of breast cancer and content based image retrieval.

  3. Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition

    Energy Technology Data Exchange (ETDEWEB)

    Gudjonsson, Thorarinn; Ronnov-Jessen, Lone; Villadsen, Rene; Rank, Fritz; Bissell, Mina J.; Petersen, Ole William

    2001-10-04

    The signals that determine the correct polarity of breast epithelial structures in vivo are not understood. We have shown previously that luminal epithelial cells can be polarized when cultured within a reconstituted basement membrane gel. We reasoned that such cues in vivo may be given by myoepithelial cells. Accordingly, we used an assay where luminal epithelial cells are incorrectly polarized to test this hypothesis. We show that culturing human primary luminal epithelial cells within collagen-I gels leads to formation of structures with no lumina and with reverse polarity as judged by dual stainings for sialomucin, epithelial specific antigen or occludin. No basement membrane is deposited, and {beta}4-integrin staining is negative. Addition of purified human myoepithelial cells isolated from normal glands corrects the inverse polarity, and leads to formation of double-layered acini with central lumina. Among the laminins present in the human breast basement membrane (laminin-1, -5 and -10/11), laminin-1 was unique in its ability to substitute for myoepithelial cells in polarity reversal. Myoepithelial cells were purified also from four different breast cancer sources including a biphasic cell line. Three out of four samples either totally lacked the ability to interact with luminal epithelial cells, or conveyed only correction of polarity in a fraction of acini. This behavior was directly related to the ability of the tumor myoepithelial cells to produce {alpha}-1 chain of laminin. In vivo, breast carcinomas were either negative for laminin-1 (7/12 biopsies) or showed a focal, fragmented deposition of a less intensely stained basement membrane (5/12 biopsies). Dual staining with myoepithelial markers revealed that tumorassociated myoepithelial cells were either negative or weakly positive for expression of laminin-1, establishing a strong correlation between loss of laminin-1 and breast cancer. We conclude that the double-layered breast acinus may be

  4. Breast development and disorders in the adolescent female.

    Science.gov (United States)

    De Silva, Nirupama K

    2018-04-01

    Breast development in the female is a process that becomes noticeable during puberty, and defines a girl's transition into adulthood. Various conditions can disrupt or alter the normal development, which may lead to abnormal breast changes and features. Further, the finding of a breast mass in adolescence can be unsettling to the patient and her family. While the majority of these breast changes and/or masses tend to be benign and self-limited, the appropriate evaluation is always warranted. This chapter will focus on the normal and abnormal development of breasts. We will also discuss the evaluation and management of breast masses that can be found in the adolescent female. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Analysis of clonal expansions through the normal and premalignant human breast epithelium reveals the presence of luminal stem cells.

    Science.gov (United States)

    Cereser, Biancastella; Jansen, Marnix; Austin, Emily; Elia, George; McFarlane, Taneisha; van Deurzen, Carolien Hm; Sieuwerts, Anieta M; Daidone, Maria G; Tadrous, Paul J; Wright, Nicholas A; Jones, Louise; McDonald, Stuart Ac

    2018-01-01

    It is widely accepted that the cell of origin of breast cancer is the adult mammary epithelial stem cell; however, demonstrating the presence and location of tissue stem cells in the human breast has proved difficult. Furthermore, we do not know the clonal architecture of the normal and premalignant mammary epithelium or its cellular hierarchy. Here, we use deficiency in the mitochondrial enzyme cytochrome c oxidase (CCO), typically caused by somatic mutations in the mitochondrial genome, as a means to perform lineage tracing in the human mammary epithelium. PCR sequencing of laser-capture microdissected cells in combination with immunohistochemistry for markers of lineage differentiation was performed to determine the clonal nature of the mammary epithelium. We have shown that in the normal human breast, clonal expansions (defined here by areas of CCO deficiency) are typically uncommon and of limited size, but can occur at any site within the adult mammary epithelium. The presence of a stem cell population was shown by demonstrating multi-lineage differentiation within CCO-deficient areas. Interestingly, we observed infrequent CCO deficiency that was restricted to luminal cells, suggesting that niche succession, and by inference stem cell location, is located within the luminal layer. CCO-deficient areas appeared large within areas of ductal carcinoma in situ, suggesting that the rate of clonal expansion was altered in the premalignant lesion. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

  6. Stokes shift spectroscopy for breast cancer diagnosis

    Science.gov (United States)

    Jeyasingh, Ebenezar; Prakashrao, Aruna; Singaravelu, Ganesan

    2010-02-01

    The objective of this study is to assess the diagnostic potential of stokes shift (SS) spectroscopy (SSS) for normal and different pathological breast tissues such as fibroadenoma and infiltrating ductal carcinoma. The SS spectra is measured by simultaneously scanning both the excitation and emission wavelengths while keeping a fixed wavelength interval Δλ=20 nm between them. Characteristic, highly resolved peaks and significant spectral differences between normal and different pathological breast tissues were observed. The SS spectra of normal and different pathological breast tissues shows the distinct peaks around 300, 350, 450, 500 and 600 nm may be attributed to tryptophan, collagen, NADH, flavin and porphyrin respectively. Using SSS technique one can obtain all the key fluorophores in a single scan and hence they can be targeted as a tumor markers in this study. In order to quantify the altered spectral differences between normal and different pathological breast tissues are verified by different ratio parameters.

  7. Optically measured microvascular blood flow contrast of malignant breast tumors.

    Directory of Open Access Journals (Sweden)

    Regine Choe

    Full Text Available Microvascular blood flow contrast is an important hemodynamic and metabolic parameter with potential to enhance in vivo breast cancer detection and therapy monitoring. Here we report on non-invasive line-scan measurements of malignant breast tumors with a hand-held optical probe in the remission geometry. The probe employs diffuse correlation spectroscopy (DCS, a near-infrared optical method that quantifies deep tissue microvascular blood flow. Tumor-to-normal perfusion ratios are derived from thirty-two human subjects. Mean (95% confidence interval tumor-to-normal ratio using surrounding normal tissue was 2.25 (1.92-2.63; tumor-to-normal ratio using normal tissues at the corresponding tumor location in the contralateral breast was 2.27 (1.94-2.66, and using normal tissue in the contralateral breast was 2.27 (1.90-2.70. Thus, the mean tumor-to-normal ratios were significantly different from unity irrespective of the normal tissue chosen, implying that tumors have significantly higher blood flow than normal tissues. Therefore, the study demonstrates existence of breast cancer contrast in blood flow measured by DCS. The new, optically accessible cancer contrast holds potential for cancer detection and therapy monitoring applications, and it is likely to be especially useful when combined with diffuse optical spectroscopy/tomography.

  8. DNA double strand break repair pathway plays a significant role in determining the radiotherapy induced normal tissue toxicity among head-and-neck and breast cancer

    International Nuclear Information System (INIS)

    Sadashiva, Satish Rao Bola; Mumbrekar, Kamalesh Dattaram; Venkatesh, Goutham Hassan; Fernandes, Donald Jerard; Bejadi, Vadhiraja Manjunath; Kapaettu, Satyamoorthy

    2014-01-01

    The ability to predict individual risk of radiotherapy induced normal tissue complications prior to the therapy may give an opportunity to personalize the treatment aiming improved therapeutic effect and quality of life. Therefore, predicting the risk of developing acute reactions before the initiation of radiation therapy may serve as a potential biomarker. DNA double-strand break (DSB) induction and its repair kinetics in lymphocytes of Head-and-Neck (n = 183) and Breast cancer (n = 132) patients undergoing chemoradiation or radiation therapy alone were analyzed by performing γ-H2AX foci, neutral comet and a modified neutral filter elution assay. Candidate radioresponsive genes like DNA repair, antioxidant pathway, profibrotic cytokine genes were screened for the common variants for their association with normal tissue toxicity outcome. Patients were stratified as non-over responders (NOR) and over responders (OR) based on their Radiation Therapy Oncology Group grading for normal tissue adverse reactions. Our results suggest that DSB repair plays a major role in the development of normal tissue adverse reactions in H and N and Breast cancer patients. The cellular (γ-H2AX analysis) and SNP analysis may have the potential to be developed into a clinically useful predictive assay for identifying the normal tissue over reactors

  9. Normal and pathological breast, the histological basis

    Energy Technology Data Exchange (ETDEWEB)

    Guinebretiere, J.M. [Department of Pathology, Centre Rene-Huguenin, 35 rue Dailly, 92210 Saint Cloud (France)]. E-mail: jm.guinebretiere@stcloud-huguenin.org; Menet, E. [Department of Pathology, Centre Rene-Huguenin, 35 rue Dailly, 92210 Saint Cloud (France); Tardivon, A. [Department of Radiology, Institut Curie, 26 rue d' Ulm, 75248 Paris Cedex 5 (France); Cherel, P. [Department of Radiology, Centre Rene-Huguenin, 35 rue Dailly, 92210 Saint Cloud (France); Vanel, D. [Department of Diagnostic Radiology, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif (France)

    2005-04-01

    Breast tissue is heterogeneous, associating connective and glandular structures, which grow and change cyclically under hormonal regulation. Hormones are also thought to be the main determinant of the major benign and malignant pathologies encountered in the breast. Benign lesions are more frequent and fibrocystic changes are by far the most common among them. They usually associate different entities (adenosis, fibrosis, cysts and hyperplasia) but vary in intensity and extension. Thus, their clinical and radiographic presentation is extremely different from one patient to another. Adenofibroma is the most frequent tumour. It also undergoes modifications according to hormonal conditions. About 90% of malignant tumours are primary carcinoma. The incidence of intra-ductal carcinoma has risen dramatically since the development of screening because of its ability to induce calcification. Two mechanisms could be involved in the formation of calcification: one active (tumour cell secretion of vesicles), the other passive (necrotic cell fragments are released). Invasive carcinoma comprises numerous histological types. Stromal reactions essentially determines their shape: a fibrous reaction commonly found in ductal carcinoma creates a stellate lesion while other stroma, inflammatory (medullary carcinoma), vascular (papillary carcinoma) or mucinous determine nodular lesions whose borders push the surrounding tissue. The histological features which give rise to the radiographic pattern will be emphasised.

  10. Diffusion weighted imaging of the normal breast: reproducibility of apparent diffusion coefficient measurements and variation with menstrual cycle and menopausal status

    International Nuclear Information System (INIS)

    O'Flynn, Elizabeth A.M.; Morgan, Veronica A.; Giles, Sharon L.; de Souza, Nandita M.

    2012-01-01

    To establish the reproducibility of apparent diffusion coefficient (ADC) measurements in normal fibroglandular breast tissue and to assess variation in ADC values with phase of the menstrual cycle and menopausal status. Thirty-one volunteers (13 premenopausal, 18 postmenopausal) underwent magnetic resonance twice (interval 11-22 days) using diffusion-weighted MRI. ADC total and a perfusion-insensitive ADC high (omitting b = 0) were calculated. Reproducibility and inter-observer variability of mean ADC values were assessed. The difference in mean ADC values between the two phases of the menstrual cycle and the postmenopausal breast were evaluated. ADC total and ADC high showed good reproducibility (r% = 17.6, 22.4). ADC high showed very good inter-observer agreement (kappa = 0.83). The intraclass correlation coefficients (ICC) were 0.93 and 0.91. Mean ADC values were significantly lower in the postmenopausal breast (ADC total 1.46 ± 0.3 x 10 -3 mm 2 /s, ADC high 1.33 ± 0.3 x 10 -3 mm 2 /s) compared with the premenopausal breast (ADC total 1.84 ± 0.26 x 10 -3 mm 2 /s, ADC high 1.77 ± 0.26 x 10 -3 mm 2 /s; both P total P = 0.2, ADC high P = 0.24) or between postmenopausal women taking or not taking oestrogen supplements (ADC total P = 0.6, ADC high P = 0.46). ADC values in fibroglandular breast tissue are reproducible. Lower ADC values within the postmenopausal breast may reduce diffusion-weighted contrast and have implications for accurately detecting tumours. (orig.)

  11. Male breast lesions

    International Nuclear Information System (INIS)

    Matushita, J.P.K.; Andrade, L.G. de; Carregal, E.; Marimatsu, R.I.; Matushita, J.S.

    1989-01-01

    Roentgenographic examination of the male breast is an important aspect of the continued, intensive investigation of the radiologic morphology of the normal and diseased breast conducted in 17 cases examined at the Instituto Nacional do Cancer - RJ. It is purpose of this report to present the Roentgen appearance of various lesions of the male breast as they have been found in our practice and also to stress some of the difficulties in the differential diagnosis of these lesions. (author) [pt

  12. How to approach breast lesions in children and adolescents

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Yiming, E-mail: yiminggao@gmail.com [New York University Langone Medical Center, 221 Lexington Ave., New York, NY 10016 (United States); Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 (United States); Saksena, Mansi A.; Brachtel, Elena F.; Meulen, Deborah C. ter; Rafferty, Elizabeth A. [Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 (United States)

    2015-07-15

    Highlights: • Recognize why the diagnostic approach to the developing breast differs from that to the adult breast. • Review of embryology, early breast development, and later pubescent breast development. • Learn the spectrum of common and uncommon pediatric breast lesions. • Develop an algorithm for diagnostic evaluation and management of pediatric breast lesions. - Abstract: Assessment of a pediatric breast lesion always starts with clinical evaluation. When imaging of a pediatric breast is indicated, ultrasound is the mainstay. The vast majority of pediatric breast complaints are of benign etiology, therefore the diagnostic/management approach emphasizes “first do no harm”. Correlation with age and clinical history helps to direct diagnosis. It is essential to be familiar with the imaging appearance of the normal developing breast at various Tanner stages, in order to diagnose physiologic breast findings and to minimize unnecessary biopsies in young breasts vulnerable to injury. Normal anatomic structures, developmental conditions, benign neoplastic and non-neoplastic lesions are common causes of breast complaints in children. Uncommon benign masses and rarely, secondary more than primary malignancies may present in a pediatric breast. Chest wall masses such as Ewing's sarcoma or rhabdomyosarcoma occur in children and may involve the breast via contiguous growth or locoregional metastasis. In addition, special attention should be given to any breast lesion in a child with risk factors predisposing to breast cancer, such as known extramammary malignancy, genetic mutations, prior mantle irradiation, or strong family history of breast cancer, which usually requires biopsy to exclude the possibility of malignancy. Conclusion: The developing breast is vulnerable to injury, and because breast malignancy is uncommon in children, diagnostic and management approach emphasizes “first do no harm”. Understanding normal breast development and the

  13. Spectral imaging of breast fibroadenoma using second-harmonic generation

    Science.gov (United States)

    Zheng, Liqin; Wang, Yuhua

    2014-09-01

    Fibroadenoma (FA), typically composed of stroma and epithelial cells, is a very common benign breast disease. Women with FA are associated with an increased risk of future breast cancer. The objective of this study was to demonstrate the potential of multiphoton laser scanning microscopy (MPLSM) for characterizing the morphology of collagen in the human breast fibroadenomas. In the study, high-contrast SHG images of human normal breast tissues and fibroadenoma tissues were obtained for comparison. The morphology of collagen was different between normal breast tissue and fibroadenoma. This study shows that MPLSM has the ability to distinguish fibroadenoma tissues from the normal breast tissues based on the noninvasive SHG imaging. With the advent of the clinical portability of miniature MPLSM, we believe that the technique has great potential to be used in vivo studies and for monitoring the treatment responses of fibroadenomas in clinical.

  14. Immunohistochemical analysis of Sonic hedgehog signalling in normal human urinary tract development

    OpenAIRE

    Jenkins, Dagan; Winyard, Paul J D; Woolf, Adrian S.

    2007-01-01

    Studies of mouse mutants have demonstrated that Sonic hedgehog (SHH) signalling has a functional role in morphogenesis and differentiation at multiple sites within the forming urinary tract, and urinary tract malformations have been reported in humans with mutations that disrupt SHH signalling. However, there is only strikingly sparse and fragmentary information about the expression of SHH and associated signalling genes in normal human urinary tract development. We used immunohistochemistry ...

  15. From single cells to tissues: interactions between the matrix and human breast cells in real time.

    Directory of Open Access Journals (Sweden)

    Clifford Barnes

    Full Text Available Mammary gland morphogenesis involves ductal elongation, branching, and budding. All of these processes are mediated by stroma--epithelium interactions. Biomechanical factors, such as matrix stiffness, have been established as important factors in these interactions. For example, epithelial cells fail to form normal acinar structures in vitro in 3D gels that exceed the stiffness of a normal mammary gland. Additionally, heterogeneity in the spatial distribution of acini and ducts within individual collagen gels suggests that local organization of the matrix may guide morphogenesis. Here, we quantified the effects of both bulk material stiffness and local collagen fiber arrangement on epithelial morphogenesis.The formation of ducts and acini from single cells and the reorganization of the collagen fiber network were quantified using time-lapse confocal microscopy. MCF10A cells organized the surrounding collagen fibers during the first twelve hours after seeding. Collagen fiber density and alignment relative to the epithelial surface significantly increased within the first twelve hours and were a major influence in the shaping of the mammary epithelium. The addition of Matrigel to the collagen fiber network impaired cell-mediated reorganization of the matrix and increased the probability of spheroidal acini rather than branching ducts. The mechanical anisotropy created by regions of highly aligned collagen fibers facilitated elongation and branching, which was significantly correlated with fiber organization. In contrast, changes in bulk stiffness were not a strong predictor of this epithelial morphology.Localized regions of collagen fiber alignment are required for ductal elongation and branching suggesting the importance of local mechanical anisotropy in mammary epithelial morphogenesis. Similar principles may govern the morphology of branching and budding in other tissues and organs.

  16. Spatial organization of adhesion: force-dependent regulation and function in tissue morphogenesis

    OpenAIRE

    Papusheva, Ekaterina; Heisenberg, Carl-Philipp

    2010-01-01

    The Heisenberg laboratory reviews the spatial organization of signalling complexes at cell–matrix and cell–cell contact sites and its impact on cell integrity, cellular polarity and tissue morphogenesis.

  17. Personalised iron supply for prophylaxis and treatment of pregnant women as a way to ensure normal iron levels in their breast milk.

    Science.gov (United States)

    Marin, G H; Mestorino, N; Errecalde, J; Huber, B; Uriarte, A; Orchuela, J

    2012-02-22

    Because the characteristics of all body fluids depends on patient's health status, is it possible that disadvantaged and socially vulnerable mothers may have lower amounts of iron in their breast milk, and that their babies receive lower content of the mineral for their normal growth and development. Assuring a preventive treatment of the mother might solve this problem. To demonstrate breast milk iron content from disadvantaged mothers and impact of personalized iron supplementation program. cross-sectional study. Breast milk samples were obtained for ferritin analysis. Health's services usually provides free folic acid and iron treatment however, treatment compliance is low. Patients were random in two groups: "A: Controls" that had free iron tablets available from Health Centre; and "B: Intervention" group where patients accepted to be periodically contacted at home by health's team for personalized iron dispensation. 360 patients were included. Profilaxis and treatment compliance were 100% and 97,6% for B group while for "Control" one was 63% and 34%(p0.0001). Higher breast milk iron levels were detected in Intervention's mothers compared with control's patients (p0.007). Personalized iron prophylaxis and treatment increased breast milk iron levels. Public health policy must ensure iron dispensation for each underserved mother in order to reduce children problems associate to iron deficiency during the first year of their life.

  18. Extending Graphic Statics for User-Controlled Structural Morphogenesis

    OpenAIRE

    Fivet, Corentin; Zastavni, Denis; Cap, Jean-François; Structural Morphology Group International Seminar 2011

    2011-01-01

    The first geometrical definitions of any structure are of primary importance when considering pertinence and efficiency in structural design processes. Engineering history has taught us how graphic statics can be a very powerful tool since it allows the designer to take shapes and forces into account simultaneously. However, current and past graphic statics methods are more suitable for analysis than structural morphogenesis. This contribution introduces new graphical methods that can supp...

  19. Reverse engineering the mechanical and molecular pathways in stem cell morphogenesis.

    Science.gov (United States)

    Lu, Kai; Gordon, Richard; Cao, Tong

    2015-03-01

    The formation of relevant biological structures poses a challenge for regenerative medicine. During embryogenesis, embryonic cells differentiate into somatic tissues and undergo morphogenesis to produce three-dimensional organs. Using stem cells, we can recapitulate this process and create biological constructs for therapeutic transplantation. However, imperfect imitation of nature sometimes results in in vitro artifacts that fail to recapitulate the function of native organs. It has been hypothesized that developing cells may self-organize into tissue-specific structures given a correct in vitro environment. This proposition is supported by the generation of neo-organoids from stem cells. We suggest that morphogenesis may be reverse engineered to uncover its interacting mechanical pathway and molecular circuitry. By harnessing the latent architecture of stem cells, novel tissue-engineering strategies may be conceptualized for generating self-organizing transplants. Copyright © 2013 John Wiley & Sons, Ltd.

  20. Mutation analysis of breast cancer gene BRCA among breast cancer Jordanian females

    International Nuclear Information System (INIS)

    Atoum, Manar F.; Al-Kayed, Sameer A.

    2004-01-01

    To screen mutations of the tumor suppressor breast cancer susceptibility gene 1 (BRCA1) within 3 exons among Jordanian breast cancer females. A total of 135 Jordanian breast cancer females were genetically analyzed by denaturing gradient electrophoresis (DGGE) for mutation detection in 3 BRCA1 exons (2, 11 and 20) between 2000-2002 in Al-Basheer Hospital, Amman, Jordan. Of the studied patients 50 had a family history of breast cancer, 28 had a family history of cancer other than breast cancer, and 57 had no family history of any cancer. Five germline mutations were detected among breast cancer females with a family history of breast cancers (one in exon 2 and 4 mutations in exon 11). Another germline mutation (within exon 11) was detected among breast cancer females with family history of cancer other than breast cancer, and no mutation was detected among breast cancer females with no family history of any cancer or among normal control females. Screening mutations within exon 2, exon 11 and exon 20 showed that most screened mutations were within BRCA1 exon 11 among breast cancer Jordanian families with a family history of breast cancer. (author)

  1. Newt tail regeneration: a model for gravity-dependent morphogenesis and clues to the molecular mechanisms involved.

    Science.gov (United States)

    Radugina, Elena A.; Almeida, Eduardo; Grigoryan, Eleonora

    Gravity alterations are widely recognized to influence living systems. They may cause temporary or permanent effects on physiology and development at different levels, from gene expression to morphogenesis. However, the molecular mechanisms underlying these effects are often unclear, and adequate model systems to study them are required. To address this problem we developed a new experimental model of how gravity affects morphogenesis during tail regeneration in the newt Pleurodeles waltl. The effects of increased gravity on newt tail morphogenesis were first documented in two joint Russian-US NASA spaceflight experiments in the Russian Foton-M2 (2005) and Foton-M3 (2007) missions. In these experiments the shape of newt tail regenerate was found to depend on the gravity level, being dorso-ventrally symmetrical in microgravity and in neutrally-buoyant aquarium controls, versus hook-like and bent downward in 1g controls. These 1g controls were conducted in spaceflight habitats using a water-saturated PVA sponge mat. These results were reproducible in multiple spaceflight, and ground laboratory studies, both in the US at NASA ARC and in Russia at IDB RAS, and were characterized in detail using morphometry and histology approaches. The role of hypergravity in shaping morphogenesis was confirmed at NASA ARC with an experiment in the ISS Testbed 8-foot diameter centrifuge operating at 2g. Animals that experienced two-week centrifugation (the period of time used in the Foton flights) developed the same hook-like regenerates as 1g controls, and morphometric analysis revealed no significant difference between 1g and 2g groups, however both were significantly different from aquarium controls. We hypothesize that exposure to 1g or 2g during tail morphogenesis constitutes excessive loading for newts that are adapted to microgravity-like conditions in their aquatic habitat. Because Heat Shock Proteins (HSPs) are stress-induced molecules that respond to a broad variety of

  2. Isomyosin expression patterns during rat heart morphogenesis: an immunohistochemical study

    NARCIS (Netherlands)

    de Groot, I. J.; Lamers, W. H.; Moorman, A. F.

    1989-01-01

    An immunohistochemical study of cardiac alpha and beta myosin heavy chain (MHC) expression during rat heart morphogenesis was performed. In tubular hearts (embryonic days, ED10-11) coexpression of both cardiac alpha and beta MHC was found throughout the heart, except for the left free wall of the

  3. Transcriptomic profiling of curcumin-treated human breast stem cells identifies a role for stearoyl-coa desaturase in breast cancer prevention.

    Science.gov (United States)

    Colacino, Justin A; McDermott, Sean P; Sartor, Maureen A; Wicha, Max S; Rozek, Laura S

    2016-07-01

    Curcumin is a potential agent for both the prevention and treatment of cancers. Curcumin treatment alone, or in combination with piperine, limits breast stem cell self-renewal, while remaining non-toxic to normal differentiated cells. We paired fluorescence-activated cell sorting with RNA sequencing to characterize the genome-wide changes induced specifically in normal breast stem cells following treatment with these compounds. We generated genome-wide maps of the transcriptional changes that occur in epithelial-like (ALDH+) and mesenchymal-like (ALDH-/CD44+/CD24-) normal breast stem/progenitor cells following treatment with curcumin and piperine. We show that curcumin targets both stem cell populations by down-regulating expression of breast stem cell genes including ALDH1A3, CD49f, PROM1, and TP63. We also identified novel genes and pathways targeted by curcumin, including downregulation of SCD. Transient siRNA knockdown of SCD in MCF10A cells significantly inhibited mammosphere formation and the mean proportion of CD44+/CD24- cells, suggesting that SCD is a regulator of breast stemness and a target of curcumin in breast stem cells. These findings extend previous reports of curcumin targeting stem cells, here in two phenotypically distinct stem/progenitor populations isolated from normal human breast tissue. We identified novel mechanisms by which curcumin and piperine target breast stem cell self-renewal, such as by targeting lipid metabolism, providing a mechanistic link between curcumin treatment and stem cell self-renewal. These results elucidate the mechanisms by which curcumin may act as a cancer-preventive compound and provide novel targets for cancer prevention and treatment.

  4. In vivo measurement of tumor estradiol and Vascular Endothelial Growth Factor in breast cancer patients

    International Nuclear Information System (INIS)

    Garvin, Stina; Dabrosin, Charlotta

    2008-01-01

    Angiogenesis, crucial for tumor progression, is a process regulated in the tissue micro-environment. Vascular endothelial growth factor (VEGF) is a potent stimulatory factor of angiogenesis and a negative prognostic indicator of breast cancer. VEGF is biologically active in the extracellular space and hitherto, there has been a lack of techniques enabling sampling of angiogenic molecules such as VEGF in situ. The majority of breast cancers are estrogen-dependent, and estrogen has been shown to regulate VEGF in normal breast tissue and experimental breast cancer. We investigated if microdialysis may be applicable in human breast cancer for sampling of extracellular VEGF in situ and to explore if there is an association with local estradiol and VEGF levels in normal and cancerous breast tissue. Microdialysis was used to sample VEGF and estradiol in tumors and adjacent normal breast tissue in postmenopausal breast cancer patients. VEGF and estradiol were also measured in plasma, and immunohistochemical staining for VEGF was performed on tumor sections. We show that in vivo levels of extracellular VEGF were significantly higher in breast cancer tumors than in normal adjacent breast tissue. There was a significant positive correlation between estradiol and extracellular VEGF in normal breast tissue. However, no correlation was detected between estradiol and VEGF in tumors or between tumor VEGF and plasma VEGF. We conclude that VEGF and estradiol correlates significantly in normal breast tissue. Microdialysis may be used to provide novel insight in breast tumor biology and the regulation of molecules in the extracellular space of human breast tumors in vivo

  5. Dynamics of Spore Coat Morphogenesis in Bacillus subtilis

    Science.gov (United States)

    McKenney, Peter T.; Eichenberger, Patrick

    2011-01-01

    SUMMARY Spores of Bacillus subtilis are encased in a protective coat made up of at least 70 proteins. The structure of the spore coat has been examined using a variety of genetic, imaging and biochemical techniques, however, the majority of these studies have focused on mature spores. In this study we use a library of 41 spore coat proteins fused to the Green Fluorescent Protein (GFP) to examine spore coat morphogenesis over the time-course of sporulation. We found considerable diversity in the localization dynamics of coat proteins and were able to establish 6 classes based on localization kinetics. Localization dynamics correlate well with the known transcriptional regulators of coat gene expression. Previously, we described the existence of multiple layers in the mature spore coat. Here, we find that the spore coat initially assembles a scaffold that is organized into multiple layers on one pole of the spore. The coat then encases the spore in multiple coordinated waves. Encasement is driven, at least partially, by transcription of coat genes and deletion of sporulation transcription factors arrests encasement. We also identify the trans-compartment SpoIIIAH-SpoIIQ channel as necessary for encasement. This is the first demonstration of a forespore contribution to spore coat morphogenesis. PMID:22171814

  6. DNA Methylation Alterations in Breast Cancer

    National Research Council Canada - National Science Library

    Yamamoto, Fumiichiro

    2002-01-01

    We have performed the NotI-MseI MS-AFLP experiments using normal and tumor DNA from breast cancer patients and determined the identity of bands exhibiting consistent changes in breast cancer DNA fingerprint...

  7. Morphogenesis of Pestiviruses: New Insights from Ultrastructural Studies of Strain Giraffe-1

    Science.gov (United States)

    Mast, Jan; Thiel, Heinz-Jürgen; König, Matthias

    2014-01-01

    Knowledge on the morphogenesis of pestiviruses is limited due to low virus production in infected cells. In order to localize virion morphogenesis and replication sites of pestiviruses and to examine intracellular virion transport, a cell culture model was established to facilitate ultrastructural studies. Based on results of virus growth kinetic analysis and quantification of viral RNA, pestivirus strain Giraffe-1 turned out to be a suitable candidate for studies on virion generation and export from culture cells. Using conventional transmission electron microscopy and single-tilt electron tomography, we found virions located predominately in the lumen of the endoplasmic reticulum (ER) in infected cells and were able to depict the budding process of virions at ER membranes. Colocalization of the viral core protein and the envelope glycoprotein E2 with the ER marker protein disulfide isomerase (PDI) was demonstrated by immunogold labeling of cryosections. Moreover, pestivirions could be shown in transport vesicles and the Golgi complex and during exocytosis. Interestingly, viral capsid protein and double-stranded RNA (dsRNA) were detected in multivesicular bodies (MVBs), which implies that the endosomal compartment plays a role in pestiviral replication. Significant cellular membrane alterations such as those described for members of the Flavivirus and Hepacivirus genera were not found. Based on the gained morphological data, we present a consistent model of pestivirus morphogenesis. PMID:24352462

  8. Expression of the pluripotency transcription factor OCT4 in the normal and aberrant mammary gland

    Directory of Open Access Journals (Sweden)

    Foteini eHassiotou

    2013-04-01

    Full Text Available Breast cancers with lactating features, some of which are associated with pregnancy and lactation, are often poorly differentiated, lack estrogen receptor, progesterone receptor and HER2 expression and have high mortality. Very little is known about the molecular mechanisms that drive uncontrolled cell proliferation in these tumors and confer lactating features. We have recently reported expression of OCT4 and associated embryonic stem cell (ESC self-renewal genes in the normal lactating breast and breastmilk stem cells (hBSCs. This prompted us to examine OCT4 expression in breast cancers with lactating features and compare it with that observed during normal lactation, using rare specimens of human lactating breast. In accordance with previous literature, the normal resting breast (from non-pregnant, non-lactating women showed minimal OCT4 nuclear expression (0.9%. However, this increased in the normal lactating breast (11.4%, with further increase in lactating adenomas, lactating carcinomas and pregnancy-associated breast cancer (30.7-48.3%. OCT4 was expressed in the epithelium and at lower levels in the stroma, and was co-localized with NANOG. Comparison of normal non-tumorigenic hBSCs with OCT4-overexpressing tumorigenic breast cell lines (OTBCs demonstrated upregulation of OCT4, SOX2 and NANOG in both systems, but OTBCs expressed OCT4 at significantly higher levels than SOX2 and NANOG. Similar to hBSCs, OTBCs displayed multi-lineage differentiation potential, including the ability to differentiate into functional lactocytes synthesizing milk proteins both in vitro and in vivo. Based on these findings, we propose a hypothesis of normal and malignant transformation in the breast, which centers on OCT4 and its associated gene network. Although minimal expression of these embryonic genes can be seen in the breast in its resting state throughout life, a controlled program of upregulation of this gene network may be a potential regulator of the

  9. Dosimetric investigation depending on tumor location in patient breast in partial breast irradiation

    International Nuclear Information System (INIS)

    Kim, Min Joo; Park, So Hyun; Jung, Joo Young; Woong, Cho; Suh, Tae Suk

    2012-01-01

    The Partial Breast Irradiation (PBI) technique, which involves radiation beam delivery techniques that use a limited range of treatment volumes, has been a challenging approach that is worthy of consideration compared to whole-breast radiation therapy (WBRT). Because of a small target volumes used in the PBI technique, the radiation dose can be safely delivered to the targeted tissue without the unwanted delivery of radiation to normal breast tissues and organ at risk (OAR), such as contralateral breast, lung and heart.Through PBI technique, better cosmetic outcomes and minimizing damages to OARs could be expected and also the daily dose can be increased with smaller number of fractionation in radiation therapy. The purpose of this study was to evaluate the dosimetric effects according to tumor locations in patient's breast for Partial Breast Irradiation (PBI) technique using three Dimensional Conformal Radiation Therapy (3DCRT), Electron Beam Radiation therapy (EBRT) and Helical-tomotherapy (H-TOMO). Dosimetric comparisons of PBI technique for 3DCRT, EBRT, and H-TOMO depending on the classified tumor locations were performed. H-TOMO delivered the low dose to lager volume to surrounding normal tissue, such as the heart and lungs compared to 3DCRT and EBRT although it had the same degree of target coverage as the other methods (3DCRT, EBRT). EBRT had a curative effect for early-stage breast cancers located in the lower and inner sections (LIQ-S, LIQ-D)

  10. NFIX Regulates Neural Progenitor Cell Differentiation During Hippocampal Morphogenesis

    Science.gov (United States)

    Heng, Yee Hsieh Evelyn; McLeay, Robert C.; Harvey, Tracey J.; Smith, Aaron G.; Barry, Guy; Cato, Kathleen; Plachez, Céline; Little, Erica; Mason, Sharon; Dixon, Chantelle; Gronostajski, Richard M.; Bailey, Timothy L.; Richards, Linda J.; Piper, Michael

    2014-01-01

    Neural progenitor cells have the ability to give rise to neurons and glia in the embryonic, postnatal and adult brain. During development, the program regulating whether these cells divide and self-renew or exit the cell cycle and differentiate is tightly controlled, and imbalances to the normal trajectory of this process can lead to severe functional consequences. However, our understanding of the molecular regulation of these fundamental events remains limited. Moreover, processes underpinning development of the postnatal neurogenic niches within the cortex remain poorly defined. Here, we demonstrate that Nuclear factor one X (NFIX) is expressed by neural progenitor cells within the embryonic hippocampus, and that progenitor cell differentiation is delayed within Nfix−/− mice. Moreover, we reveal that the morphology of the dentate gyrus in postnatal Nfix−/− mice is abnormal, with fewer subgranular zone neural progenitor cells being generated in the absence of this transcription factor. Mechanistically, we demonstrate that the progenitor cell maintenance factor Sry-related HMG box 9 (SOX9) is upregulated in the hippocampus of Nfix−/− mice and demonstrate that NFIX can repress Sox9 promoter-driven transcription. Collectively, our findings demonstrate that NFIX plays a central role in hippocampal morphogenesis, regulating the formation of neuronal and glial populations within this structure. PMID:23042739

  11. ONSET PENGELUARAN KOLOSTRUM PERSALINAN NORMAL LEBIH CEPAT DARIPADA PERSALINAN SECTIO CAESARIA

    Directory of Open Access Journals (Sweden)

    Maria NSW Kause

    2016-12-01

    Full Text Available Background: Lactation onset is a term of multiplying breast milk until the release of breast milk for the first time. It is also perceived by mothers as a bit hard breast, inflammed, and full of breast milk or the release of colostrum. Colostrum is the first liquid secreted by breast milk gland since the first day until the fourth day of labour. One of the factors that influences lactation onset is labour methods. Mothers who undergo sectio caesaria surgery will experience pain and prolonged effects of anesthesia compared to mothers with normal labors. Objective: To investigate the difference of colostrum releasing onset in post partum mothers with normal labors and sectio caesaria in Panembahan Senopati General Hospital, Bantul. Method: This study was quantitative with cross sectional design. The number of samples were 80 respondents selected with purposive sampling technique. Study instrument was observational sheets. Data analysis applied Mann-Whitney test. Result: The majority of respondents who had normal labors and sectio caesaria experienced different colostrum onset. In normal labors, the time of colostrum release was 1 day. In sectio caesaria labors, the time of colostrum release was 2 days. The average duration of post partum mothers with normal labors was 13,6 hours and post partum mothers with sectio caesaria was 22,6 hours. The result of Mann-Whitney test was that there was a difference between colostrum release onset of post partum mothers with normal labors and sectio caesaria with p-value of 0,001 (p<0,05. Conclusion: Colostrum onsets were different in normal labors and sectio caesaria labors.

  12. CA 15-3 and lipid profile in preoperative breast cancer patients

    International Nuclear Information System (INIS)

    Jamall, S.; Ishaq, M.; Khadim, M.; Alam, J.M.

    2010-01-01

    The transmembrane glycoprotein CA 15-3 is the most widely used serum tumor marker in breast cancer. At present the main uses of CA 15-3 are in pre-clinically detecting recurrent breast cancer and monitoring the treatment of patients with advanced breast cancer. The aim of this study was to define the role of preoperative concentrations of serum CA 15-3a sp rognostic factor and to determine its sensitivity. Serum and plasma samples from breast cancer patients and normal individuals under fasting condition were used to estimate CAlS-3 and lipid profile. The lipid profile was done in order to assess the impact of plasma lipid on the progression of breast cancer. The serum concentration of the tumor marker CAlS-3 in preoperative breast cancer patients was found to be significantly higher (p<0.001) as compared to the normal individuals. The plasma cholesterol (TC), triglyceride (TRG) and total lipid (TL) levels in breast cancer patients were found to be significantly higher (p< O.OI) for TC, TRG and TL as compared to the normal individuals. Moreover, plasma LDL-C levels in breast cancer patients were found to be significantly higher (p< O.OI) compared to the normal individuals. (author)

  13. Binding of glutathione to enterovirus capsids is essential for virion morphogenesis.

    NARCIS (Netherlands)

    Thibaut, H.J.; Linden, L. van der; Jiang, P.; Thys, B.; Canela, M.D.; Aguado, L.; Rombaut, B.; Wimmer, E.; Paul, A.; Perez-Perez, M.J.; Kuppeveld, F.J.M. van; Neyts, J.

    2014-01-01

    Enteroviruses (family of the Picornaviridae) cover a large group of medically important human pathogens for which no antiviral treatment is approved. Although these viruses have been extensively studied, some aspects of the viral life cycle, in particular morphogenesis, are yet poorly understood. We

  14. Binding of glutathione to enterovirus capsids is essential for virion morphogenesis

    NARCIS (Netherlands)

    Thibaut, Hendrik Jan; van der Linden, Lonneke; Jiang, Ping; Thys, Bert; Canela, María-Dolores; Aguado, Leire; Rombaut, Bart; Wimmer, Eckard; Paul, Aniko; Pérez-Pérez, María-Jesús; van Kuppeveld, Frank J M; Neyts, Johan

    Enteroviruses (family of the Picornaviridae) cover a large group of medically important human pathogens for which no antiviral treatment is approved. Although these viruses have been extensively studied, some aspects of the viral life cycle, in particular morphogenesis, are yet poorly understood. We

  15. Myoepithelial Cells: Their Origin and Function in Lacrimal Gland Morphogenesis, Homeostasis, and Repair.

    Science.gov (United States)

    Makarenkova, Helen P; Dartt, Darlene A

    2015-09-01

    Lacrimal gland (LG) is an exocrine tubuloacinar gland that secretes the aqueous layer of the tear film. LG epithelium is composed of ductal, acinar, and myoepithelial cells (MECs) bordering the basal lamina and separating the epithelial layer from the extracellular matrix. Mature MECs have contractile ability and morphologically resemble smooth muscle cells; however, they exhibit features typical for epithelial cells, such as the presence of specific cytokeratin filaments. Increasing evidence supports the assertion that myoepithelial cells (MECs) play key roles in the lacrimal gland development, homeostasis, and stabilizing the normal structure and polarity of LG secretory acini. MECs take part in the formation of extracellular matrix gland and participate in signal exchange between epithelium and stroma. MECs have a high level of plasticity and are able to differentiate into several cell lineages. Here, we provide a review on some of the MEC characteristics and their role in LG morphogenesis, maintenance, and repair.

  16. Essential role for fibrillin-2 in zebrafish notochord and vascular morphogenesis.

    Science.gov (United States)

    Gansner, John M; Madsen, Erik C; Mecham, Robert P; Gitlin, Jonathan D

    2008-10-01

    Recent studies demonstrate that lysyl oxidase cuproenzymes are critical for zebrafish notochord formation, but the molecular mechanisms of copper-dependent notochord morphogenesis are incompletely understood. We, therefore, conducted a forward genetic screen for zebrafish mutants that exhibit notochord sensitivity to lysyl oxidase inhibition, yielding a mutant with defects in notochord and vascular morphogenesis, puff daddygw1 (pfdgw1). Meiotic mapping and cloning reveal that the pfdgw1 phenotype results from disruption of the gene encoding the extracellular matrix protein fibrillin-2, and the spatiotemporal expression of fibrillin-2 is consistent with the pfdgw1 phenotype. Furthermore, each aspect of the pfdgw1 phenotype is recapitulated by morpholino knockdown of fibrillin-2. Taken together, the data reveal a genetic interaction between fibrillin-2 and the lysyl oxidases in notochord formation and demonstrate the importance of fibrillin-2 in specific early developmental processes in zebrafish. Copyright (c) 2008 Wiley-Liss, Inc.

  17. Semaphorin-Plexin Signaling Controls Mitotic Spindle Orientation during Epithelial Morphogenesis and Repair

    DEFF Research Database (Denmark)

    Xia, Jingjing; Swiercz, Jakub M.; Bañón-Rodríguez, Inmaculada

    2015-01-01

    Morphogenesis, homeostasis, and regeneration of epithelial tissues rely on the accurate orientation of cell divisions, which is specified by the mitotic spindle axis. To remain in the epithelial plane, symmetrically dividing epithelial cells align their mitotic spindle axis with the plane. Here, we...... show that this alignment depends on epithelial cell-cell communication via semaphorin-plexin signaling. During kidney morphogenesis and repair, renal tubular epithelial cells lacking the transmembrane receptor Plexin-B2 or its semaphorin ligands fail to correctly orient the mitotic spindle, leading...... to severe defects in epithelial architecture and function. Analyses of a series of transgenic and knockout mice indicate that Plexin-B2 controls the cell division axis by signaling through its GTPase-activating protein (GAP) domain and Cdc42. Our data uncover semaphorin-plexin signaling as a central...

  18. A novel ALS-associated variant in UBQLN4 regulates motor axon morphogenesis

    Science.gov (United States)

    Edens, Brittany M; Yan, Jianhua; Miller, Nimrod; Deng, Han-Xiang; Siddique, Teepu; Ma, Yongchao C

    2017-01-01

    The etiological underpinnings of amyotrophic lateral sclerosis (ALS) are complex and incompletely understood, although contributions to pathogenesis by regulators of proteolytic pathways have become increasingly apparent. Here, we present a novel variant in UBQLN4 that is associated with ALS and show that its expression compromises motor axon morphogenesis in mouse motor neurons and in zebrafish. We further demonstrate that the ALS-associated UBQLN4 variant impairs proteasomal function, and identify the Wnt signaling pathway effector beta-catenin as a UBQLN4 substrate. Inhibition of beta-catenin function rescues the UBQLN4 variant-induced motor axon phenotypes. These findings provide a strong link between the regulation of axonal morphogenesis and a new ALS-associated gene variant mediated by protein degradation pathways. DOI: http://dx.doi.org/10.7554/eLife.25453.001 PMID:28463112

  19. Diffusion weighted imaging of the normal breast: reproducibility of apparent diffusion coefficient measurements and variation with menstrual cycle and menopausal status

    Energy Technology Data Exchange (ETDEWEB)

    O' Flynn, Elizabeth A.M.; Morgan, Veronica A.; Giles, Sharon L. [Cancer Research UK and ESPSRC Cancer Imaging Centre, Clinical Magnetic Resonance Group, Surrey (United Kingdom); deSouza, Nandita M. [Royal Marsden NHS Foundation Trust, Clinical Magnetic Resonance Group, Institute of Cancer Research, Surrey (United Kingdom)

    2012-07-15

    To establish the reproducibility of apparent diffusion coefficient (ADC) measurements in normal fibroglandular breast tissue and to assess variation in ADC values with phase of the menstrual cycle and menopausal status. Thirty-one volunteers (13 premenopausal, 18 postmenopausal) underwent magnetic resonance twice (interval 11-22 days) using diffusion-weighted MRI. ADC{sub total} and a perfusion-insensitive ADC{sub high} (omitting b = 0) were calculated. Reproducibility and inter-observer variability of mean ADC values were assessed. The difference in mean ADC values between the two phases of the menstrual cycle and the postmenopausal breast were evaluated. ADC{sub total} and ADC{sub high} showed good reproducibility (r% = 17.6, 22.4). ADC{sub high} showed very good inter-observer agreement (kappa = 0.83). The intraclass correlation coefficients (ICC) were 0.93 and 0.91. Mean ADC values were significantly lower in the postmenopausal breast (ADC{sub total} 1.46 {+-} 0.3 x 10{sup -3} mm{sup 2}/s, ADC{sub high} 1.33 {+-} 0.3 x 10{sup -3} mm{sup 2}/s) compared with the premenopausal breast (ADC{sub total} 1.84 {+-} 0.26 x 10{sup -3} mm{sup 2}/s, ADC{sub high} 1.77 {+-} 0.26 x 10{sup -3} mm{sup 2}/s; both P < 0.001). No significant difference was seen in ADC values in relation to menstrual cycle (ADC{sub total} P = 0.2, ADC{sub high} P = 0.24) or between postmenopausal women taking or not taking oestrogen supplements (ADC{sub total} P = 0.6, ADC{sub high} P = 0.46). ADC values in fibroglandular breast tissue are reproducible. Lower ADC values within the postmenopausal breast may reduce diffusion-weighted contrast and have implications for accurately detecting tumours. (orig.)

  20. Association between local inflammation and breast tissue age-related lobular involution among premenopausal and postmenopausal breast cancer patients.

    Directory of Open Access Journals (Sweden)

    Mirette Hanna

    Full Text Available Increased levels of pro-inflammatory markers and decreased levels of anti-inflammatory markers in the breast tissue can result in local inflammation. We aimed to investigate whether local inflammation in the breast tissue is associated with age-related lobular involution, a process inversely related to breast cancer risk. Levels of eleven pro- and anti-inflammatory markers were assessed by immunohistochemistry in normal breast tissue obtained from 164 pre- and postmenopausal breast cancer patients. Involution status of the breast (degree of lobular involution and the predominant lobule type was microscopically assessed in normal breast tissue on hematoxylin-eosin stained mastectomy slides. Multivariate generalized linear models were used to assess the associations. In age-adjusted analyses, higher levels of pro-inflammatory markers IL-6, TNF-α, CRP, COX-2, leptin, SAA1 and IL-8; and anti-inflammatory marker IL-10, were inversely associated with the prevalence of complete lobular involution (all P≤0.04. Higher levels of the pro-inflammatory marker COX-2 were also associated with lower prevalence of predominant type 1/no type 3 lobules in the breast, an indicator of complete involution, in age-adjusted analysis (P = 0.017. Higher tissue levels of inflammatory markers, mainly the pro-inflammatory ones, are associated with less involuted breasts and may consequently be associated with an increased risk of developing breast cancer.

  1. Giga-voxel computational morphogenesis for structural design

    DEFF Research Database (Denmark)

    Aage, Niels; Andreassen, Erik; Lazarov, Boyan Stefanov

    2017-01-01

    In the design of industrial products ranging from hearing aidsto automobiles and aeroplanes, material is distributed so as to maximize the performance and minimize the cost. Historically, human intuition and insight have driven the evolution of mechanical design, recently assisted by computer...... aeroplane wing designs, which translates into are duction in fuel consumption of about 40–200 tonnes per year per aeroplane. Our morphogenesis process is generally applicable, not only to mechanical design, but also to flow systems3, antennas4,nano-optics5 and micro-systems6,7...

  2. Traço e estado de ansiedade de nutrizes com indicadores de hipogalactia e nutrizes com galactia normal Trazo y estado de ansiedad de mujeres lactantes con indicadores de hipogalactia y mujeres lactantes con galactia normal Trace and anxiety of nursing mothers with insufficient and normal breast feeding indicators

    Directory of Open Access Journals (Sweden)

    Ilva Marico Mizumoto Aragaki

    2006-09-01

    haber sido consecuencia de la corrección de la técnica de amamantamiento y apoyo a las mujeres lactantes.The objective of this study was to identify and compare the trace and the anxiety state on the 10th day postpartum and the anxiety state on the 30th day postpartum of primiparous and multiparous nursing mothers who present insufficient breast feeding indicators and nursing mothers with normal breast feeding, in order to verify the possible relationships between the anxiety state of the nursing mothers in those two moments with the insufficient breast feeding indicators presented. This is an exploratory and descriptive study, whose data has been gotten from 168 nursing mothers and their children by means of interviews in nursing consultations in the 10th and 30th day postpartum. The results obtained showed that primiparous and multiparous with insufficient breast feeding and primiparous with normal lactation presented higher anxiety state trace than the anxiety state on the 10th and 30th day postpartum. There was remission of the maternal signals of anxiety with the passing of time, which may be caused by the correction of the breast feeding technique and support to the nursing mothers.

  3. Hypoxia-inducible factor 1α regulates branching morphogenesis during kidney development.

    Science.gov (United States)

    Tsuji, Kenji; Kitamura, Shinji; Makino, Hirofumi

    2014-04-25

    The kidneys are exposed to hypoxic conditions during development. Hypoxia-inducible factor (HIF), an important mediator of the response to hypoxia, is believed to have an important role in development. However, the relationship between HIF and branching morphogenesis has not been elucidated clearly. In this study, we examined whether HIF regulates kidney development. We harvested kidneys from day 13 rat embryos (E13Ks) and cultured the organs under normoxic (20% O2/5% CO2) or hypoxic (5% O2/5% CO2) conditions. We evaluated the kidneys based on morphology and gene expression. E13Ks cultured under hypoxic conditions had significantly more ureteric bud (UB) branching than the E13Ks cultured under normoxic conditions. In addition, the mRNA levels of GDNF and GDNF receptor (GFR-α1), increased under hypoxic conditions in E13Ks. When we cultured E13Ks with the HIF-1α inhibitor digoxin or with siRNA targeting HIF-1α under hypoxic conditions, we did not observe increased UB branching. In addition, the expression of GDNF and GFR-α1 was inhibited under hypoxic conditions when the kidneys were treated with siRNA targeting HIF-1α. We also elucidated that hypoxia inhibited UB cell apoptosis and promoted the expression of FGF7 mRNA levels in metanephric mesenchymal (MM) cells in vitro. These findings suggest that hypoxic condition has important roles in inducing branching morphogenesis during kidney development. Hypoxia might mediate branching morphogenesis via not only GDNF/Ret but also FGF signaling pathway. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Expression characteristic of CXCR1 in different breast tissues and the relevance between its expression and efficacy of neo-adjuvant chemotherapy in breast cancer.

    Science.gov (United States)

    Xue, Miao-Qun; Liu, Jun; Sang, Jian-Feng; Su, Lei; Yao, Yong-Zhong

    2017-07-25

    To investigate chemokine receptor CXCR1 expression characteristic in different breast tissues and analyze the relationship between CXCR1 expression changes in breast cancer tissue and efficacy of neo-adjuvant chemotherapy. Chemokine receptor CXCR1 was lowly expressed in normal breast tissues and breast fibroadenoma, but highly expressed in breast cancer. It was significantly correlated with pathological stage, tumor cell differentiation, and lymph node metastasis (P breast cancer tissues decreased. Among these 104 breast cancer patients with different molecular subtypes, the survival rate with Luminal A was the highest, followed by the Luminal B breast cancer, TNBC was the worst. 104 cases with breast carcinoma, 20 cases with normal breast and 20 cases with breast fibroadenoma were included and followed up. Immunohistochemistry was used to detect the expression of CXCR1 in the various tissues. The relationship between the CXCR1 expression changes in breast cancer biopsies and surgical specimens, as well as the efficacy of neo-adjuvant chemotherapy, was analyzed. Chemokine receptor CXCR1 could be used as an indicator to predict benign or malignant breast disease, and it can even predict the malignancy degree of breast cancer, as well as its invasive ability and prognosis.

  5. Optical diagnostic of breast cancer using Raman, polarimetric and fluorescence spectroscopy

    Science.gov (United States)

    Anwar, Shahzad; Firdous, Shamaraz; Rehman, Aziz-ul; Nawaz, Muhammed

    2015-04-01

    We presented the optical diagnostic of normal and cancerous human breast tissues using Raman, polarimetric and fluorescence spectroscopic techniques. Breast cancer is the second leading cause of cancer death among women worldwide. Optical diagnostics of cancer offered early intervention and the greatest chance of cure. Spectroscopic data were collected from freshly excised surgical specimens of normal tissues with Raman bands at 800, 1171 and 1530 cm-1 arising mainly by lipids, nucleic acids, proteins, carbohydrates and amino acids. For breast cancer, Raman bands are observed at 1070, 1211, 1495, 1583 and 1650 cm-1. Results demonstrate that the spectra of normal tissue are dominated by lipids and amino acids. Polarization decomposition of the Mueller matrix and confocal microscopic fluorescence provides detailed description of cancerous tissue and distinguishes between the normal and malignant one. Based on these findings, we successfully differentiate normal and malignant breast tissues at an early stage of disease. There is a need to develop a new tool for noninvasive, real-time diagnosis of tissue abnormalities and a test procedure for detecting breast cancer at an early stage.

  6. Squamous cell carcinoma of the breast : a case report

    NARCIS (Netherlands)

    Flikweert, Elvira R.; Hofstee, Mans; Liem, Mike S. L.

    2008-01-01

    Background: Squamous cells are normally not found inside the breast, so a primary squamous cell carcinoma of the breast is an exceptional phenomenon. There is a possible explanation for these findings. Case presentation: A 72-year-old woman presented with a breast abnormality suspected for breast

  7. Comparison of telomere length and insulin-like growth factor-binding protein 7 promoter methylation between breast cancer tissues and adjacent normal tissues in Turkish women.

    Science.gov (United States)

    Kaya, Zehra; Akkiprik, Mustafa; Karabulut, Sevgi; Peker, Irem; Gullu Amuran, Gokce; Ozmen, Tolga; Gulluoglu, Bahadır M; Kaya, Handan; Ozer, Ayse

    2017-09-01

    Both insulin-like growth factor-binding protein 7 (IGFBP7) and telomere length (TL) are associated with proliferation and senescence of human breast cancer. This study assessed the clinical significance of both TL and IGFBP7 methylation status in breast cancer tissues compared with adjacent normal tissues. We also investigated whether IGFBP7 methylation status could be affecting TL. Telomere length was measured by quantitative PCR to compare tumors with their adjacent normal tissues. The IGFBP7 promoter methylation status was evaluated by methylation-specific PCR and its expression levels were determined by western blotting. Telomeres were shorter in tumor tissues compared to controls (Pbreast cancer with invasive ductal carcinoma (IDC; n=72; P=.014) compared with other histological type (n=29), and TL in IDC with HER2 negative (n=53; P=.017) was higher than TL in IDC with HER2 positive (n=19). However, telomeres were shortened in advanced stages and growing tumors. IGFBP7 methylation was observed in 90% of tumor tissues and 59% of controls (P=.0002). Its frequency was significantly higher in IDC compared with invasive mixed carcinoma (IMC; P=.002) and it was not correlated either with protein expression or the other clinicopathological parameters. These results suggest that IGFBP7 promoter methylation and shorter TL in tumor compared with adjacent tissues may be predictive biomarkers for breast cancer. Telomere maintenance may be indicative of IDC and IDC with HER2 (-) of breast cancer. Further studies with larger number of cases are necessary to verify this association. © 2016 Wiley Periodicals, Inc.

  8. The ERM protein Moesin is essential for neuronal morphogenesis and long-term memory in Drosophila.

    Science.gov (United States)

    Freymuth, Patrick S; Fitzsimons, Helen L

    2017-08-29

    Moesin is a cytoskeletal adaptor protein that plays an important role in modification of the actin cytoskeleton. Rearrangement of the actin cytoskeleton drives both neuronal morphogenesis and the structural changes in neurons that are required for long-term memory formation. Moesin has been identified as a candidate memory gene in Drosophila, however, whether it is required for memory formation has not been evaluated. Here, we investigate the role of Moesin in neuronal morphogenesis and in short- and long-term memory formation in the courtship suppression assay, a model of associative memory. We found that both knockdown and overexpression of Moesin led to defects in axon growth and guidance as well as dendritic arborization. Moreover, reduction of Moesin expression or expression of a constitutively active phosphomimetic in the adult Drosophila brain had no effect on short term memory, but prevented long-term memory formation, an effect that was independent of its role in development. These results indicate a critical role for Moesin in both neuronal morphogenesis and long-term memory formation.

  9. Mammary collective cell migration involves transient loss of epithelial features and individual cell migration within the epithelium

    Science.gov (United States)

    Ewald, Andrew J.; Huebner, Robert J.; Palsdottir, Hildur; Lee, Jessie K.; Perez, Melissa J.; Jorgens, Danielle M.; Tauscher, Andrew N.; Cheung, Kevin J.; Werb, Zena; Auer, Manfred

    2012-01-01

    Normal mammary morphogenesis involves transitions between simple and multilayered epithelial organizations. We used electron microscopy and molecular markers to determine whether intercellular junctions and apico-basal polarity were maintained in the multilayered epithelium. We found that multilayered elongating ducts had polarized apical and basal tissue surfaces both in three-dimensional culture and in vivo. However, individual cells were only polarized on surfaces in contact with the lumen or extracellular matrix. The basolateral marker scribble and the apical marker atypical protein kinase C zeta localized to all interior cell membranes, whereas PAR3 displayed a cytoplasmic localization, suggesting that the apico-basal polarity was incomplete. Despite membrane localization of E-cadherin and β-catenin, we did not observe a defined zonula adherens connecting interior cells. Instead, interior cells were connected through desmosomes and exhibited complex interdigitating membrane protrusions. Single-cell labeling revealed that individual cells were both protrusive and migratory within the epithelial multilayer. Inhibition of Rho kinase (ROCK) further reduced intercellular adhesion on apical and lateral surfaces but did not disrupt basal tissue organization. Following morphogenesis, segregated membrane domains were re-established and junctional complexes re-formed. We observed similar epithelial organization during mammary morphogenesis in organotypic culture and in vivo. We conclude that mammary epithelial morphogenesis involves a reversible, spatially limited, reduction in polarity and intercellular junctions and active individualistic cell migration. Our data suggest that reductions in polarity and adhesion during breast cancer progression might reflect partial recapitulation of a normal developmental program. PMID:22344263

  10. HER2 induced EMT and tumorigenicity in breast epithelial progenitor cells is inhibited by coexpression of EGFR.

    Science.gov (United States)

    Ingthorsson, S; Andersen, K; Hilmarsdottir, B; Maelandsmo, G M; Magnusson, M K; Gudjonsson, T

    2016-08-11

    The members of the epidermal growth factor receptor (EGFR) kinase family are important players in breast morphogenesis and cancer. EGFR2/HER2 and EGFR expression have a prognostic value in certain subtypes of breast cancer such as HER2-amplified, basal-like and luminal type B. Many clinically approved small molecular inhibitors and monoclonal antibodies have been designed to target HER2, EGFR or both. There is, however, still limited knowledge on how the two receptors are expressed in normal breast epithelium, what effects they have on cellular differentiation and how they participate in neoplastic transformation. D492 is a breast epithelial cell line with stem cell properties that can undergo epithelial to mesenchyme transition (EMT), generate luminal- and myoepithelial cells and form complex branching structures in three-dimensional (3D) culture. Here, we show that overexpression of HER2 in D492 (D492(HER2)) resulted in EMT, loss of contact growth inhibition and increased oncogenic potential in vivo. HER2 overexpression, furthermore, inhibited endogenous EGFR expression. Re-introducing EGFR in D492(HER2) (D492(HER2/EGFR)) partially reversed the mesenchymal state of the cells, as an epithelial phenotype reappeared both in 3D cultures and in vivo. The D492(HER2/EGFR) xenografts grow slower than the D492(HER2) tumors, while overexpression of EGFR alone (D492(EGFR)) was not oncogenic in vivo. Consistent with the EGFR-mediated epithelial phenotype, overexpression of EGFR drove the cells toward a myoepithelial phenotype in 3D culture. The effect of two clinically approved anti-HER2 and EGFR therapies, trastuzumab and cetuximab, was tested alone and in combination on D492(HER2) xenografts. While trastuzumab had a growth inhibitory effect compared with untreated control, the effect of cetuximab was limited. When administered in combination, the growth inhibitory effect of trastuzumab was less pronounced. Collectively, our data indicate that in HER2-overexpressing D492

  11. Primary osteosarcoma of the breast presenting as a large breast abscess

    Directory of Open Access Journals (Sweden)

    Nadeesha J Nawarathna

    2016-01-01

    Full Text Available Primary extra osseous osteogenic sarcoma is one of the rarest forms of malignant tumor of the breast. It can arise as a result of osseous metaplasia of a preexisting neoplasm or from a none-phylloides sarcoma of a previously normal breast. Due to its rarity, the natural history and optimal treatment methods remain unclear. Sixty-year-old patient presented to the surgical casualty with a large breast abscess. Abscess wall histology revealed an osteosarcoma of the breast. Left total mastectomy with axillary clearance was performed. Histology and subsequent imunohistochemical studies confirmed the diagnosis of osteogenic sarcoma without lymph nodal metastasis. Patient was referred to the oncologist for further management. Rare types of breast tumors can be presented as breast abscess. Incision and drainage together with wall biopsy aid to exclude associated sinister pathologies. Diagnosis of primary osteosarcoma of the breast was made using histological and immunohistochemical findings once the possible primary from the bones of sternum and ribs was excluded. Treatment is as for sarcomas affecting other locations and should comprise a multidisciplinary approach.

  12. Fibroblast radiosensitivity versus acute and late normal skin responses in patients treated for breast cancer

    International Nuclear Information System (INIS)

    Brock, William A.; Tucker, Susan L.; Geara, Fady B.; Wike, Jennifer; Peters, Lester J.; Turesson, Ingela; Nyman, Jan

    1995-01-01

    Purpose/Objective: To determine if the radiosensitivity of normal human skin fibroblasts, measured in early passage cultures, is significantly correlated with the degree of acute or late normal skin damage in patients treated for breast cancer with radiotherapy. Methods and Materials: In the 1970s, a series of breast cancer patients was treated at the Department of Oncology in Gothenburg, Sweden with postoperative irradiation to the parasternal region. Patients were treated bilaterally using different fractionation schedules and doses to the right and left fields. Peak acute reactions were scored on a six-point scale, and skin erythema was measured by reflectance spectrophotometry. Telangiectasia was graded over time on a six-point scale. In April 1992, two small skin biopsies were obtained from 22 patients in two treatment groups (i.e., four dose-fractionation schedules) and, using either delayed or immediate plating, fibroblast radiosensitivity was measured in early passage cultures by clonogenic survival, after high and low dose-rate irradiations. Survival at 2.0 Gy (SF2) was calculated from complete survival curves. Results: To test assay reproducibility, SF2 values derived from paired biopsies of the same patient (12 cases) were compared. A reasonably good correlation (p = 0.075) was obtained for SF2s determined by high dose-rate irradiations with immediate plating, but not for delayed plating or low dose-rate treatments. The median coefficient of variation in the replicate SF2s after high dose-rate treatment and immediate plating was 13%, suggesting that the poor correlation in paired SF2 values is due to the magnitude of the uncertainty in SF2 relative to the overall spread in SF2 values between patients (CV = 28%). Individual SF2 values and averaged values from patients with data from two biopsies were compared with the acute and late clinical reactions. A significant negative correlation was found between SF2 and relative clinical response, but only when

  13. Ott1 (Rbm15) is essential for placental vascular branching morphogenesis and embryonic development of the heart and spleen.

    Science.gov (United States)

    Raffel, Glen D; Chu, Gerald C; Jesneck, Jonathan L; Cullen, Dana E; Bronson, Roderick T; Bernard, Olivier A; Gilliland, D Gary

    2009-01-01

    The infant leukemia-associated gene Ott1 (Rbm15) has broad regulatory effects within murine hematopoiesis. However, germ line Ott1 deletion results in fetal demise prior to embryonic day 10.5, indicating additional developmental requirements for Ott1. The spen gene family, to which Ott1 belongs, has a transcriptional activation/repression domain and RNA recognition motifs and has a significant role in the development of the head and thorax in Drosophila melanogaster. Early Ott1-deficient embryos show growth retardation and incomplete closure of the notochord. Further analysis demonstrated placental defects in the spongiotrophoblast and syncytiotrophoblast layers, resulting in an arrest of vascular branching morphogenesis. The rescue of the placental defect using a conditional allele with a trophoblast-sparing cre transgene allowed embryos to form a normal placenta and survive gestation. This outcome showed that the process of vascular branching morphogenesis in Ott1-deficient animals was regulated by the trophoblast compartment rather than the fetal vasculature. Mice surviving to term manifested hyposplenia and abnormal cardiac development. Analysis of global gene expression of Ott1-deficient embryonic hearts showed an enrichment of hypoxia-related genes and a significant alteration of several candidate genes critical for cardiac development. Thus, Ott1-dependent pathways, in addition to being implicated in leukemogenesis, may also be important for the pathogenesis of placental insufficiency and cardiac malformations.

  14. FLI-1 Flightless-1 and LET-60 Ras control germ line morphogenesis in C. elegans

    Directory of Open Access Journals (Sweden)

    Dentler William L

    2008-05-01

    Full Text Available Abstract Background In the C. elegans germ line, syncytial germ line nuclei are arranged at the cortex of the germ line as they exit mitosis and enter meiosis, forming a nucleus-free core of germ line cytoplasm called the rachis. Molecular mechanisms of rachis formation and germ line organization are not well understood. Results Mutations in the fli-1 gene disrupt rachis organization without affecting meiotic differentiation, a phenotype in C. elegans referred to here as the germ line morphogenesis (Glm phenotype. In fli-1 mutants, chains of meiotic germ nuclei spanned the rachis and were partially enveloped by invaginations of germ line plasma membrane, similar to nuclei at the cortex. Extensions of the somatic sheath cells that surround the germ line protruded deep inside the rachis and were associated with displaced nuclei in fli-1 mutants. fli-1 encodes a molecule with leucine-rich repeats and gelsolin repeats similar to Drosophila flightless 1 and human Fliih, which have been shown to act as cytoplasmic actin regulators as well as nuclear transcriptional regulators. Mutations in let-60 Ras, previously implicated in germ line development, were found to cause the Glm phenotype. Constitutively-active LET-60 partially rescued the fli-1 Glm phenotype, suggesting that LET-60 Ras and FLI-1 might act together to control germ line morphogenesis. Conclusion FLI-1 controls germ line morphogenesis and rachis organization, a process about which little is known at the molecular level. The LET-60 Ras GTPase might act with FLI-1 to control germ line morphogenesis.

  15. MO-F-CAMPUS-I-04: Characterization of Fan Beam Coded Aperture Coherent Scatter Spectral Imaging Methods for Differentiation of Normal and Neoplastic Breast Structures

    Energy Technology Data Exchange (ETDEWEB)

    Morris, R; Albanese, K; Lakshmanan, M; Greenberg, J; Kapadia, A [Duke University Medical Center, Durham, NC, Carl E Ravin Advanced Imaging Laboratories, Durham, NC (United States)

    2015-06-15

    Purpose: This study intends to characterize the spectral and spatial resolution limits of various fan beam geometries for differentiation of normal and neoplastic breast structures via coded aperture coherent scatter spectral imaging techniques. In previous studies, pencil beam raster scanning methods using coherent scatter computed tomography and selected volume tomography have yielded excellent results for tumor discrimination. However, these methods don’t readily conform to clinical constraints; primarily prolonged scan times and excessive dose to the patient. Here, we refine a fan beam coded aperture coherent scatter imaging system to characterize the tradeoffs between dose, scan time and image quality for breast tumor discrimination. Methods: An X-ray tube (125kVp, 400mAs) illuminated the sample with collimated fan beams of varying widths (3mm to 25mm). Scatter data was collected via two linear-array energy-sensitive detectors oriented parallel and perpendicular to the beam plane. An iterative reconstruction algorithm yields images of the sample’s spatial distribution and respective spectral data for each location. To model in-vivo tumor analysis, surgically resected breast tumor samples were used in conjunction with lard, which has a form factor comparable to adipose (fat). Results: Quantitative analysis with current setup geometry indicated optimal performance for beams up to 10mm wide, with wider beams producing poorer spatial resolution. Scan time for a fixed volume was reduced by a factor of 6 when scanned with a 10mm fan beam compared to a 1.5mm pencil beam. Conclusion: The study demonstrates the utility of fan beam coherent scatter spectral imaging for differentiation of normal and neoplastic breast tissues has successfully reduced dose and scan times whilst sufficiently preserving spectral and spatial resolution. Future work to alter the coded aperture and detector geometries could potentially allow the use of even wider fans, thereby making coded

  16. Characterization of human breast disease using phosphorus magnetic resonance spectroscopy and proton magnetic resonance imaging

    International Nuclear Information System (INIS)

    Merchant, T.E.

    1992-01-01

    This thesis provides the fundamental characterization and differentiation of breast tissues using in vivo and ex vivo MR techniques in the hope that these techniques and experimental findings will be used on a larger scale and in a predictive manner in order to improve the specificity of diagnosis and treatment of breast cancer. In this dissertation, clinical studies were performed using proton magnetic resonance imaging and phosphorus magnetic resonance spectro-scopy ( 31 P MRS) to characterize and differentiate malignant breast tumors, benign breast tumors and normal breast tissues in vivo. These studies were carried out following the methodical characterization of chemical extracts of malignant breast tumor, benign breast tumor and normal breast parenchymal surgical tissue specimens using high resolution 31 P MRS. Alterations in breast tissue metabolism, as a result of pathological processes, were postulated to be responsible for measurable differences between malignant breast tumors, benign breast tumors and normal breast tissues using magnetic resonance techniques. (author). 365 refs.; 37 figs.; 25 tabs

  17. Exocrine Gland Morphogenesis: Insights into the Role of Amphiregulin from Development to Disease.

    Science.gov (United States)

    Sisto, Margherita; Lorusso, Loredana; Ingravallo, Giuseppe; Lisi, Sabrina

    2017-12-01

    Amphiregulin (AREG) is a well-characterized member of the epidermal growth factor (EGF) family and is one of the ligands of the EGF receptor (EGFR). AREG plays a key role in mammalian development and in the control of branching morphogenesis in various organs. Furthermore, AREG participates in a wide range of physiological and pathological processes activating the major intracellular signalling cascades governing cell survival, proliferation and motility. In this article, we review current advances in exocrine glands morphogenesis, focusing on the salivary gland, and discuss the essential aspects of AREG structure, function and regulation, and its differential role within the EGFR family of ligands. Finally, we identify emerging aspects in AREG research applied to mammary gland development and the salivary gland autoimmune disease, Sjögren's syndrome.

  18. Notochord morphogenesis in mice: Current understanding & open questions.

    Science.gov (United States)

    Balmer, Sophie; Nowotschin, Sonja; Hadjantonakis, Anna-Katerina

    2016-05-01

    The notochord is a structure common to all chordates, and the feature that the phylum Chordata has been named after. It is a rod-like mesodermal structure that runs the anterior-posterior length of the embryo, adjacent to the ventral neural tube. The notochord plays a critical role in embryonic tissue patterning, for example the dorsal-ventral patterning of the neural tube. The cells that will come to form the notochord are specified at gastrulation. Axial mesodermal cells arising at the anterior primitive streak migrate anteriorly as the precursors of the notochord and populate the notochordal plate. Yet, even though a lot of interest has centered on investigating the functional and structural roles of the notochord, we still have a very rudimentary understanding of notochord morphogenesis. The events driving the formation of the notochord are rapid, taking place over the period of approximately a day in mice. In this commentary, we provide an overview of our current understanding of mouse notochord morphogenesis, from the initial specification of axial mesendodermal cells at the primitive streak, the emergence of these cells at the midline on the surface of the embryo, to their submergence and organization of the stereotypically positioned notochord. We will also discuss some key open questions. Developmental Dynamics 245:547-557, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. The Human Cell Surfaceome of Breast Tumors

    Science.gov (United States)

    da Cunha, Júlia Pinheiro Chagas; Galante, Pedro Alexandre Favoretto; de Souza, Jorge Estefano Santana; Pieprzyk, Martin; Carraro, Dirce Maria; Old, Lloyd J.; Camargo, Anamaria Aranha; de Souza, Sandro José

    2013-01-01

    Introduction. Cell surface proteins are ideal targets for cancer therapy and diagnosis. We have identified a set of more than 3700 genes that code for transmembrane proteins believed to be at human cell surface. Methods. We used a high-throuput qPCR system for the analysis of 573 cell surface protein-coding genes in 12 primary breast tumors, 8 breast cell lines, and 21 normal human tissues including breast. To better understand the role of these genes in breast tumors, we used a series of bioinformatics strategies to integrates different type, of the datasets, such as KEGG, protein-protein interaction databases, ONCOMINE, and data from, literature. Results. We found that at least 77 genes are overexpressed in breast primary tumors while at least 2 of them have also a restricted expression pattern in normal tissues. We found common signaling pathways that may be regulated in breast tumors through the overexpression of these cell surface protein-coding genes. Furthermore, a comparison was made between the genes found in this report and other genes associated with features clinically relevant for breast tumorigenesis. Conclusions. The expression profiling generated in this study, together with an integrative bioinformatics analysis, allowed us to identify putative targets for breast tumors. PMID:24195083

  20. Caveolin-1 expression in benign and malignant lesions of the breast

    Directory of Open Access Journals (Sweden)

    Kiesel Ludwig

    2007-10-01

    Full Text Available Abstract Background Caveolin-1 is thought to have an important impact on both signal transduction and mediation of intracellular processes. Furthermore, it has been suggested that Caveolin-1 may contribute to certain steps of carcinogenesis in various types of cancer. We examined the potential clinical relevance of Caveolin-1 in normal, benign and malignant breast tissue specimens. Methods Using tissue microarray (TMA technology cases of invasive breast cancer, DCIS, benign breast disease (i.e. fibroadenoma, sclerosing adenosis, ductal hyperplasia and radial scar and normal breast tissue were evaluated for Caveolin-1 expression. Immunohistochemical staining with an anti-Caveolin-1-antibody was performed. Staining intensity was quantified semiquantitatively. In invasive lesions staining results were correlated with clinical and pathological data. Results No Caveolin-1 expression was observed in epithelial cells of normal breast tissue (n = 5, benign breast disease (n = 295 and DCIS (n = 108. However, Caveolin-1 expression was found in 32 of 109 cases of invasive breast carcinomas (29.4%. Caveolin-1 expression in invasive breast cancer could neither be correlated with survival parameters such as overall or disease-free survival nor with established clinical and pathological markers. Conclusion In this study we demonstrated expression of Caveolin-1 in one third of invasive breast cancers. A significant increase in Caveolin-1 expression was observed comparing invasive breast cancer to both benign breast tissue and non-invasive breast cancer. Since inhibitors of Caveolin-1 signalling are available, targeting Caveolin-1 in breast cancer may represent a potential option for future breast cancer treatment.

  1. Breast Cancer Biomarkers Based on Nipple and Fine Needle Aspirates

    National Research Council Canada - National Science Library

    Russo, Irma H

    2005-01-01

    ... of the cytological normal breast epithelium of women at high risk for breast cancer. This signature will serve as an intermediate biomarker for evaluating the response of the breast to novel chemopreventive agents...

  2. Regulation of cellulase expression, sporulation, and morphogenesis by velvet family proteins in Trichoderma reesei.

    Science.gov (United States)

    Liu, Kuimei; Dong, Yanmei; Wang, Fangzhong; Jiang, Baojie; Wang, Mingyu; Fang, Xu

    2016-01-01

    Homologs of the velvet protein family are encoded by the ve1, vel2, and vel3 genes in Trichoderma reesei. To test their regulatory functions, the velvet protein-coding genes were disrupted, generating Δve1, Δvel2, and Δvel3 strains. The phenotypic features of these strains were examined to identify their functions in morphogenesis, sporulation, and cellulase expression. The three velvet-deficient strains produced more hyphal branches, indicating that velvet family proteins participate in the morphogenesis in T. reesei. Deletion of ve1 and vel3 did not affect biomass accumulation, while deletion of vel2 led to a significantly hampered growth when cellulose was used as the sole carbon source in the medium. The deletion of either ve1 or vel2 led to the sharp decrease of sporulation as well as a global downregulation of cellulase-coding genes. In contrast, although the expression of cellulase-coding genes of the ∆vel3 strain was downregulated in the dark, their expression in light condition was unaffected. Sporulation was hampered in the ∆vel3 strain. These results suggest that Ve1 and Vel2 play major roles, whereas Vel3 plays a minor role in sporulation, morphogenesis, and cellulase expression.

  3. Differentiated roles for MreB-actin isologues and autolytic enzymes in Bacillus subtilis morphogenesis.

    Science.gov (United States)

    Domínguez-Cuevas, Patricia; Porcelli, Ida; Daniel, Richard A; Errington, Jeff

    2013-09-01

    Cell morphogenesis in most bacteria is governed by spatiotemporal growth regulation of the peptidoglycan cell wall layer. Much is known about peptidoglycan synthesis but regulation of its turnover by hydrolytic enzymes is much less well understood. Bacillus subtilis has a multitude of such enzymes. Two of the best characterized are CwlO and LytE: cells lacking both enzymes have a lethal block in cell elongation. Here we show that activity of CwlO is regulated by an ABC transporter, FtsEX, which is required for cell elongation, unlike cell division as in Escherichia coli. Actin-like MreB proteins are thought to play a key role in orchestrating cell wall morphogenesis. B. subtilis has three MreB isologues with partially differentiated functions. We now show that the three MreB isologues have differential roles in regulation of the CwlO and LytE systems and that autolysins control different aspects of cell morphogenesis. The results add major autolytic activities to the growing list of functions controlled by MreB isologues in bacteria and provide new insights into the different specialized functions of essential cell wall autolysins. © 2013 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.

  4. Comparative proteomic analysis of off-type and normal phenotype somatic plantlets derived from somatic embryos of Feijoa (Acca sellowiana (O. Berg) Burret).

    Science.gov (United States)

    Fraga, Hugo Pacheco de Freitas; Agapito-Tenfen, Sarah Zanon; Caprestano, Clarissa Alves; Nodari, Rubens Onofre; Guerra, Miguel Pedro

    2013-09-01

    Morphological disorders in a relevant portion of emerged somatic embryos have been a limiting factor in the true-to-type plantlet formation in Acca sellowiana. In this sense, the present study undertook a comparison between normal phenotype and off-type somatic plantlets protein profiles by means of the 2-D DIGE proteomics approach. Off-type and normal phenotype somatic plantlets obtained at 10 and 20 days conversion were evaluated. Results indicated 12 exclusive spots between normal and off-type plantlets at 10 days conversion, and 17 exclusive spots at 20 days conversion. Also at 20 days conversion, 4 spots were differentially expressed, up- or down-regulated. Two proteins related to carbohydrate metabolism were only expressed in off-types at 10 days conversion, suggesting a more active respiratory pathway. A vicilin-like storage protein was only found in off-types at 20 days conversion, indicating that plantlets may present an abnormality in the mobilization of storage compounds, causing reduced vigor in the development of derived plantlets. The presence of heat shock proteins were only observed during formation of normal phenotype somatic plantlets, indicating that these proteins may be involved in normal morphogenesis of plantlets formed. These new findings shed light on possible genetic or epigenetic mechanisms governing A. sellowiana morphogenesis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  5. Spermine modulates fungal morphogenesis and activates plasma membrane H+-ATPase during yeast to hyphae transition

    Directory of Open Access Journals (Sweden)

    Antônio Jesus Dorighetto Cogo

    2018-02-01

    Full Text Available Polyamines play a regulatory role in eukaryotic cell growth and morphogenesis. Despite many molecular advances, the underlying mechanism of action remains unclear. Here, we investigate a mechanism by which spermine affects the morphogenesis of a dimorphic fungal model of emerging relevance in plant interactions, Yarrowia lipolytica, through the recruitment of a phytohormone-like pathway involving activation of the plasma membrane P-type H+-ATPase. Morphological transition was followed microscopically, and the H+-ATPase activity was analyzed in isolated membrane vesicles. Proton flux and acidification were directly probed at living cell surfaces by a non-invasive selective ion electrode technique. Spermine and indol-3-acetic acid (IAA induced the yeast-hypha transition, influencing the colony architecture. Spermine induced H+-ATPase activity and H+ efflux in living cells correlating with yeast-hypha dynamics. Pharmacological inhibition of spermine and IAA pathways prevented the physio-morphological responses, and indicated that spermine could act upstream of the IAA pathway. This study provides the first compelling evidence on the fungal morphogenesis and colony development as modulated by a spermine-induced acid growth mechanism analogous to that previously postulated for the multicellular growth regulation of plants.

  6. Growth and morphogenesis of embryonic mouse organs on non-coated and extracellular matrix-coated Biopore membrane

    Science.gov (United States)

    Hardman, P.; Klement, B. J.; Spooner, B. S.

    1993-01-01

    Embryonic mouse salivary glands, pancreata, and kidneys were isolated from embryos of appropriate gestational age by microdissection, and were cultured on Biopore membrane either non-coated or coated with type I collagen or Matrigel. As expected, use of Biopore membrane allowed high quality photomicroscopy of the living organs. In all organs extensive mesenchymal spreading was observed in the presence of type I collagen or Matrigel. However, differences were noted in the effects of extracellular matrix (ECM) coatings on epithelial growth and morphogenesis: salivary glands were minimally affected, pancreas morphogenesis was adversely affected, and kidney growth and branching apparently was enhanced. It is suggested that these differences in behaviour reflect differences in the strength of interactions between the mesenchymal cells and their surrounding endogenous matrix, compared to the exogenous ECM macromolecules. This method will be useful for culture of these and other embryonic organs. In particular, culture of kidney rudiments on ECM-coated Biopore offers a great improvement over previously used methods which do not allow morphogenesis to be followed in vitro.

  7. Competing endogenous RNA network analysis identifies critical genes among the different breast cancer subtypes.

    Science.gov (United States)

    Chen, Juan; Xu, Juan; Li, Yongsheng; Zhang, Jinwen; Chen, Hong; Lu, Jianping; Wang, Zishan; Zhao, Xueying; Xu, Kang; Li, Yixue; Li, Xia; Zhang, Yan

    2017-02-07

    Although competing endogenous RNAs (ceRNAs) have been implicated in many solid tumors, their roles in breast cancer subtypes are not well understood. We therefore generated a ceRNA network for each subtype based on the significance of both, positive co-expression and the shared miRNAs, in the corresponding subtype miRNA dys-regulatory network, which was constructed based on negative regulations between differentially expressed miRNAs and targets. All four subtype ceRNA networks exhibited scale-free architecture and showed that the common ceRNAs were at the core of the networks. Furthermore, the common ceRNA hubs had greater connectivity than the subtype-specific hubs. Functional analysis of the common subtype ceRNA hubs highlighted factors involved in proliferation, MAPK signaling pathways and tube morphogenesis. Subtype-specific ceRNA hubs highlighted unique subtype-specific pathways, like the estrogen response and inflammatory pathways in the luminal subtypes or the factors involved in the coagulation process that participates in the basal-like subtype. Ultimately, we identified 29 critical subtype-specific ceRNA hubs that characterized the different breast cancer subtypes. Our study thus provides new insight into the common and specific subtype ceRNA interactions that define the different categories of breast cancer and enhances our understanding of the pathology underlying the different breast cancer subtypes, which can have prognostic and therapeutic implications in the future.

  8. Human breast cancer; in vivo and in vitro H MR spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Tae Woong; Kang, Heoung Keun; Jeong, Gwang Woo; Park, Jin Gyoon; Seo, Jeong Jin; Lee, Jung Hee [Ulsan Univ. College of Medicine, Seoul (Korea, Republic of)

    2001-02-01

    The purpose of this study was to determione, using in vivo and in vitro H MRS (MR spectroscopy), the characteristic biochemical metabolites related with breast cancer, and to assess the clinical usefulness and limitations of this modality. For in vivo H MRS, nine patients with breast cancer and two normal volunteers were examined on a 1.5T MR imager equipped with facilities for spectroscopy. In order to localize the breast lesion, axial and sagittal T1-weighted images and fat-suppressed T2-weighted images were obtained just prior to MRS: MR spectra were acquired at TR=3000 msec and TE=144 msec. For in vitro H MRS, breast tumor and adjacent normal tissue were extracted from 13 patients with breast cancer, and in two of these, both in vivo and in vitro H MRS were performed. All in vitro H MRS specimens were immediately immersed in liquid nitrogen, and then in a preparation of perchloric acid. For quantitative analysis of the MR spectra of cancerous and normal breast tissue, the paired t-test was used (p<0.05). At H MRS in vivo, choline and two lipids were identified at 3.21 ppm and 0.9ppm, respectively. The distinction between cancerous and normal breast tissue was based on the higher level of choline (3.21 ppm) present in the former. At H MRS in vitro, on the other hand, mean and standard deviation (% standard deviation) for the various metabolites in cancerous and normal breast tissue were as follows; choline, 30.195 2.448(8.108) and 22.648 1.938(8.556): trimethylamine, diagnosis of breast cancer. resolution, may be very useful0.335(9.769) and 0.640 0.099(15.394): lactate, 16.388 1.134(6.922) and 9.715 0.385(3.965): inositol, 1.970 0.282(14.334) and 3.859 0.502(13.020): and taurine, 6.614 0.556(8.412) and 10.748 1.206(11.222). High levels of choline (p=0.026), trimethylamine (p=0.001), sarcosine (p=0.009), and lactate (p=0.009), and lower levels of inositol(p=0.006) and taurine (p=0.008) were characteristic findings in cancerous as compared with normal breast

  9. Early Detection of Breast Cancer Using Molecular Beacons

    National Research Council Canada - National Science Library

    Yang, Lily

    2008-01-01

    .... We proposed to use molecular beacon technology to detect the level of expression of several biomarker genes that are highly expressed in breast cancer cells but not in normal breast epithelial cells...

  10. Esterification of all-trans-retinol in normal human epithelial cell strains and carcinoma lines from oral cavity, skin and breast: reduced expression of lecithin:retinol acyltransferase in carcinoma lines.

    Science.gov (United States)

    Guo, X; Ruiz, A; Rando, R R; Bok, D; Gudas, L J

    2000-11-01

    When exogenous [(3)H]retinol (vitamin A) was added to culture medium, normal human epithelial cells from the oral cavity, skin, lung and breast took up and esterified essentially all of the [(3)H]retinol within a few hours. As shown by [(3)H]retinol pulse-chase experiments, normal epithelial cells then slowly hydrolyzed the [(3)H]retinyl esters to [(3)H]retinol, some of which was then oxidized to [(3)H]retinoic acid (RA) over a period of several days. In contrast, cultured normal human fibroblasts and human umbilical vein endothelial cells (HUVEC) did not esterify significant amounts of [(3)H]retinol; this lack of [(3)H]retinol esterification was correlated with a lack of expression of lecithin:retinol acyltransferase (LRAT) transcripts in normal fibroblast and HUVEC strains. These results indicate that normal, differentiated cell types differ in their ability to esterify retinol. Human carcinoma cells (neoplastically transformed epithelial cells) of the oral cavity, skin and breast did not esterify much [(3)H]retinol and showed greatly reduced LRAT expression. Transcripts of the neutral, bile salt-independent retinyl ester hydrolase and the bile salt-dependent retinyl ester hydrolase were undetectable in all of the normal cell types, including the epithelial cells. These experiments suggest that retinoid-deficiency in the tumor cells could develop because of the lack of retinyl esters, a storage form of retinol.

  11. Breast Cancer Prevention And Detection | Ihezue | Highland Medical ...

    African Journals Online (AJOL)

    The breasts are phylogentically considered as modifications of sweat glands. They are present in all mammals and particularly become prominent in females as the hallmark of pubertal development. Like all bilateral structures, slight inequality in the size of the breast is normal. The male breast is small, though it is subject to ...

  12. ADAMTS-1 Is Found in the Nuclei of Normal and Tumoral Breast Cells.

    Directory of Open Access Journals (Sweden)

    Suély V Silva

    Full Text Available Proteins secreted in the extracellular matrix microenvironment (ECM by tumor cells are involved in cell adhesion, motility, intercellular communication and invasion. The tumor microenvironment is expansively modified and remodeled by proteases, resulting in important changes in both cell-cell and cell-ECM interactions and in the generation of new signals from the cell surface. Metalloproteinases belonging to the ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs family have been implicated in tissue remodeling events observed in cancer development, growth and progression. Here we investigated the subcellular localization of ADAMTS-1 in normal-like (MCF10-A and tumoral (MCF7 and MDA-MB-231 human breast cells. ADAMTS-1 is a secreted protease found in the extracellular matrix. However, in this study we show for the first time that ADAMTS-1 is also present in the nuclei and nucleoli of the three mammary cell lines studied here. Our findings indicate that ADAMTS-1 has proteolytic functions in the nucleus through its interaction with aggrecan substrate.

  13. Clinical significance of Mena and Her-2 expression in breast cancer.

    Science.gov (United States)

    Du, J W; Xu, K Y; Fang, L Y; Qi, X L

    2012-01-01

    The aim of this study was to determine the expression patterns of Mena and Her-2 in breast cancer tissues and to explore their clinical significance and correlation with clinicopathological parameters. The expression of Mena and Her-2 was detected in 40 breast cancer tissues and 14 normal breast tissues by immunohistochemistry, and the relationship of Mena and Her-2 expression with clinicopathological parameters was analyzed. Both Mena (70%) and Her-2 (40%) were more commonly expressed in breast cancer than in normal breast tissue (7.1%, 0%, respectively; p Mena and Her-2 expression in breast cancer were positively correlated (r = 0.530, p Mena and Her-2 were both associated with axillary lymph node metastasis and TNM stage (p Mena and Her-2 are related to the malignancy degree and metastasis of breast cancer, and thus may play a coordinating role in the occurrence and progression of breast cancer.

  14. Plant morphogenesis, auxin, and the signal-trafficking network incompleteness theorem

    Directory of Open Access Journals (Sweden)

    Karl J. Niklas

    2012-03-01

    Full Text Available Plant morphogenesis (the development of form and function requires signal-trafficking and cross-talking among all levels of organization to coordinate the operation of metabolic and genomic networked systems. Many if not all of these biological features can be rendered as logic circuits supervising the operation of one or more signal-activated metabolic or genome networks. This approach simplifies complex morphogenetic phenomena and allows for their aggregation into diagrams of larger, more "global" networked systems. This conceptualization is illustrated for morphogenesis in model plants such as maize (Zea mays and Thale cress (Arabidopsis thaliana from an evolutionary perspective. The phytohormone indole-acetic acid (IAA is used as an example for a well-known signaling chemical and discussed in terms of the logic circuits and signal-activated sub-systems for hormone-mediated wall loosening and cell expansion as well as polar/lateral intercellular IAA transport. For each of these phenomena, a circuit/sub-system diagram highlights missing components, either in the logic circuit or in the sub-system it supervises, that must be identified experimentally if each of these basic phenomena is to be fully understood within a phylogen

  15. ANALYSES ON DIFFERENTIALLY EXPRESSED GENES ASSOCIATED WITH HUMAN BREAST CANCER

    Institute of Scientific and Technical Information of China (English)

    MENG Xu-li; DING Xiao-wen; XU Xiao-hong

    2006-01-01

    Objective: To investigate the molecular etiology of breast cancer by way of studying the differential expression and initial function of the related genes in the occurrence and development of breast cancer. Methods: Two hundred and eighty-eight human tumor related genes were chosen for preparation of the oligochips probe. mRNA was extracted from 16 breast cancer tissues and the corresponding normal breast tissues, and cDNA probe was prepared through reverse-transcription and hybridized with the gene chip. A laser focused fluorescent scanner was used to scan the chip. The different gene expressions were thereafter automatically compared and analyzed between the two sample groups. Cy3/Cy5>3.5 meant significant up-regulation. Cy3/Cy5<0.25 meant significant down-regulation. Results: The comparison between the breast cancer tissues and their corresponding normal tissues showed that 84 genes had differential expression in the Chip. Among the differently expressed genes, there were 4 genes with significant down-regulation and 6 with significant up-regulation. Compared with normal breast tissues, differentially expressed genes did partially exist in the breast cancer tissues. Conclusion: Changes in multi-gene expression regulations take place during the occurrence and development of breast cancer; and the research on related genes can help understanding the mechanism of tumor occurrence.

  16. Tissue Motion and Assembly During Early Cardiovascular Morphogenesis

    Science.gov (United States)

    Rongish, Brenda

    2010-03-01

    Conventional dogma in the field of cardiovascular developmental biology suggests that cardiac precursor cells migrate to the embryonic midline to form a tubular heart. These progenitors are believed to move relative to their extracellular matrix (ECM); responding to stimulatory and inhibitory cues in their environment. The tubular heart that is formed by 30 hours post fertilization is comprised of two concentric layers: the muscular myocardium and the endothelial-like endocardium, which are separated by a thick layer of ECM believed to be secreted predominantly by the myocardial cells. Here we describe the origin and motility of fluorescently tagged endocardial precursors in transgenic (Tie1-YFP) quail embryos (R. Lansford, Caltech) using epifluorescence time-lapse imaging. To visualize the environment of migrating endocardial progenitors, we labeled two ECM components, fibronectin and fibrillin-2, via in vivo microinjection of fluorochrome-conjugated monoclonal antibodies. Dynamic imaging was performed at stages encompassing tubular heart assembly and early looping. We established the motion of endocardial precursor cells and presumptive cardiac ECM fibrils using both object tracking and particle image velocimetry (image cross correlation). We determined the relative importance of directed cell autonomous motility versus passive tissue movements in endocardial morphogenesis. The data show presumptive endocardial cells and cardiac ECM fibrils are swept passively into the anterior and posterior poles of the elongating tubular heart. These quantitative data indicate the contribution of cell autonomous motility displayed by endocardial precursors is limited. Thus, tissue motion drives most of the cell displacements during endocardial morphogenesis.

  17. CRIM1 Complexes with ß-catenin and Cadherins, Stabilizes Cell-Cell Junctions and Is Critical for Neural Morphogenesis

    OpenAIRE

    Ponferrada, Virgilio G.; Fan, Jieqing; Vallance, Jefferson E.; Hu, Shengyong; Mamedova, Aygun; Rankin, Scott A.; Kofron, Matthew; Zorn, Aaron M.; Hegde, Rashmi S.; Lang, Richard A.

    2012-01-01

    In multicellular organisms, morphogenesis is a highly coordinated process that requires dynamically regulated adhesion between cells. An excellent example of cellular morphogenesis is the formation of the neural tube from the flattened epithelium of the neural plate. Cysteine-rich motor neuron protein 1 (CRIM1) is a single-pass (type 1) transmembrane protein that is expressed in neural structures beginning at the neural plate stage. In the frog Xenopus laevis, loss of function studies using C...

  18. Estrogen sulfotransferases in breast and endometrial cancers.

    Science.gov (United States)

    Pasqualini, Jorge Raul

    2009-02-01

    Estrogen sulfotransferase is significantly more active in the normal breast cell (e.g., Human 7) than in the cancer cell (e.g., MCF-7). The data suggest that in breast cancer sulfoconjugated activity is carried out by another enzyme, the SULT1A, which acts at high concentration of the substrates. In breast cancer cells sulfotransferase (SULT) activity can be stimulated by various progestins: medrogestone, promegestone, and nomegestrol acetate, as well as by tibolone and its metabolites. SULT activities can also be controlled by other substances including phytoestrogens, celecoxib, flavonoids (e.g., quercetin, resveratrol), and isoflavones. SULT expression was localized in breast cancer cells, which can be stimulated by promegestone and correlated with the increase of the enzyme activity. The estrogen sulfotransferase (SULT1E1), which acts at nanomolar concentration of estradiol, can inactivate most of this hormone present in the normal breast; however, in the breast cancer cells, the sulfotransferase denoted as SULT1A1 is mainly present, and this acts at micromolar concentrations of E(2). A correlation was postulated among breast cancer cell proliferation, the effect of various progestins, and sulfotransferase stimulation. In conclusion, it is suggested that factors involved in the stimulation of the estrogen sulfotransferases could provide new possibilities for the treatment of patients with hormone-dependent breast and endometrial cancers.

  19. Hornerin, an S100 family protein, is functional in breast cells and aberrantly expressed in breast cancer

    International Nuclear Information System (INIS)

    Fleming, Jodie M; Ginsburg, Erika; Oliver, Shannon D; Goldsmith, Paul; Vonderhaar, Barbara K

    2012-01-01

    Recent evidence suggests an emerging role for S100 protein in breast cancer and tumor progression. These ubiquitous proteins are involved in numerous normal and pathological cell functions including inflammatory and immune responses, Ca 2+ homeostasis, the dynamics of cytoskeleton constituents, as well as cell proliferation, differentiation, and death. Our previous proteomic analysis demonstrated the presence of hornerin, an S100 family member, in breast tissue and extracellular matrix. Hornerin has been reported in healthy skin as well as psoriatic and regenerating skin after wound healing, suggesting a role in inflammatory/immune response or proliferation. In the present study we investigated hornerin’s potential role in normal breast cells and breast cancer. The expression levels and localization of hornerin in human breast tissue, breast tumor biopsies, primary breast cells and breast cancer cell lines, as well as murine mammary tissue were measured via immunohistochemistry, western blot analysis and PCR. Antibodies were developed against the N- and C-terminus of the protein for detection of proteolytic fragments and their specific subcellular localization via fluorescent immunocytochemisty. Lastly, cells were treated with H 2 O 2 to detect changes in hornerin expression during induction of apoptosis/necrosis. Breast epithelial cells and stromal fibroblasts and macrophages express hornerin and show unique regulation of expression during distinct phases of mammary development. Furthermore, hornerin expression is decreased in invasive ductal carcinomas compared to invasive lobular carcinomas and less aggressive breast carcinoma phenotypes, and cellular expression of hornerin is altered during induction of apoptosis. Finally, we demonstrate the presence of post-translational fragments that display differential subcellular localization. Our data opens new possibilities for hornerin and its proteolytic fragments in the control of mammary cell function and breast

  20. Hornerin, an S100 family protein, is functional in breast cells and aberrantly expressed in breast cancer

    Directory of Open Access Journals (Sweden)

    Fleming Jodie M

    2012-06-01

    Full Text Available Abstract Background Recent evidence suggests an emerging role for S100 protein in breast cancer and tumor progression. These ubiquitous proteins are involved in numerous normal and pathological cell functions including inflammatory and immune responses, Ca2+ homeostasis, the dynamics of cytoskeleton constituents, as well as cell proliferation, differentiation, and death. Our previous proteomic analysis demonstrated the presence of hornerin, an S100 family member, in breast tissue and extracellular matrix. Hornerin has been reported in healthy skin as well as psoriatic and regenerating skin after wound healing, suggesting a role in inflammatory/immune response or proliferation. In the present study we investigated hornerin’s potential role in normal breast cells and breast cancer. Methods The expression levels and localization of hornerin in human breast tissue, breast tumor biopsies, primary breast cells and breast cancer cell lines, as well as murine mammary tissue were measured via immunohistochemistry, western blot analysis and PCR. Antibodies were developed against the N- and C-terminus of the protein for detection of proteolytic fragments and their specific subcellular localization via fluorescent immunocytochemisty. Lastly, cells were treated with H2O2 to detect changes in hornerin expression during induction of apoptosis/necrosis. Results Breast epithelial cells and stromal fibroblasts and macrophages express hornerin and show unique regulation of expression during distinct phases of mammary development. Furthermore, hornerin expression is decreased in invasive ductal carcinomas compared to invasive lobular carcinomas and less aggressive breast carcinoma phenotypes, and cellular expression of hornerin is altered during induction of apoptosis. Finally, we demonstrate the presence of post-translational fragments that display differential subcellular localization. Conclusions Our data opens new possibilities for hornerin and its

  1. Technological quality, mineral profile, and sensory attributes of broiler chicken breasts affected by White Striping and Wooden Breast myopathies.

    Science.gov (United States)

    Tasoniero, G; Cullere, M; Cecchinato, M; Puolanne, E; Dalle Zotte, A

    2016-11-01

    The aim of the research was to study the impact of white striping and wooden breast myopathies on the technological quality, mineral, and sensory profile of poultry meat. With this purpose, a total of 138 breasts were selected for a control group with normal breasts (N), a group of breasts characterised by white striping (WS) myopathy, and a group of breasts having both white striping and wooden breast myopathies (WSWB). Data revealed that the simultaneous presence of the two myopathies, with respect to the WS lesion individually considered, had a further detrimental effect on pH (6.04 vs. 5.96; P white striping and wooden breast myopathies. © 2016 Poultry Science Association Inc.

  2. Giga-voxel computational morphogenesis for structural design

    Science.gov (United States)

    Aage, Niels; Andreassen, Erik; Lazarov, Boyan S.; Sigmund, Ole

    2017-10-01

    In the design of industrial products ranging from hearing aids to automobiles and aeroplanes, material is distributed so as to maximize the performance and minimize the cost. Historically, human intuition and insight have driven the evolution of mechanical design, recently assisted by computer-aided design approaches. The computer-aided approach known as topology optimization enables unrestricted design freedom and shows great promise with regard to weight savings, but its applicability has so far been limited to the design of single components or simple structures, owing to the resolution limits of current optimization methods. Here we report a computational morphogenesis tool, implemented on a supercomputer, that produces designs with giga-voxel resolution—more than two orders of magnitude higher than previously reported. Such resolution provides insights into the optimal distribution of material within a structure that were hitherto unachievable owing to the challenges of scaling up existing modelling and optimization frameworks. As an example, we apply the tool to the design of the internal structure of a full-scale aeroplane wing. The optimized full-wing design has unprecedented structural detail at length scales ranging from tens of metres to millimetres and, intriguingly, shows remarkable similarity to naturally occurring bone structures in, for example, bird beaks. We estimate that our optimized design corresponds to a reduction in mass of 2-5 per cent compared to currently used aeroplane wing designs, which translates into a reduction in fuel consumption of about 40-200 tonnes per year per aeroplane. Our morphogenesis process is generally applicable, not only to mechanical design, but also to flow systems, antennas, nano-optics and micro-systems.

  3. Overexpression of Robo2 causes defects in the recruitment of metanephric mesenchymal cells and ureteric bud branching morphogenesis

    International Nuclear Information System (INIS)

    Ji, Jiayao; Li, Qinggang; Xie, Yuansheng; Zhang, Xueguang; Cui, Shaoyuan; Shi, Suozhu; Chen, Xiangmei

    2012-01-01

    Highlights: ► Overexpression of Robo2 caused reduced UB branching and glomerular number. ► Fewer MM cells surrounding the UB after overexpression of Robo2 in vitro. ► No abnormal Epithelial Morphology of UB or apoptosis of mm cells in the kidney. ► Overexpression of Robo2 affected MM cells migration and caused UB deficit. ► The reduced glomerular number can also be caused by fewer MM cells. -- Abstract: Roundabout 2 (Robo2) is a member of the membrane protein receptor family. The chemorepulsive effect of Slit2–Robo2 signaling plays vital roles in nervous system development and neuron migration. Slit2–Robo2 signaling is also important for maintaining the normal morphogenesis of the kidney and urinary collecting system, especially for the branching of the ureteric bud (UB) at the proper site. Slit2 or Robo2 mouse mutants exhibit multilobular kidneys, multiple ureters, and dilatation of the ureter, renal pelvis, and collecting duct system, which lead to vesicoureteral reflux. To understand the effect of Robo2 on kidney development, we used microinjection and electroporation to overexpress GFP-Robo2 in an in vitro embryonic kidney model. Our results show reduced UB branching and decreased glomerular number after in vitro Robo2 overexpression in the embryonic kidneys. We found fewer metanephric mesenchymal (MM) cells surrounding the UB but no abnormal morphology in the branching epithelial UB. Meanwhile, no significant change in MM proliferation or apoptosis was observed. These findings indicate that Robo2 is involved in the development of embryonic kidneys and that the normal expression of Robo2 can help maintain proper UB branching and glomerular morphogenesis. Overexpression of Robo2 leads to reduced UB branching caused by fewer surrounding MM cells, but MM cell apoptosis is not involved in this effect. Our study demonstrates that overexpression of Robo2 by microinjection in embryonic kidneys is an effective approach to study the function of Robo2.

  4. Overexpression of Robo2 causes defects in the recruitment of metanephric mesenchymal cells and ureteric bud branching morphogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Ji, Jiayao [Institute of Nephrology, State Key Laboratory of Kidney Disease (2011DAV00088), The Chinese PLA General Hospital, Beijing 100853 (China); Medical College of NanKai University, Tianjin (China); Li, Qinggang; Xie, Yuansheng; Zhang, Xueguang; Cui, Shaoyuan; Shi, Suozhu [Institute of Nephrology, State Key Laboratory of Kidney Disease (2011DAV00088), The Chinese PLA General Hospital, Beijing 100853 (China); Chen, Xiangmei, E-mail: xmchen301@126.com [Institute of Nephrology, State Key Laboratory of Kidney Disease (2011DAV00088), The Chinese PLA General Hospital, Beijing 100853 (China); Medical College of NanKai University, Tianjin (China)

    2012-05-11

    Highlights: Black-Right-Pointing-Pointer Overexpression of Robo2 caused reduced UB branching and glomerular number. Black-Right-Pointing-Pointer Fewer MM cells surrounding the UB after overexpression of Robo2 in vitro. Black-Right-Pointing-Pointer No abnormal Epithelial Morphology of UB or apoptosis of mm cells in the kidney. Black-Right-Pointing-Pointer Overexpression of Robo2 affected MM cells migration and caused UB deficit. Black-Right-Pointing-Pointer The reduced glomerular number can also be caused by fewer MM cells. -- Abstract: Roundabout 2 (Robo2) is a member of the membrane protein receptor family. The chemorepulsive effect of Slit2-Robo2 signaling plays vital roles in nervous system development and neuron migration. Slit2-Robo2 signaling is also important for maintaining the normal morphogenesis of the kidney and urinary collecting system, especially for the branching of the ureteric bud (UB) at the proper site. Slit2 or Robo2 mouse mutants exhibit multilobular kidneys, multiple ureters, and dilatation of the ureter, renal pelvis, and collecting duct system, which lead to vesicoureteral reflux. To understand the effect of Robo2 on kidney development, we used microinjection and electroporation to overexpress GFP-Robo2 in an in vitro embryonic kidney model. Our results show reduced UB branching and decreased glomerular number after in vitro Robo2 overexpression in the embryonic kidneys. We found fewer metanephric mesenchymal (MM) cells surrounding the UB but no abnormal morphology in the branching epithelial UB. Meanwhile, no significant change in MM proliferation or apoptosis was observed. These findings indicate that Robo2 is involved in the development of embryonic kidneys and that the normal expression of Robo2 can help maintain proper UB branching and glomerular morphogenesis. Overexpression of Robo2 leads to reduced UB branching caused by fewer surrounding MM cells, but MM cell apoptosis is not involved in this effect. Our study demonstrates that

  5. A pilot study to determine the timing and effect of bevacizumab on vascular normalization of metastatic brain tumors in breast cancer

    International Nuclear Information System (INIS)

    Chen, Bang-Bin; Lu, Yen-Shen; Lin, Ching-Hung; Chen, Wei-Wu; Wu, Pei-Fang; Hsu, Chao-Yu; Yu, Chih-Wei; Wei, Shwu-Yuan; Cheng, Ann-Lii; Shih, Tiffany Ting-Fang

    2016-01-01

    To determine the appropriate time of concomitant chemotherapy administration after antiangiogenic treatment, we investigated the timing and effect of bevacizumab administration on vascular normalization of metastatic brain tumors in breast cancer patients. Eight patients who participated in a phase II trial for breast cancer-induced refractory brain metastases were enrolled and subjected to 4 dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) examinations that evaluated Peak, Slope, iAUC 60 , and Ktrans before and after treatment. The treatment comprised bevacizumab on Day 1, etoposide on Days 2–4, and cisplatin on Day 2 in a 21-day cycle for a maximum of 6 cycles. DCE-MRI was performed before treatment and at 1 h, 24 h, and 21 days after bevacizumab administration. Values of the 4 DCE-MRI parameters reduced after bevacizumab administration. Compared with baseline values, the mean reductions at 1 and 24 h were −12.8 and −24.7 % for Peak, −46.6 and −65.8 % for Slope, −27.9 and −55.5 % for iAUC 60 , and −46.6 and −63.9 % for Ktrans, respectively (all P < .05). The differences in the 1 and 24 h mean reductions were significant (all P < .05) for all the parameters. The generalized estimating equation linear regression analyses of the 4 DCE-MRI parameters revealed that vascular normalization peaked 24 h after bevacizumab administration. Bevacizumab induced vascular normalization of brain metastases in humans at 1 and 24 h after administration, and the effect was significantly higher at 24 h than at 1 h. ClinicalTrials.gov, identifier NCT01281696, registered prospectively on December 24, 2010

  6. CLINICAL BREAST EXAMINATION SCREENING BY TRAINED LAYWOMEN IN MALAWI INTEGRATED WITH OTHER HEALTH SERVICES.

    Science.gov (United States)

    Gutnik, L; Lee, C; Msosa, J

    2017-06-01

    Breast cancer awareness and early detection are limited in Sub-Saharan Africa. Resource limitations make screening mammography or clinical breast examination (CBE) by physicians or nurses impractical in many settings. Four laywomen were trained to deliver breast cancer educational talks and conduct CBE. After training, screening was implemented in diverse urban health clinics. Eligible women were 30 years old, with no prior breast cancer or breast surgery, and clinic attendance for reasons other than a breast concern. Women with abnormal CBE were referred to a study surgeon. All palpable masses confirmed by surgeon examination were pathologically sampled. Patients with abnormal screening CBE but normal surgeon examination underwent breast ultrasound confirmation. In addition, 50 randomly selected women with normal screening CBE underwent breast ultrasound, and 45 different women with normal CBE were randomly assigned to surgeon examination. Among 1220 eligible women, 1000 (82%) agreed to CBE. Lack of time (69%) was the commonest reason for refusal. Educational talk attendance was associated with higher CBE participation (83% versus 77%, P ¼ 0.012). Among 1000 women screened, 7% had abnormal CBE. Of 45 women with normal CBE randomised to physician examination, 43 had normal examinations and two had axillary lymphadenopathy not detected by CBE. Sixty of 67 women (90%) with abnormal CBE attended the referral visit. Of these, 29 (48%) had concordant abnormal physician examination. Thirty-one women (52%) had discordant normal physician examination, all of whom also had normal breast ultrasounds. Compared with physician examination, sensitivity for CBE by laywomen was 94% (confidence interval [CI] 79%-99%), specificity 58% (CI, 46%-70%), positive predictive value 48% (CI, 35%-62%), and negative predictive value 96% (CI, 85%-100%). Of 13 women who underwent recommended pathologic sampling of a breast lesion, two had cytologic dysplasia and all others benign Results. CBE

  7. A protocadherin-cadherin-FLRT3 complex controls cell adhesion and morphogenesis.

    Directory of Open Access Journals (Sweden)

    Xuejun Chen

    2009-12-01

    Full Text Available Paraxial protocadherin (PAPC and fibronectin leucine-rich domain transmembrane protein-3 (FLRT3 are induced by TGFbeta signaling in Xenopus embryos and both regulate morphogenesis by inhibiting C-cadherin mediated cell adhesion.We have investigated the functional and physical relationships between PAPC, FLRT3, and C-cadherin. Although neither PAPC nor FLRT3 are required for each other to regulate C-cadherin adhesion, they do interact functionally and physically, and they form a complex with cadherins. By itself PAPC reduces cell adhesion physiologically to induce cell sorting, while FLRT3 disrupts adhesion excessively to cause cell dissociation. However, when expressed together PAPC limits the cell dissociating and tissue disrupting activity of FLRT3 to make it effective in physiological cell sorting. PAPC counteracts FLRT3 function by inhibiting the recruitment of the GTPase RND1 to the FLRT3 cytoplasmic domain.PAPC and FLRT3 form a functional complex with cadherins and PAPC functions as a molecular "governor" to maintain FLRT3 activity at the optimal level for physiological regulation of C-cadherin adhesion, cell sorting, and morphogenesis.

  8. ATM induction insufficiency in a radiosensitive breast-cancer patient

    International Nuclear Information System (INIS)

    Clarke, R.A.; Fang, Z.H.; Marr, P.J.; Kearsley, J.H.; Papadatos, G.; Lee, C.S.; University of Sydney, Camperdown, NSW

    2002-01-01

    ATM induction insufficiency in a radiosensitive breast-cancer patient The ataxia telangiectasia (A-T) gene (ATM) is a dominant breast cancer gene with tumour suppressor activity. ATM also regulates cellular sensitivity to ionising radiation (IR) presumably through its role as a facilitator of DNA repair. In normal cells and tissues the ATM protein is rapidly induced by IR to threshold/maximum levels. The kinase function of the ATM protein is also rapidly activated in response to IR. The fact that women carriers of ATM mutations can have an increased risk of developing breast cancer and that many sporadic breast tumours have reduced levels of the ATM protein broadens the scope of ATM's tumour suppressor within the breast. This report describes the downregulation of ATM protein levels in a radiosensitive breast cancer patient. Postinduction ATM levels were up to tenfold lower in the patient's fresh tissues compared to normal controls. These results might indicate a much broader role for ATM anomalies in breast cancer aetiology. Copyright (2002) Blackwell Science Pty Ltd

  9. An integrated miRNA functional screening and target validation method for organ morphogenesis.

    Science.gov (United States)

    Rebustini, Ivan T; Vlahos, Maryann; Packer, Trevor; Kukuruzinska, Maria A; Maas, Richard L

    2016-03-16

    The relative ease of identifying microRNAs and their increasing recognition as important regulators of organogenesis motivate the development of methods to efficiently assess microRNA function during organ morphogenesis. In this context, embryonic organ explants provide a reliable and reproducible system that recapitulates some of the important early morphogenetic processes during organ development. Here we present a method to target microRNA function in explanted mouse embryonic organs. Our method combines the use of peptide-based nanoparticles to transfect specific microRNA inhibitors or activators into embryonic organ explants, with a microRNA pulldown assay that allows direct identification of microRNA targets. This method provides effective assessment of microRNA function during organ morphogenesis, allows prioritization of multiple microRNAs in parallel for subsequent genetic approaches, and can be applied to a variety of embryonic organs.

  10. Estrogenic effect of soy isoflavones on mammary gland morphogenesis and gene expression profile

    DEFF Research Database (Denmark)

    Thomsen, Anni R.; Almstrup, Kristian; Nielsen, John E.

    2006-01-01

    We examined the effect of 17 beta-estradiol (E2) and soy isoflavones' exposure on morphogenesis and global gene expression in the murine mammary gland. Three exposure regimens were applied: isoflavones added to the diet throughout either the lactational period (via the dams) or the postweaning...... period and E2 administered orally during the lactational period. Whole mounts of mammary glands were evaluated both in juvenile and adult animals with respect to branching morphogenesis and terminal end bud (TEB) formation. At postnatal day (PND) 28, we observed a significant increase in branching...... isoflavone and E2 exposure was further substantiated by changes in gene expression, since the same groups of genes were up- and downregulated, particularly in the E2 and postweaning isoflavone regimen. All changes in gene expression correlated with changes in the cellular composition of the gland, i.e., more...

  11. Epigenetic suppression of neprilysin regulates breast cancer invasion.

    Science.gov (United States)

    Stephen, H M; Khoury, R J; Majmudar, P R; Blaylock, T; Hawkins, K; Salama, M S; Scott, M D; Cosminsky, B; Utreja, N K; Britt, J; Conway, R E

    2016-03-07

    In women, invasive breast cancer is the second most common cancer and the second cause of cancer-related death. Therefore, identifying novel regulators of breast cancer invasion could lead to additional biomarkers and therapeutic targets. Neprilysin, a cell-surface enzyme that cleaves and inactivates a number of substrates including endothelin-1 (ET1), has been implicated in breast cancer, but whether neprilysin promotes or inhibits breast cancer cell progression and metastasis is unclear. Here, we asked whether neprilysin expression predicts and functionally regulates breast cancer cell invasion. RT-PCR and flow cytometry analysis of MDA-MB-231 and MCF-7 breast cancer cell lines revealed decreased neprilysin expression compared with normal epithelial cells. Expression was also suppressed in invasive ductal carcinoma (IDC) compared with normal tissue. In addition, in vtro invasion assays demonstrated that neprilysin overexpression decreased breast cancer cell invasion, whereas neprilysin suppression augmented invasion. Furthermore, inhibiting neprilysin in MCF-7 breast cancer cells increased ET1 levels significantly, whereas overexpressing neprilysin decreased extracellular-signal related kinase (ERK) activation, indicating that neprilysin negatively regulates ET1-induced activation of mitogen-activated protein kinase (MAPK) signaling. To determine whether neprilysin was epigenetically suppressed in breast cancer, we performed bisulfite conversion analysis of breast cancer cells and clinical tumor samples. We found that the neprilysin promoter was hypermethylated in breast cancer; chemical reversal of methylation in MDA-MB-231 cells reactivated neprilysin expression and inhibited cancer cell invasion. Analysis of cancer databases revealed that neprilysin methylation significantly associates with survival in stage I IDC and estrogen receptor-negative breast cancer subtypes. These results demonstrate that neprilysin negatively regulates the ET axis in breast cancer

  12. A C-terminal, cysteine-rich site in poliovirus 2C(ATPase) is required for morphogenesis.

    Science.gov (United States)

    Wang, Chunling; Ma, Hsin-Chieh; Wimmer, Eckard; Jiang, Ping; Paul, Aniko V

    2014-06-01

    The morphogenesis of viruses belonging to the genus Enterovirus in the family Picornaviridae is still poorly understood despite decades-long investigations. However, we recently provided evidence that 2C(ATPase) gives specificity to poliovirus encapsidation through an interaction with capsid protein VP3. The polypeptide 2C(ATPase) is a highly conserved non-structural protein of enteroviruses with important roles in RNA replication, encapsidation and uncoating. We have identified a site (K279/R280) near the C terminus of the polypeptide that is required for morphogenesis. The aim of the current project was to search for additional functional sites near the C terminus of the 2C(ATPase) polypeptide, with particular interest in those that are required for encapsidation. We selected for analysis a cysteine-rich site of the polypeptide and constructed four mutants in which cysteines or a histidine was changed to an alanine. The RNA transcripts were transfected into HeLa cells yielding two lethal, one temperature-sensitive and one quasi-infectious mutants. All four mutants exhibited normal protein translation in vitro and three of them possessed severe RNA replication defects. The quasi-infectious mutant (C286A) yielded variants with a pseudo-reversion at the original site (A286D), but some also contained one additional mutation: A138V or M293V. The temperature-sensitive mutant (C272A/H273A) exhibited an encapsidation and possibly also an uncoating defect at 37 °C. Variants of this mutant revealed suppressor mutations at three different sites in the 2C(ATPase) polypeptide: A138V, M293V and K295R. We concluded that the cysteine-rich site near the C terminus of 2C(ATPase) is involved in encapsidation, possibly through an interaction with an upstream segment located between boxes A and B of the nucleotide-binding domain. © 2014 The Authors.

  13. Differential expression of follistatin and FLRG in human breast proliferative disorders

    Directory of Open Access Journals (Sweden)

    Amaral Vania F

    2009-09-01

    Full Text Available Abstract Background Activins are growth factors acting on cell growth and differentiation. Activins are expressed in high grade breast tumors and they display an antiproliferative effect inducing G0/G1 cell cycle arrest in breast cancer cell lines. Follistatin and follistatin- related gene (FLRG bind and neutralize activins. In order to establish if these activin binding proteins are involved in breast tumor progression, the present study evaluated follistatin and FLRG pattern of mRNA and protein expression in normal human breast tissue and in different breast proliferative diseases. Methods Paraffin embedded specimens of normal breast (NB - n = 8; florid hyperplasia without atypia (FH - n = 17; fibroadenoma (FIB - n = 17; ductal carcinoma in situ (DCIS - n = 10 and infiltrating ductal carcinoma (IDC - n = 15 were processed for follistatin and FLRG immunohistochemistry and in situ hybridization. The area and intensity of chromogen epithelial and stromal staining were analyzed semi-quantitatively. Results Follistatin and FLRG were expressed both in normal tissue and in all the breast diseases investigated. Follistatin staining was detected in the epithelial cytoplasm and nucleus in normal, benign and malignant breast tissue, with a stronger staining intensity in the peri-alveolar stromal cells of FIB at both mRNA and protein levels. Conversely, FLRG area and intensity of mRNA and protein staining were higher both in the cytoplasm and in the nucleus of IDC epithelial cells when compared to NB, while no significant changes in the stromal intensity were observed in all the proliferative diseases analyzed. Conclusion The present findings suggest a role for follistatin in breast benign disease, particularly in FIB, where its expression was increased in stromal cells. The up regulation of FLRG in IDC suggests a role for this protein in the progression of breast malignancy. As activin displays an anti-proliferative effect in human mammary cells, the

  14. A study of morphogenesis of digital malformation on rat embryo by x-irradiation

    International Nuclear Information System (INIS)

    Kim, Jhai Dhuck; You, Dong Soo

    1981-01-01

    The author studied in the effects of x-irradiation to the development of digital malformation in gestation rats. The time-matings occurred between 6 p.m. and 8 a.m. and females with copulation plugs at 8 a.m. were isolated and properly marked for evidence of copulation. The lower abdomen of mothers were exposed to x-irradiation on the 11 1/2th day of gestation, the critical period developing digital malformation, respectively 100, 150, 200, 250, 300 and 350 rads. At 18 1/2th day of post-conception total 50 pregnant females were dissected and the incidence of digital malformations were obtained. Rat embryos on the 12, 13, 14, 15, 16th day of gestation irradiated by 250 rads were examined for morphogenesis of digital malformation. Digital radiating lines were examined in water and histologically by H-E stain. Supra vital stain samples by Nile-blue sulfate in 37 .deg. C normal saline were prepared for the observation of cell necrosis regions and morphogenesis of digits. The results obtained were as follows; 1. By x-irradiation on 11th day of gestation, digital malformations of Ectrodactylia, Syndactylia, Polydactylia and Hematodactylia were developed. Ectrodactylia showed the effective relationship to the amount of irradiation, however Syndactylia and Poydactylia did not. 2. By x-irradiation, cell necrosis of digital germ was appeared markedly, but in 48 hours after irradiation was depressed to the periphery of digital germ and in 72 hours after irradiation was disappeared. Digital radiating line showed marked state of malformation in 48 hours after irradiation and continued to show the same amount of physiological cell necrosis as the compared control group in 72 hours after irradiation. But in the Syndactylia, physiological cell necrosis was not able to be recognized. 3. Ectrodactylia induced by x-irradiation was considered as the direct result of cell necrosis of digital origin, however, Polydactylia and Syndactylia were considered as the result of some effect in

  15. Breast augmentation - slideshow

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/presentations/100205.htm Breast augmentation - series—Normal anatomy To use the sharing features ... Bethesda, MD 20894 U.S. Department of Health and Human Services National Institutes of Health Page last updated: ...

  16. Label-free detection of breast masses using multiphoton microscopy.

    Directory of Open Access Journals (Sweden)

    Xiufeng Wu

    Full Text Available Histopathology forms the gold standard for the diagnosis of breast cancer. Multiphoton microscopy (MPM has been proposed to be a potentially powerful adjunct to current histopathological techniques. A label-free imaging based on two- photon excited fluorescence and second-harmonic generation is developed for differentiating normal breast tissues, benign, as well as breast cancer tissues. Human breast biopsies (including human normal breast tissues, benign as well as breast cancer tissues that are first imaged (fresh, unfixed, and unstained with MPM and are then processed for routine H-E histopathology. Our results suggest that the MPM images, obtained from these unprocessed biopsies, can readily distinguish between benign lesions and breast cancers. In the tissues of breast cancers, MPM showed that the tumor cells displayed marked cellular and nuclear pleomorphism. The tumor cells, characterized by irregular size and shape, enlarged nuclei, and increased nuclear-cytoplasmic ratio, infiltrated into disrupted connective tissue, leading to the loss of second-harmonic generation signals. For breast cancer, MPM diagnosis was 100% correct because the tissues of breast cancers did not have second-harmonic generation signals in MPM imaging. On the contrary, in benign breast masses, second-harmonic generation signals could be seen easily in MPM imaging. These observations indicate that MPM could be an important potential tool to provide label-free noninvasive diagnostic impressions that can guide surgeon in biopsy and patient management.

  17. Fibroadenoma in axilla: another manifestation of ectopic breast.

    Science.gov (United States)

    Tiwary, Satyendra K; Kumar, Puneet; Khanna, Ajay Kumar

    2015-04-26

    Fibroadenoma of an accessory breast is a rare disease. The clinical significance lies in the fact that a number of cystic, inflammatory, neoplastic diseases similar to those of a normal breast have been reported in accessory breasts as well. Vigilant self-assessment and complete clinical examination are always encouraged to detect earliest malignancy in the axilla. We report two cases of ectopic breast fibroadenoma with the relevant literature. 2015 BMJ Publishing Group Ltd.

  18. Epstein-Barr virus, human papillomavirus and mouse mammary tumour virus as multiple viruses in breast cancer.

    Science.gov (United States)

    Glenn, Wendy K; Heng, Benjamin; Delprado, Warick; Iacopetta, Barry; Whitaker, Noel J; Lawson, James S

    2012-01-01

    The purpose of this investigation is to determine if Epstein Barr virus (EBV), high risk human papillomavirus (HPV), and mouse mammary tumour viruses (MMTV) co-exist in some breast cancers. All the specimens were from women residing in Australia. For investigations based on standard PCR, we used fresh frozen DNA extracts from 50 unselected invasive breast cancers. For normal breast specimens, we used DNA extracts from epithelial cells from milk donated by 40 lactating women. For investigations based on in situ PCR we used 27 unselected archival formalin fixed breast cancer specimens and 18 unselected archival formalin fixed normal breast specimens from women who had breast reduction surgery. Thirteen of these fixed breast cancer specimens were ductal carcinoma in situ (dcis) and 14 were predominantly invasive ductal carcinomas (idc). EBV sequences were identified in 68%, high risk HPV sequences in 50%, and MMTV sequences in 78% of DNA extracted from 50 invasive breast cancer specimens. These same viruses were identified in selected normal and breast cancer specimens by in situ PCR. Sequences from more than one viral type were identified in 72% of the same breast cancer specimens. Normal controls showed these viruses were also present in epithelial cells in human milk - EBV (35%), HPV, 20%) and MMTV (32%) of 40 milk samples from normal lactating women, with multiple viruses being identified in 13% of the same milk samples. We conclude that (i) EBV, HPV and MMTV gene sequences are present and co-exist in many human breast cancers, (ii) the presence of these viruses in breast cancer is associated with young age of diagnosis and possibly an increased grade of breast cancer.

  19. SACE_0012, a TetR-family transcriptional regulator, affects the morphogenesis of Saccharopolyspora erythraea.

    Science.gov (United States)

    Yin, Xiaojuan; Xu, Xinqiang; Wu, Hang; Yuan, Li; Huang, Xunduan; Zhang, Buchang

    2013-12-01

    Saccharopolyspora erythraea, a mycelium-forming actinomycete, produces a clinically important antibiotic erythromycin. Extensive investigations have provided insights into erythromycin biosynthesis in S. erythraea, but knowledge of its morphogenesis remains limited. By gene inactivation and complementation strategies, the TetR-family transcriptional regulator SACE_0012 was identified to be a negative regulator of mycelium formation of S. erythraea A226. Detected by quantitative real-time PCR, the relative transcription of SACE_7115, the amfC homolog for an aerial mycelium formation protein, was dramatically increased in SACE_0012 mutant, whereas erythromycin biosynthetic gene eryA, a pleiotropic regulatory gene bldD, and the genes SACE_2141, SACE_6464, SACE_6040, that are the homologs to the sporulation regulators WhiA, WhiB, WhiG, were not differentially expressed. SACE_0012 disruption could not restore its defect of aerial development in bldD mutant, and also did not further accelerate the mycelium formation in the mutant of SACE_7040 gene, that was previously identified to be a morphogenesis repressor. Furthermore, the transcriptional level of SACE_0012 had not markedly changed in bldD and SACE_7040 mutant over A226. Taken together, these results suggest that SACE_0012 is a negative regulator of S. erythraea morphogenesis by mainly increasing the transcription of amfC gene, independently of the BldD regulatory system.

  20. Mechanism and preclinical prevention of increased breast cancer risk caused by pregnancy.

    Science.gov (United States)

    Haricharan, Svasti; Dong, Jie; Hein, Sarah; Reddy, Jay P; Du, Zhijun; Toneff, Michael; Holloway, Kimberly; Hilsenbeck, Susan G; Huang, Shixia; Atkinson, Rachel; Woodward, Wendy; Jindal, Sonali; Borges, Virginia F; Gutierrez, Carolina; Zhang, Hong; Schedin, Pepper J; Osborne, C Kent; Tweardy, David J; Li, Yi

    2013-12-31

    While a first pregnancy before age 22 lowers breast cancer risk, a pregnancy after age 35 significantly increases life-long breast cancer risk. Pregnancy causes several changes to the normal breast that raise barriers to transformation, but how pregnancy can also increase cancer risk remains unclear. We show in mice that pregnancy has different effects on the few early lesions that have already developed in the otherwise normal breast-it causes apoptosis evasion and accelerated progression to cancer. The apoptosis evasion is due to the normally tightly controlled STAT5 signaling going astray-these precancerous cells activate STAT5 in response to pregnancy/lactation hormones and maintain STAT5 activation even during involution, thus preventing the apoptosis normally initiated by oncoprotein and involution. Short-term anti-STAT5 treatment of lactation-completed mice bearing early lesions eliminates the increased risk after a pregnancy. This chemoprevention strategy has important implications for preventing increased human breast cancer risk caused by pregnancy. DOI: http://dx.doi.org/10.7554/eLife.00996.001.

  1. Achieving a predictable 24-hour return to normal activities after breast augmentation: part II. Patient preparation, refined surgical techniques, and instrumentation.

    Science.gov (United States)

    Tebbetts, John B

    2006-12-01

    The goal of this study was to develop practices that would allow patients undergoing subpectoral augmentation to predictably return to full normal activities within 24 hours after the operation, free of postoperative adjuncts. Part I of this study used motion and time study principles to reduce operative times, medication dosages, perioperative morbidity, and recovery times in augmentation mammaplasty. Part II of the study focuses on details of patient education, preoperative planning, instrumentation, and surgical technique modifications that were identified, modified, and implemented to achieve the results reported in part I. Two groups of 16 patients each (groups 1 and 2) were studied retrospectively for comparison to a third group of 627 patients (group 3) studied prospectively. Patients in group 1 had axillary partial retropectoral breast augmentations in 1982-1983, using dissociative anesthesia, blunt instrument implant pocket dissection, and Dow Corning, double-lumen implants containing 20 mg of methylprednisolone and 20 cc of saline in the outer lumen of the implants. Patients in group 2 (1990) had inframammary, retromammary augmentations by using a combination of blunt and electrocautery dissection, Surgitek Replicon polyurethane-covered, silicone gel-filled implants, and general endotracheal anesthesia. Patients in group 3 (1998 to 2001, n = 627) had inframammary partial retropectoral, inframammary retromammary, and axillary partial retropectoral augmentations under general endotracheal anesthesia. Refined practices and surgical techniques from studies of groups 1 and 2 were applied in group 3. Videotapes from operative procedures of groups 1 and 2 were analyzed with macromotion and micromotion study principles, and tables of events were formulated for each move during the operation for all personnel in the operating room. Extensive details of surgical technique were examined and reexamined in 13 different stages by using principles of motion and time

  2. Effects of light quality on flowering and morphogenesis in Hyoscyamus niger L.

    NARCIS (Netherlands)

    Hattab, El A.H.

    1968-01-01

    The present paper is concerned with bolting and morphogenesis of Hyoscyamus niger L. as reactions upon radiation in the visible spectrum.

    Experiments are described in which Hyoscyamus plants were exposed to light of various well defined spectral regions. The light of these

  3. Mis-expression of grainyhead-like transcription factors in zebrafish leads to defects in enveloping layer (EVL) integrity, cellular morphogenesis and axial extension.

    Science.gov (United States)

    Miles, Lee B; Darido, Charbel; Kaslin, Jan; Heath, Joan K; Jane, Stephen M; Dworkin, Sebastian

    2017-12-14

    The grainyhead-like (grhl) transcription factors play crucial roles in craniofacial development, epithelial morphogenesis, neural tube closure, and dorso-ventral patterning. By utilising the zebrafish to differentially regulate expression of family members grhl2b and grhl3, we show that both genes regulate epithelial migration, particularly convergence-extension (CE) type movements, during embryogenesis. Genetic deletion of grhl3 via CRISPR/Cas9 results in failure to complete epiboly and pre-gastrulation embryonic rupture, whereas morpholino (MO)-mediated knockdown of grhl3 signalling leads to aberrant neural tube morphogenesis at the midbrain-hindbrain boundary (MHB), a phenotype likely due to a compromised overlying enveloping layer (EVL). Further disruptions of grhl3-dependent pathways (through co-knockdown of grhl3 with target genes spec1 and arhgef19) confirm significant MHB morphogenesis and neural tube closure defects. Concomitant MO-mediated disruption of both grhl2b and grhl3 results in further extensive CE-like defects in body patterning, notochord and somite morphogenesis. Interestingly, over-expression of either grhl2b or grhl3 also leads to numerous phenotypes consistent with disrupted cellular migration during gastrulation, including embryo dorsalisation, axial duplication and impaired neural tube migration leading to cyclopia. Taken together, our study ascribes novel roles to the Grhl family in the context of embryonic development and morphogenesis.

  4. Expression of Tyrosine Kinase Syk in Breast Cancer and Their Clinical Significance

    Institute of Scientific and Technical Information of China (English)

    DINGYong-bin; WUZheng-yan; WANGShui; FANPing; ZHAXiao-ming; ZHENGWei; LIUXiao-an

    2004-01-01

    To evaluate the effects of the Syk mRNA expression in human breast cancer on tummor growth and metastasis, and the correlalion of the Syk gene expression with ER, PR, 1)53, and HER2/neu. Methods: Using se~i-RT-PCR,specimens from 40 breast cancer palients( tumor 1issues,adjacent normal tissues),and 15 filmmdenoma were detected for the expression of the Syk gene and level of Syk mRNA. Meanwhile, Eli, PR, P53, llER2/neu were detected in 40 tumor tissues from breast cancer with immunohistoch~mical staining. Resu/ts:Expression of the Syk gene was detected in all normal breast 1issues. Unlike normal breast tissue, 31 out of 40 breast cancer tissues did not show any detectable Syk mRNA expression,and there were significant differences in two groups(P <0.05).The level of Syk mRNA in the primary breast cancer 1issues was significantly lower than that in the adjacent non-cancerous breast tissues and benign fibroadenonm breast tissues( P < 0.05). Furthermore, only two breast cancer tissues in 18 pa ",tights with lymph node metastasis had the Syk mRNA expression. The Syk mRNA expression was negatively correlated to lymph nodemetastasis,HER2/neuproteinexpression(P<0.05). Conc/us/on.. The expression of the Syk gene may play an important role in suppressing growth and metastasis of breast cancer.

  5. Breast cancer and steroid metabolizing enzymes: the role of progestogens.

    Science.gov (United States)

    Pasqualini, Jorge R

    2009-12-01

    It is well documented that breast tissue, both normal and cancerous, contains all the enzymatic systems necessary for the bioformation and metabolic transformation of estrogens, androgens and progesterone. These include sulfatases, aromatase, hydroxysteroid-dehydrogenases, sulfotransferases, hydroxylases and glucuronidases. The control of these enzymes plays an important role in the development and pathogenesis of hormone-dependent breast cancer. As discussed in this review, various progestogens including dydrogesterone and its 20alpha-dihydro-derivative, medrogestone, promegestone, nomegestrol acetate and norelgestromin can reduce intratissular levels of estradiol in breast cancer by blocking sulfatase and 17beta-hydroxysteroid-dehydrogenase type 1 activities. A possible correlation has been postulated between breast cell proliferation and estrogen sulfotransferase activity. Progesterone is largely transformed in the breast; normal breast produces mainly 4-ene derivatives, whereas 5alpha-derivatives are most common in breast cancer tissue. It has been suggested that this specific conversion of progesterone may be involved in breast carcinogenesis. In conclusion, treatment with anti-aromatases combined with anti-sulfatase or 17beta-hydroxysteroid-dehydrogenase type 1 could provide new therapeutic possibilities in the treatment of patients with hormone-dependent breast cancer. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  6. Protection of the contralateral breast during radiation therapy for breast cancer

    International Nuclear Information System (INIS)

    Garrigo, E.; Zunino, S.; Germanier, A.

    2008-01-01

    Conformal Radiation Therapy (3DCRT) and Intensity Modulated Radiotherapy (IMRT) improve the relationship between tumor control and complications in normal tissue. However, these techniques may cause an increase of the normal tissue volume irradiated with low doses or an increase of the doses outside the beam. The aim of this work was to measure and compare the scatter dose to the contralateral breast using both the conventional two-field technique and the 3DCRT technique with blocks. The contralateral breast dose was measured with thermoluminescent dosimeters. The present work is divided in three parts: 1)Characterization of the radiation field outside the treatment beam; 2) Determination of the dose to the contralateral breast; 3) Design and construction of a shield to reduce the scatter dose to the contralateral breast. Treatment using 3DCRT technique was delivered to a phantom. From one to ten 2 mm thick lead sheets were placed on the dosimeters to attenuate radiation to the contralateral breast from the head, without blocking the treatment beam. Using the conventional technique the average dose to the contralateral breast was 2.09 Gy,4.18%(2.9%-19%) of the 50 Gy prescribed dose. The contribution of the medial field was 3.36% (2.3%-21.1%) and of the lateral field 0.86%(0.4%-3.7%). When using 3DCRT technique the average dose to the opposite breast was 5,9 Gy,11.8% (7.9%-24%) of the prescribed dose. The contribution of the medial field was 10.3% (6.7%-20%) and of the lateral field 1.6% (1.1%-3.8%). A 2 mm thick lead shield with a 0.2 g/cm2 thick wax coat was constructed which reduced the dose from 11.8% to less than 2%. The blocks increase the dose to the contralateral breast, the highest dose being attributed to the medial field. Our shield reduced the dose, which allowed the regular use of 3DCRT with blocks. In addition, we found that this shield was comfortable for the patients and easy to position for the therapists. (author)

  7. Characterizing Spatial Organization of Cell Surface Receptors in Human Breast Cancer with STORM

    Science.gov (United States)

    Lyall, Evan; Chapman, Matthew R.; Sohn, Lydia L.

    2012-02-01

    Regulation and control of complex biological functions are dependent upon spatial organization of biological structures at many different length scales. For instance Eph receptors and their ephrin ligands bind when opposing cells come into contact during development, resulting in spatial organizational changes on the nanometer scale that lead to changes on the macro scale, in a process known as organ morphogenesis. One technique able to probe this important spatial organization at both the nanometer and micrometer length scales, including at cell-cell junctions, is stochastic optical reconstruction microscopy (STORM). STORM is a technique that localizes individual fluorophores based on the centroids of their point spread functions and then reconstructs a composite image to produce super resolved structure. We have applied STORM to study spatial organization of the cell surface of human breast cancer cells, specifically the organization of tyrosine kinase receptors and chemokine receptors. A better characterization of spatial organization of breast cancer cell surface proteins is necessary to fully understand the tumorigenisis pathways in the most common malignancy in United States women.

  8. Dichotomous roles for the orphan nuclear receptor NURR1 in breast cancer

    International Nuclear Information System (INIS)

    Llopis, Shawn; Singleton, Brittany; Duplessis, Tamika; Carrier, Latonya; Rowan, Brian; Williams, Christopher

    2013-01-01

    NR4A orphan nuclear receptors are involved in multiple biological processes which are important in tumorigenesis such as cell proliferation, apoptosis, differentiation, and glucose utilization. The significance of NR4A family member NURR1 (NR4A2) in breast cancer etiology has not been elucidated. The purpose of this study was to ascertain the impact of NURR1 expression on breast transformation, tumor growth, and breast cancer patient survival. We determined the expression of NURR1 in normal breast versus breast carcinoma in tissue microarrays (immunohistochemistry), tissue lysates (immunoblot), and at the mRNA level (publically available breast microarrays). In addition NURR1 expression was compared among breast cancer patients in cohorts based on p53 expression, estrogen receptor α expression, tumor grade, and lymph node metastases. Kaplan-Meier survival plots were used to determine the correlation between NURR1 expression and relapse free survival (RFS). Using shRNA-mediated silencing, we determined the effect of NURR1 expression on tumor growth in mouse xenografts. Results from breast cancer tissue arrays demonstrate a higher NURR1 expression in the normal breast epithelium compared to breast carcinoma cells (p ≤ 0.05). Among cases of breast cancer, NURR1 expression in the primary tumors was inversely correlated with lymph node metastases (p ≤ 0.05) and p53 expression (p ≤ 0.05). Clinical stage and histological grade were not associated with variation in NURR1 expression. In gene microarrays, 4 of 5 datasets showed stronger mean expression of NURR1 in normal breast as compared to transformed breast. Additionally, NURR1 expression was strongly correlated with increase relapse free survival (HR = 0.7) in a cohort of all breast cancer patients, but showed no significant difference in survival when compared among patients whom have not been treated systemically (HR = 0.91). Paradoxically, NURR1 silenced breast xenografts showed significantly decreased growth

  9. The classification of normal screening mammograms

    Science.gov (United States)

    Ang, Zoey Z. Y.; Rawashdeh, Mohammad A.; Heard, Robert; Brennan, Patrick C.; Lee, Warwick; Lewis, Sarah J.

    2016-03-01

    Rationale and objectives: To understand how breast screen readers classify the difficulty of normal screening mammograms using common lexicon describing normal appearances. Cases were also assessed on their suitability for a single reader strategy. Materials and Methods: 15 breast readers were asked to interpret a test set of 29 normal screening mammogram cases and classify them by rating the difficulty of the case on a five-point Likert scale, identifying the salient features and assessing their suitability for single reading. Using the False Positive Fractions from a previous study, the 29 cases were classified into 10 "low", 10 "medium" and nine "high" difficulties. Data was analyzed with descriptive statistics. Spearman's correlation was used to test the strength of association between the difficulty of the cases and the readers' recommendation for single reading strategy. Results: The ratings from readers in this study corresponded to the known difficulty level of cases for the 'low' and 'high' difficulty cases. Uniform ductal pattern and density, symmetrical mammographic features and the absence of micro-calcifications were the main reasons associated with 'low' difficulty cases. The 'high' difficulty cases were described as having `dense breasts'. There was a statistically significant negative correlation between the difficulty of the cases and readers' recommendation for single reading (r = -0.475, P = 0.009). Conclusion: The findings demonstrated potential relationships between certain mammographic features and the difficulty for readers to classify mammograms as 'normal'. The standard Australian practice of double reading was deemed more suitable for most cases. There was an inverse moderate association between the difficulty of the cases and the recommendations for single reading.

  10. Expression of matrix metalloproteinases (MMPs) in primary human breast cancer and breast cancer cell lines: New findings and review of the literature

    International Nuclear Information System (INIS)

    Köhrmann, Andrea; Kammerer, Ulrike; Kapp, Michaela; Dietl, Johannes; Anacker, Jelena

    2009-01-01

    Matrix metalloproteinases (MMPs) are a family of structural and functional related endopeptidases. They play a crucial role in tumor invasion and building of metastatic formations because of their ability to degrade extracellular matrix proteins. Under physiological conditions their activity is precisely regulated in order to prevent tissue disruption. This physiological balance seems to be disrupted in cancer making tumor cells capable of invading the tissue. In breast cancer different expression levels of several MMPs have been found. To fill the gap in our knowledge about MMP expression in breast cancer, we analyzed the expression of all known human MMPs in a panel of twenty-five tissue samples (five normal breast tissues, ten grade 2 (G2) and ten grade 3 (G3) breast cancer tissues). As we found different expression levels for several MMPs in normal breast and breast cancer tissue as well as depending on tumor grade, we additionally analyzed the expression of MMPs in four breast cancer cell lines (MCF-7, MDA-MB-468, BT 20, ZR 75/1) commonly used in research. The results could thus be used as model for further studies on human breast cancer. Expression analysis was performed on mRNA and protein level using semiquantitative RT-PCR, Western blot, immunohistochemistry and immunocytochemistry. In summary, we identified several MMPs (MMP-1, -2, -8, -9, -10, -11, -12, -13, -15, -19, -23, -24, -27 and -28) with a stronger expression in breast cancer tissue compared to normal breast tissue. Of those, expression of MMP-8, -10, -12 and -27 is related to tumor grade since it is higher in analyzed G3 compared to G2 tissue samples. In contrast, MMP-7 and MMP-27 mRNA showed a weaker expression in tumor samples compared to healthy tissue. In addition, we demonstrated that the four breast cancer cell lines examined, are constitutively expressing a wide variety of MMPs. Of those, MDA-MB-468 showed the strongest mRNA and protein expression for most of the MMPs analyzed. MMP-1, -2

  11. UPTAKE AND PERFORMANCE OF CLINICAL BREAST EXAM SCREENING BY TRAINED LAYWOMEN IN MALAWI.

    Science.gov (United States)

    Gutnik, L; Lee, C; Msosa, V

    2017-09-01

    Breast cancer awareness and early detection are limited in sub-saharan Africa. Resource limitations make screening mammography or clinical breast examination (CBE) by physicians or nurses impractical in many settings. We aimed to assess feasibility and performance of CBE by laywomen in urban health clinics. Four laywomen were trained to deliver breast cancer educational talks and conduct CBE. Eligible women were 30 years, with no prior breast cancer or breast surgery, and clinic attendance for reasons other than a breast concern. Women with abnormal CBE were referred to a study surgeon. All palpable masses confirmed by surgeon examination were pathologically sampled. Patients with abnormal screening CBE but normal surgeon examination underwent breast ultrasound confirmation. Among 1220 eligible women, 1000 (82%) agreed to CBE. Lack of time (69%) was the commonest reason for refusal. Educational talk attendance was associated with higher CBE participation (83% versus 77%, P¼ 0.012). Among 1000 women screened, 7% had abnormal CBE. Of 45 women with normal CBE randomized to physician examination, 43 had normal examinations and two had axillary lymphadenopathy not detected by CBE. Sixty of 67 women (90%) with abnormal CBE attended the referral visit. Of these, 29 (48%) had concordant abnormal physician examination. Thirty-one women (52%) had discordant normal physician examination, all of whom also had normal breast ultrasounds. Compared with physician examination, sensitivity for CBE by laywomen was 94% (confidence interval (CI, 79%-99%), specificity 58% (CI, 46%-70%), positive predictive value 48% (CI, 35%-62%), and negative predictive value 96% (CI, 85%-100%). Of 13 women who underwent recommended pathologic sampling of a breast lesion, two had cytologic dysplasia and all others benign results. CBE uptake in Lilongwe clinics was high. CBE by laywomen compared favourably with physician examination and followup was good. Our intervention can serve as a model for wider

  12. Intensity modulated radiotherapy for breast cancer

    International Nuclear Information System (INIS)

    Riou, O.; Fenoglietto, P.; Lemanski, C.; Azria, D.

    2012-01-01

    Intensity modulated radiotherapy (IMRT) is a technique allowing dose escalation and normal tissue sparing for various cancer types. For breast cancer, the main goals when using IMRT were to improve dose homogeneity within the breast and to enhance coverage of complex target volumes. Nonetheless, better heart and lung protections are achievable with IMRT as compared to standard irradiation for difficult cases. Three prospective randomized controlled trials of IMRT versus standard treatment showed that a better breast homogeneity can translate into better overall cosmetic results. Dosimetric and clinical studies seem to indicate a benefit of IMRT for lymph nodes irradiation, bilateral treatment, left breast and chest wall radiotherapy, or accelerated partial breast irradiation. The multiple technical IMRT solutions available tend to indicate a widespread use for breast irradiation. Nevertheless, indications for breast IMRT should be personalized and selected according to the expected benefit for each individual. (authors)

  13. Microbial Biofilms and Breast Tissue Expanders

    Directory of Open Access Journals (Sweden)

    Melissa J. Karau

    2013-01-01

    Full Text Available We previously developed and validated a vortexing-sonication technique for detection of biofilm bacteria on the surface of explanted prosthetic joints. Herein, we evaluated this technique for diagnosis of infected breast tissue expanders and used it to assess colonization of breast tissue expanders. From April 2008 to December 2011, we studied 328 breast tissue expanders at Mayo Clinic, Rochester, MN, USA. Of seven clinically infected breast tissue expanders, six (85.7% had positive cultures, one of which grew Propionibacterium species. Fifty-two of 321 breast tissue expanders (16.2%, 95% CI, 12.3–20.7% without clinical evidence of infection also had positive cultures, 45 growing Propionibacterium species and ten coagulase-negative staphylococci. While vortexing-sonication can detect clinically infected breast tissue expanders, 16 percent of breast tissue expanders appear to be asymptomatically colonized with normal skin flora, most commonly, Propionibacterium species.

  14. Significance of TLR4/MyD88 expression in breast cancer

    Science.gov (United States)

    Chen, Xiangjin; Zhao, Feng; Zhang, Huihao; Zhu, Youzhi; Wu, Kunlin; Tan, Guozheng

    2015-01-01

    Objective: To investigate the expression of TLR4/MyD88 in breast cancer, and explore the relationship between their expression and breast cancer tumor growth and invasion. Methods: We examined the protein expression of TLR4 and MyD88 in 60 cases of histologically confirmed breast cancer. The relationship of their protein expressions with clinical features including age at diagnosis, tumor size and stage, lymph node metastasis and distant metastasis were analyzed. Results: The IHC results showed that TLR4 and MyD88 were expressed in 63.3% (38/60) and 58.3% (35/60) of malignant breast tumors respectively. TLR4 expression in breast cancer were significantly higher than in fibroadenoma (n = 4, 20.0%) and adjacent normal tissues (n = 2, 10.0%) (P fibroadenoma (n = 4, 20.0%) and adjacent normal tissue (n = 3, 15.0%) (P fibroadenoma and adjacent normal tissues (P < 0.05). The protein expressions of TLR4 and MyD88 were also significantly associated with poor clinical features (P < 0.05). Conclusion: TLR4 and MyD88 expression might be associated with breast cancer growth and regional and distant metastases. PMID:26261595

  15. Rac1 modulates mammalian lung branching morphogenesis in part through canonical Wnt signaling.

    Science.gov (United States)

    Danopoulos, Soula; Krainock, Michael; Toubat, Omar; Thornton, Matthew; Grubbs, Brendan; Al Alam, Denise

    2016-12-01

    Lung branching morphogenesis relies on a number of factors, including proper epithelial cell proliferation and differentiation, cell polarity, and migration. Rac1, a small Rho GTPase, orchestrates a number of these cellular processes, including cell proliferation and differentiation, cellular alignment, and polarization. Furthermore, Rac1 modulates both noncanonical and canonical Wnt signaling, important pathways in lung branching morphogenesis. Culture of embryonic mouse lung explants in the presence of the Rac1 inhibitor (NSC23766) resulted in a dose-dependent decrease in branching. Increased cell death and BrdU uptake were notably seen in the mesenchyme, while no direct effect on the epithelium was observed. Moreover, vasculogenesis was impaired following Rac1 inhibition as shown by decreased Vegfa expression and impaired LacZ staining in Flk1-Lacz reporter mice. Rac1 inhibition decreased Fgf10 expression in conjunction with many of its associated factors. Moreover, using the reporter lines TOPGAL and Axin2-LacZ, there was an evident decrease in canonical Wnt signaling in the explants treated with the Rac1 inhibitor. Activation of canonical Wnt pathway using WNT3a or WNT7b only partially rescued the branching inhibition. Moreover, these results were validated on human explants, where Rac1 inhibition resulted in impaired branching and decreased AXIN2 and FGFR2b expression. We therefore conclude that Rac1 regulates lung branching morphogenesis, in part through canonical Wnt signaling. However, the exact mechanisms by which Rac1 interacts with canonical Wnt in human and mouse lung requires further investigation. Copyright © 2016 the American Physiological Society.

  16. Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis.

    Science.gov (United States)

    Mote, P A; Bartow, S; Tran, N; Clarke, C L

    2002-03-01

    Progesterone receptor (PR) mediates the effects of progesterone in mammary tissues and plays a crucial role in normal breast development and in breast cancer. PR proteins are expressed as two isoforms, PRA and PRB, that have different capacities to activate target genes, yet it is unknown whether progesterone action in normal and malignant breast is mediated by PRA and/or PRB. This study determines the relative expression of PRA and PRB in normal breast and in benign, premalignant and malignant archival breast lesions by dual immunofluorescent histochemistry. In normal breast and in proliferative disease without atypia (PDWA) PRA and PRB were co-expressed within the same cells in comparable amounts, implicating both isoforms in progesterone action. In atypical lesions, however, there was a significant increase in predominant expression of PRA or PRB, with lesion progression from the normal state to malignancy. PR isoform predominance, especially PRA predominance, was evident in a high proportion of ductal carcinomas in situ (DCIS) and invasive breast lesions. In the normal breast and in PDWA, the relative expression of PRA and PRB in adjacent cells was homogenous. There was a significant increase in cell-to-cell heterogeneity of PR isoform expression in ADH and DCIS lesions and in the majority of breast cancers. Heterogeneous cell-to-cell expression of PR isoforms occurred prior to overall predominant expression of one isoform in premalignant breast lesions, demonstrating that loss of control of relative PRA:PRB expression is an early event in the development of breast cancer. PRA:PRB ratios within a breast lesion are likely to be important as both markers and effectors of tumor growth and development, and progressively aberrant PR isoform expression may play a role in the etiology of breast cancer.

  17. Fibroblast radiosensitivity versus acute and late normal skin responses in patients treated for breast cancer

    International Nuclear Information System (INIS)

    Brock, W.A.; Wike, J.; Tucker, S.L.

    1995-01-01

    To determine if the radiosensitivity of normal human skin fibroblasts, measured in early passage cultures, is significantly correlated with the degree of acute or late normal skin damage in patients treated for breast cancer with radiotherapy. To test assay reproducibility, SF2 values derived from paired biopsies of the same patient (12 cases) were compared. A reasonably good correlation (p = 0.075) was obtained for SF2s determined by high dose-rate irradiations with immediated plating, but not for delayed plating or low dose-rate treatments. The median coefficient of variation in the replicate SF2s after high dose-rate treatment and immediate plating was 13%, suggesting that the poor correlation in paired SF2 values is due to the magnitude of the uncertainty in SF2 relative to the overall spread in SF2 values between patients (CV = 28%). Individual SF2 values and averaged values from patients with data from two biopsies were compared with the acute and late clinical reactions. A significant negative correlation was found between SF2 and relative clinical response, but only when averaged high dose-rate SF2 values and telangiectasia scores were compared. There was no significant correlation between average SF2 values and acute responses or between individual SF2 measurements and either the acute or late clinical response. The results of this study suggest that the degree of late telangiectasia is at least partially dependent upon the intrinsic cellular radiosensitivity of normal fibroblasts, but the relationship is not clear cut. Multiple replicate assays are necessary to obtain reliable estimates of fibroblast SF2 values using current techniques. 20 refs., 3 figs., 3 tabs

  18. Development of three-dimensional radiotherapy techniques in breast cancer

    Science.gov (United States)

    Coles, Charlotte E.

    Radiotherapy following conservation surgery decreases local relapse and death from breast cancer. Currently, the challenge is to minimise the morbidity caused by this treatment without losing efficacy. Despite many advances in radiation techniques in other sites of the body, the majority of breast cancer patients are still planned and treated using 2-dimensional simple radiotherapy techniques. In addition, breast irradiation currently consumes 30% of the UK's radiotherapy workload. Therefore, any change to more complex treatment should be of proven benefit. The primary objective of this research is to develop and evaluate novel radiotherapy techniques to decrease irradiation of normal structures and improve localisation of the tumour bed. I have developed a forward-planned intensity modulated (IMRT) breast radiotherapy technique, which has shown improved dosimetry results compared to standard breast radiotherapy. Subsequently, I have developed and implemented a phase III randomised controlled breast IMRT trial. This National Cancer Research Network adopted trial will answer an important question regarding the clinical benefit of breast IMRT. It will provide DNA samples linked with high quality clinical outcome data, for a national translational radiogenomics study investigating variation in normal tissue toxicity. Thus, patients with significant late normal tissue side effects despite good dose homogeneity will provide the best model for finding differences due to underlying genetics. I evaluated a novel technique using high definition free-hand 3-dimensional (3D) ultrasound in a phantom study, and the results suggested that this is an accurate and reproducible method for tumour bed localisation. I then compared recognised methods of tumour bed localisation with the 3D ultrasound method in a clinical study. The 3D ultrasound technique appeared to accurately represent the shape and spatial position of the tumour cavity. This tumour bed localisation research

  19. AZU-1: A Candidate Breast Tumor Suppressor and Biomarker for Tumor Progression

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Huei-Mei; Schmeichel, Karen L; Mian, I. Saira; Lelie`vre, Sophie; Petersen, Ole W; Bissell, Mina J

    2000-02-04

    To identify genes misregulated in the final stages of breast carcinogenesis, we performed differential display to compare the gene expression patterns of the human tumorigenic mammary epithelial cells, HMT-3522-T4-2, with those of their immediate premalignant progenitors, HMT-3522-S2. We identified a novel gene, called anti-zuai-1 (AZU-1), that was abundantly expressed in non- and premalignant cells and tissues but was appreciably reduced in breast tumor cell types and in primary tumors. The AZU-1 gene encodes an acidic 571-amino-acid protein containing at least two structurally distinct domains with potential protein-binding functions: an N-terminal serine and proline-rich domain with a predicted immunoglobulin-like fold and a C-terminal coiled-coil domain. In HMT-3522 cells, the bulk of AZU-1 protein resided in a detergent-extractable cytoplasmic pool and was present at much lower levels in tumorigenic T4-2 cells than in their nonmalignant counterparts. Reversion of the tumorigenic phenotype of T4-2 cells, by means described previously, was accompanied by the up-regulation of AZU-1. In addition, reexpression of AZU-1 in T4-2 cells, using viral vectors, was sufficient to reduce their malignant phenotype substantially, both in culture and in vivo. These results indicate that AZU-1 is a candidate breast tumor suppressor that may exert its effects by promoting correct tissue morphogenesis.

  20. Hormone replacement therapy dependent changes in breast cancer-related gene expression in breast tissue of healthy postmenopausal women.

    Science.gov (United States)

    Sieuwerts, Anieta M; De Napoli, Giuseppina; van Galen, Anne; Kloosterboer, Helenius J; de Weerd, Vanja; Zhang, Hong; Martens, John W M; Foekens, John A; De Geyter, Christian

    2011-12-01

    Risk assessment of future breast cancer risk through exposure to sex steroids currently relies on clinical scorings such as mammographic density. Knowledge about the gene expression patterns in existing breast cancer tumors may be used to identify risk factors in the breast tissue of women still free of cancer. The differential effects of estradiol, estradiol together with gestagens, or tibolone on breast cancer-related gene expression in normal breast tissue samples taken from postmenopausal women may be used to identify gene expression profiles associated with a higher breast cancer risk. Breast tissue samples were taken from 33 healthy postmenopausal women both before and after a six month treatment with either 2mg micronized estradiol [E2], 2mg micronized estradiol and 1mg norethisterone acetate [E2+NETA], 2.5mg tibolone [T] or [no HRT]. Except for [E2], which was only given to women after hysterectomy, the allocation to each of the three groups was randomized. The expression of 102 mRNAs and 46 microRNAs putatively involved in breast cancer was prospectively determined in the biopsies of 6 women receiving [no HRT], 5 women receiving [E2], 5 women receiving [E2+NETA], and 6 receiving [T]. Using epithelial and endothelial markers genes, non-representative biopsies from 11 women were eliminated. Treatment of postmenopausal women with [E2+NETA] resulted in the highest number of differentially (pbreast tissue with a change in the expression of genes putatively involved in breast cancer. Our data suggest that normal mammary cells triggered by [E2+NETA] adjust for steroidogenic up-regulation through down-regulation of the estrogen-receptor pathway. This feasibility study provides the basis for whole genome analyses to identify novel markers involved in increased breast cancer risk. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  1. Prostate-derived Ets factor, an oncogenic driver in breast cancer.

    Science.gov (United States)

    Sood, Ashwani K; Geradts, Joseph; Young, Jessica

    2017-05-01

    Prostate-derived Ets factor (PDEF), a member of the Ets family of transcription factors, differs from other family members in its restricted expression in normal tissues and its unique DNA-binding motif. These interesting attributes coupled with its aberrant expression in cancer have rendered PDEF a focus of increasing interest by tumor biologists. This review provides a current understanding of the characteristics of PDEF expression and its role in breast cancer. The bulk of the evidence is consistent with PDEF overexpression in most breast tumors and an oncogenic role for this transcription factor in breast cancer. In addition, high PDEF expression in estrogen receptor-positive breast tumors showed significant correlation with poor overall survival in several independent cohorts of breast cancer patients. Together, these findings demonstrate PDEF to be an oncogenic driver of breast cancer and a biomarker of poor prognosis in this cancer. Based on this understanding and the limited expression of PDEF in normal human tissues, the development of PDEF-based therapeutics for prevention and treatment of breast cancer is also discussed.

  2. Cardiac septation: a late contribution of the embryonic primary myocardium to heart morphogenesis

    NARCIS (Netherlands)

    Lamers, Wouter H.; Moorman, Antoon F. M.

    2002-01-01

    Heart morphogenesis comprises 2 major consecutive steps, viz. chamber formation followed by septation. Septation is the remodeling of the heart from a single-channel peristaltic pump to a dual-channel, synchronously contracting device with 1-way valves. In the human heart, septation occurs between 4

  3. Clinical breast examination screening by trained laywomen in Malawi integrated with other health services.

    Science.gov (United States)

    Gutnik, Lily; Lee, Clara; Msosa, Vanessa; Moses, Agnes; Stanley, Christopher; Mzumara, Suzgo; Liomba, N George; Gopal, Satish

    2016-07-01

    Breast cancer awareness and early detection are limited in sub-Saharan Africa. Resource limitations make screening mammography or clinical breast examination (CBE) by physicians or nurses impractical in many settings. We aimed to assess feasibility and performance of CBE by laywomen in urban health clinics in Malawi. Four laywomen were trained to deliver breast cancer educational talks and conduct CBE. After training, screening was implemented in diverse urban health clinics. Eligible women were ≥30 y, with no prior breast cancer or breast surgery, and clinic attendance for reasons other than a breast concern. Women with abnormal CBE were referred to a study surgeon. All palpable masses confirmed by surgeon examination were pathologically sampled. Patients with abnormal screening CBE but normal surgeon examination underwent breast ultrasound confirmation. In addition, 50 randomly selected women with normal screening CBE underwent breast ultrasound, and 45 different women with normal CBE were randomly assigned to surgeon examination. Among 1220 eligible women, 1000 (82%) agreed to CBE. Lack of time (69%) was the commonest reason for refusal. Educational talk attendance was associated with higher CBE participation (83% versus 77%, P = 0.012). Among 1000 women screened, 7% had abnormal CBE. Of 45 women with normal CBE randomized to physician examination, 43 had normal examinations and two had axillary lymphadenopathy not detected by CBE. Sixty of 67 women (90%) with abnormal CBE attended the referral visit. Of these, 29 (48%) had concordant abnormal physician examination. Thirty-one women (52%) had discordant normal physician examination, all of whom also had normal breast ultrasounds. Compared with physician examination, sensitivity for CBE by laywomen was 94% (confidence interval [CI] 79%-99%), specificity 58% (CI, 46%-70%), positive predictive value 48% (CI, 35%-62%), and negative predictive value 96% (CI, 85%-100%). Of 13 women who underwent recommended

  4. Quantitative ultrasound characterization of locally advanced breast cancer by estimation of its scatterer properties

    Energy Technology Data Exchange (ETDEWEB)

    Tadayyon, Hadi [Physical Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 2M9 (Canada); Sadeghi-Naini, Ali; Czarnota, Gregory, E-mail: Gregory.Czarnota@sunnybrook.ca [Physical Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 2M9 (Canada); Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada); Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5T 1P5 (Canada); Wirtzfeld, Lauren [Department of Physics, Ryerson University, Toronto, Ontario M5B 2K3 (Canada); Wright, Frances C. [Division of Surgical Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5 (Canada)

    2014-01-15

    Purpose: Tumor grading is an important part of breast cancer diagnosis and currently requires biopsy as its standard. Here, the authors investigate quantitative ultrasound parameters in locally advanced breast cancers that can potentially separate tumors from normal breast tissue and differentiate tumor grades. Methods: Ultrasound images and radiofrequency data from 42 locally advanced breast cancer patients were acquired and analyzed. Parameters related to the linear regression of the power spectrum—midband fit, slope, and 0-MHz-intercept—were determined from breast tumors and normal breast tissues. Mean scatterer spacing was estimated from the spectral autocorrelation, and the effective scatterer diameter and effective acoustic concentration were estimated from the Gaussian form factor. Parametric maps of each quantitative ultrasound parameter were constructed from the gated radiofrequency segments in tumor and normal tissue regions of interest. In addition to the mean values of the parametric maps, higher order statistical features, computed from gray-level co-occurrence matrices were also determined and used for characterization. Finally, linear and quadratic discriminant analyses were performed using combinations of quantitative ultrasound parameters to classify breast tissues. Results: Quantitative ultrasound parameters were found to be statistically different between tumor and normal tissue (p < 0.05). The combination of effective acoustic concentration and mean scatterer spacing could separate tumor from normal tissue with 82% accuracy, while the addition of effective scatterer diameter to the combination did not provide significant improvement (83% accuracy). Furthermore, the two advanced parameters, including effective scatterer diameter and mean scatterer spacing, were found to be statistically differentiating among grade I, II, and III tumors (p = 0.014 for scatterer spacing, p = 0.035 for effective scatterer diameter). The separation of the tumor

  5. Quantitative ultrasound characterization of locally advanced breast cancer by estimation of its scatterer properties

    International Nuclear Information System (INIS)

    Tadayyon, Hadi; Sadeghi-Naini, Ali; Czarnota, Gregory; Wirtzfeld, Lauren; Wright, Frances C.

    2014-01-01

    Purpose: Tumor grading is an important part of breast cancer diagnosis and currently requires biopsy as its standard. Here, the authors investigate quantitative ultrasound parameters in locally advanced breast cancers that can potentially separate tumors from normal breast tissue and differentiate tumor grades. Methods: Ultrasound images and radiofrequency data from 42 locally advanced breast cancer patients were acquired and analyzed. Parameters related to the linear regression of the power spectrum—midband fit, slope, and 0-MHz-intercept—were determined from breast tumors and normal breast tissues. Mean scatterer spacing was estimated from the spectral autocorrelation, and the effective scatterer diameter and effective acoustic concentration were estimated from the Gaussian form factor. Parametric maps of each quantitative ultrasound parameter were constructed from the gated radiofrequency segments in tumor and normal tissue regions of interest. In addition to the mean values of the parametric maps, higher order statistical features, computed from gray-level co-occurrence matrices were also determined and used for characterization. Finally, linear and quadratic discriminant analyses were performed using combinations of quantitative ultrasound parameters to classify breast tissues. Results: Quantitative ultrasound parameters were found to be statistically different between tumor and normal tissue (p < 0.05). The combination of effective acoustic concentration and mean scatterer spacing could separate tumor from normal tissue with 82% accuracy, while the addition of effective scatterer diameter to the combination did not provide significant improvement (83% accuracy). Furthermore, the two advanced parameters, including effective scatterer diameter and mean scatterer spacing, were found to be statistically differentiating among grade I, II, and III tumors (p = 0.014 for scatterer spacing, p = 0.035 for effective scatterer diameter). The separation of the tumor

  6. Characterization of human breast cancer tissues by infrared imaging.

    Science.gov (United States)

    Verdonck, M; Denayer, A; Delvaux, B; Garaud, S; De Wind, R; Desmedt, C; Sotiriou, C; Willard-Gallo, K; Goormaghtigh, E

    2016-01-21

    Fourier Transform InfraRed (FTIR) spectroscopy coupled to microscopy (IR imaging) has shown unique advantages in detecting morphological and molecular pathologic alterations in biological tissues. The aim of this study was to evaluate the potential of IR imaging as a diagnostic tool to identify characteristics of breast epithelial cells and the stroma. In this study a total of 19 breast tissue samples were obtained from 13 patients. For 6 of the patients, we also obtained Non-Adjacent Non-Tumor tissue samples. Infrared images were recorded on the main cell/tissue types identified in all breast tissue samples. Unsupervised Principal Component Analyses and supervised Partial Least Square Discriminant Analyses (PLS-DA) were used to discriminate spectra. Leave-one-out cross-validation was used to evaluate the performance of PLS-DA models. Our results show that IR imaging coupled with PLS-DA can efficiently identify the main cell types present in FFPE breast tissue sections, i.e. epithelial cells, lymphocytes, connective tissue, vascular tissue and erythrocytes. A second PLS-DA model could distinguish normal and tumor breast epithelial cells in the breast tissue sections. A patient-specific model reached particularly high sensitivity, specificity and MCC rates. Finally, we showed that the stroma located close or at distance from the tumor exhibits distinct spectral characteristics. In conclusion FTIR imaging combined with computational algorithms could be an accurate, rapid and objective tool to identify/quantify breast epithelial cells and differentiate tumor from normal breast tissue as well as normal from tumor-associated stroma, paving the way to the establishment of a potential complementary tool to ensure safe tumor margins.

  7. The research on distinguishing benign from malignant breast lesions by diffusion-weighted MR imaging

    International Nuclear Information System (INIS)

    Zhao Bin; Peng Hongjuan; Cai Shifeng; Gao Peihong

    2005-01-01

    Objective: To investigate the value of apparent diffusion coefficient (ADC) of diffusion- weighted magnetic resonance imaging (DW-MRI) in distinguishing benign from malignant breast lesions. Methods: ADC in 26 normal breasts, 24 malignant breast lesions, and 30 benign breast lesions confirmed by operation and pathology were calculated, respectively, and their differentiations in statistics were compared. The differentiations of different ADCs (b=1000-0, 500-0, 1000-500 s/mm 2 ) were also compared. EPI (TR 2900 ms, TE 84 ms, thickness 5 mm) was used in order to acquire the imaging. Results: There were significant differences among the ADC values of normal breast tissue, benign, and malignant lesions. The ADC of malignant lesions was lower than those of normal breast tissue and benign lesions, and the ADC of benign lesions was lower than that of normal breast tissue. There were significant differences among the ADC value of b=1000-0, 1000-500, and 500-0 s/mm 2 . The lower the b value, the higher the ADC. The sensitivity and specificity of ADC for the diagnosis of malignant lesion were 64% and 96.7% if the upper bound of 95% confidence interval was set as a differential level. Conclusion: The differentiation of benign from malignant breast lesions by ADC is applicable, although the sensitivity is low, the specificity is high. (authors)

  8. Aberrantly methylated DNA as a biomarker in breast cancer.

    Science.gov (United States)

    Kristiansen, Søren; Jørgensen, Lars M; Guldberg, Per; Sölétormos, György

    2013-01-01

    Aberrant DNA hypermethylation at gene promoters is a frequent event in human breast cancer. Recent genome-wide studies have identified hundreds of genes that exhibit differential methylation between breast cancer cells and normal breast tissue. Due to the tumor-specific nature of DNA hypermethylation events, their use as tumor biomarkers is usually not hampered by analytical signals from normal cells, which is a general problem for existing protein tumor markers used for clinical assessment of breast cancer. There is accumulating evidence that DNA-methylation changes in breast cancer patients occur early during tumorigenesis. This may open up for effective screening, and analysis of blood or nipple aspirate may later help in diagnosing breast cancer. As a more detailed molecular characterization of different types of breast cancer becomes available, the ability to divide patients into subgroups based on DNA biomarkers may improve prognosis. Serial monitoring of DNA-methylation markers in blood during treatment may be useful, particularly when the cancer burden is below the detection level for standard imaging techniques. Overall, aberrant DNA methylation has a great potential as a versatile biomarker tool for screening, diagnosis, prognosis and monitoring of breast cancer. Standardization of methods and biomarker panels will be required to fully exploit this clinical potential.

  9. Quantification of local matrix deformations and mechanical properties during capillary morphogenesis in 3D.

    Science.gov (United States)

    Kniazeva, Ekaterina; Weidling, John W; Singh, Rahul; Botvinick, Elliot L; Digman, Michelle A; Gratton, Enrico; Putnam, Andrew J

    2012-04-01

    Reciprocal mechanical interactions between cells and the extracellular matrix (ECM) are thought to play important instructive roles in branching morphogenesis. However, most studies to date have failed to characterize these interactions on a length scale relevant to cells, especially in three-dimensional (3D) matrices. Here we utilized two complementary methods, spatio-temporal image correlation spectroscopy (STICS) and laser optical tweezers-based active microrheology (AMR), to quantify endothelial cell (EC)-mediated deformations of individual ECM elements and the local ECM mechanical properties, respectively, during the process of capillary morphogenesis in a 3D cell culture model. In experiments in which the ECM density was systematically varied, STICS revealed that the rate at which ECs deformed individual ECM fibers on the microscale positively correlated with capillary sprouting on the macroscale. ECs expressing constitutively active V14-RhoA displaced individual matrix fibers at significantly faster rates and displayed enhanced capillary sprouting relative to wild-type cells, while those expressing dominant-negative N19-RhoA behaved in an opposite fashion. In parallel, AMR revealed a local stiffening of the ECM proximal to the tips of sprouting ECs. By quantifying the dynamic physical properties of the cell-ECM interface in both space and time, we identified a correlation linking ECM deformation rates and local ECM stiffening at the microscale with capillary morphogenesis at the macroscale. This journal is © The Royal Society of Chemistry 2012

  10. The assay of estrogen receptors in three components of human breast cancer tissue

    International Nuclear Information System (INIS)

    Lu Hanping; Gui Zhining

    1992-01-01

    The binding capacities of estrogen receptors in nuclear matrix, nuclei and cytosol of human breast cancer tissue (EmR, EnR, EcR) were estimated with radioligand binding assay of receptors. The average B max values of these components in 21 breast cancer specimens are 417.54 ± 170.95, 147.75 ± 98.32, 7.34 ± 5.33 fmol/mg protein, and those in 10 normal breast tissue specimens are 42.33 ± 8.49, 25.05 ± 7.81, 5.91 ± 2.28 fmol/mg protein. Comparing the cancer and normal breast tissues, there is significant difference in B max values of EmR and EnR (P max values of EcR (P > 0.10). The EmR/EnR value of 21 breast cancer tissue is 0.65 ± 0.10, and that of 10 normal breast tissue is 0.42 ± 0.04. There is statistical difference between the cancer and normal. 10 of 13 (77%) patients, who are EcR-positive, have higher EmR/EnR values (≥0.50). The results suggest that estrogen receptors are mainly located at the nuclear matrix, ER levels in nucleus, especially in nuclear matrix of breast cancer tissue are valuable parameters and may be useful for predicting whether the patient will be responsible to endocrine therapy

  11. Squamous cell carcinoma of the breast: a case report

    Directory of Open Access Journals (Sweden)

    Hofstee Mans

    2008-12-01

    Full Text Available Abstract Background Squamous cells are normally not found inside the breast, so a primary squamous cell carcinoma of the breast is an exceptional phenomenon. There is a possible explanation for these findings. Case presentation A 72-year-old woman presented with a breast abnormality suspected for breast carcinoma. After the operation the pathological examination revealed a primary squamous cell carcinoma of the breast. Conclusion The presentation of squamous cell carcinoma could be similar to that of an adenocarcinoma. However, a squamous cell carcinoma of the breast could also develop from a complicated breast cyst or abscess. Therefore, pathological examination of these apparent benign abnormalities is mandatory.

  12. Septins from the phytopathogenic fungus Ustilago maydis are required for proper morphogenesis but dispensable for virulence.

    Directory of Open Access Journals (Sweden)

    Isabel Alvarez-Tabarés

    Full Text Available BACKGROUND: Septins are a highly conserved family of GTP-binding proteins involved in multiple cellular functions, including cell division and morphogenesis. Studies of septins in fungal cells underpin a clear correlation between septin-based structures and fungal morphology, providing clues to understand the molecular frame behind the varied morphologies found in fungal world. METHODOLOGY/PRINCIPAL FINDINGS: Ustilago maydis genome has the ability to encode four septins. Here, using loss-of-function as well as GFP-tagged alleles of these septin genes, we investigated the roles of septins in the morphogenesis of this basidiomycete fungus. We described that septins in U. maydis could assemble into at least three different structures coexisting in the same cell: bud neck collars, band-like structures at the growing tip, and long septin fibers that run from pole to pole near the cell cortex. We also found that in the absence of septins, U. maydis cells lost their elongated shape, became wider at the central region and ended up losing their polarity, pointing to an important role of septins in the morphogenesis of this fungus. These morphological defects were alleviated in the presence of an osmotic stabilizer suggesting that absence of septins affected the proper formation of the cell wall, which was coherent with a higher sensitivity of septin defective cells to drugs that affect cell wall construction as well as exocytosis. As U. maydis is a phytopathogen, we analyzed the role of septins in virulence and found that in spite of the described morphological defects, septin mutants were virulent in corn plants. CONCLUSIONS/SIGNIFICANCE: Our results indicated a major role of septins in morphogenesis in U. maydis. However, in contrast to studies in other fungal pathogens, in which septins were reported to be necessary during the infection process, we found a minor role of septins during corn infection by U. maydis.

  13. Lactation following conservation surgery and radiotherapy for breast cancer

    International Nuclear Information System (INIS)

    Varsos, G.; Yahalom, J.

    1991-01-01

    A 38-year-old woman with early stage invasive breast cancer was treated with wide excision of the tumor, axillary lymph node dissection, and breast irradiation. Three years later, she gave birth to a normal baby. She attempted breast feeding and had full lactation from the untreated breast. The irradiated breast underwent only minor changes during pregnancy and postpartum but produced small amounts of colostrum and milk for 2 weeks postpartum. There are only a few reports of lactation after breast irradiation. These cases are reviewed, and possible factors affecting breast function after radiotherapy are discussed. Because of scant information available regarding its safety for the infant, nursing from the irradiated breast is not recommended

  14. The microRNA-200 family coordinately regulates cell adhesion and proliferation in hair morphogenesis.

    Science.gov (United States)

    Hoefert, Jaimee E; Bjerke, Glen A; Wang, Dongmei; Yi, Rui

    2018-06-04

    The microRNA (miRNA)-200 (miR-200) family is highly expressed in epithelial cells and frequently lost in metastatic cancer. Despite intensive studies into their roles in cancer, their targets and functions in normal epithelial tissues remain unclear. Importantly, it remains unclear how the two subfamilies of the five-miRNA family, distinguished by a single nucleotide within the seed region, regulate their targets. By directly ligating miRNAs to their targeted mRNA regions, we identify numerous miR-200 targets involved in the regulation of focal adhesion, actin cytoskeleton, cell cycle, and Hippo/Yap signaling. The two subfamilies bind to largely distinct target sites, but many genes are coordinately regulated by both subfamilies. Using inducible and knockout mouse models, we show that the miR-200 family regulates cell adhesion and orientation in the hair germ, contributing to precise cell fate specification and hair morphogenesis. Our findings demonstrate that combinatorial targeting of many genes is critical for miRNA function and provide new insights into miR-200's functions. © 2018 Hoefert et al.

  15. Time-lapse analysis and mathematical characterization elucidate novel mechanisms underlying muscle morphogenesis.

    Directory of Open Access Journals (Sweden)

    Chelsi J Snow

    2008-10-01

    Full Text Available Skeletal muscle morphogenesis transforms short muscle precursor cells into long, multinucleate myotubes that anchor to tendons via the myotendinous junction (MTJ. In vertebrates, a great deal is known about muscle specification as well as how somitic cells, as a cohort, generate the early myotome. However, the cellular mechanisms that generate long muscle fibers from short cells and the molecular factors that limit elongation are unknown. We show that zebrafish fast muscle fiber morphogenesis consists of three discrete phases: short precursor cells, intercalation/elongation, and boundary capture/myotube formation. In the first phase, cells exhibit randomly directed protrusive activity. The second phase, intercalation/elongation, proceeds via a two-step process: protrusion extension and filling. This repetition of protrusion extension and filling continues until both the anterior and posterior ends of the muscle fiber reach the MTJ. Finally, both ends of the muscle fiber anchor to the MTJ (boundary capture and undergo further morphogenetic changes as they adopt the stereotypical, cylindrical shape of myotubes. We find that the basement membrane protein laminin is required for efficient elongation, proper fiber orientation, and boundary capture. These early muscle defects in the absence of either lamininbeta1 or laminingamma1 contrast with later dystrophic phenotypes in lamininalpha2 mutant embryos, indicating discrete roles for different laminin chains during early muscle development. Surprisingly, genetic mosaic analysis suggests that boundary capture is a cell-autonomous phenomenon. Taken together, our results define three phases of muscle fiber morphogenesis and show that the critical second phase of elongation proceeds by a repetitive process of protrusion extension and protrusion filling. Furthermore, we show that laminin is a novel and critical molecular cue mediating fiber orientation and limiting muscle cell length.

  16. Indications for breast imaging in women under age 35

    International Nuclear Information System (INIS)

    Harris, V.J.; Jackson, V.P.

    1988-01-01

    Many women under age 35 years undergo breast imaging, and the vast majority of studies are normal or compatible with benign disease. In our series of 649 patients aged 13 - 34, the only significant indicators were a palpable mass or infection. In the 383 patients with either of these indications, mammographic and/or US findings were normal in 53%, compatible with benign disease in 14%, and suggestive of malignancy in 33%. Biopsy performed in 80 of these women revealed breast cancer in five (6%). None of the 266 women with low-yield indications (pain, modularity, galactorrhea, fibrocystic disease, screening) had significant imaging findings or clinical or surgical evidence of breast cancer

  17. Fidelity of DNA Replication in Normal and Malignant Human Breast Cells

    National Research Council Canada - National Science Library

    Sekowski, Jennifer

    1998-01-01

    In order to determine the degree to which the accumulation of mutations in breast cancer cells is due to a change in the fidelity of the cellular DNA replication machinery we have completed a series...

  18. Concurrent breast stroma sarcoma and breast carcinoma: a case report

    Directory of Open Access Journals (Sweden)

    Carvalho Teresa

    2010-12-01

    Full Text Available Abstract Introduction Breast cancer is one of the most important health problems in the world and affects a great number of women over the entire globe. This group of tumors rarely presents as bilateral disease and, when it does happen, normally occurs within the same histological type. We report a rare case of concurrent bilateral breast cancer with two different histology types, a breast carcinoma and a breast sarcoma, in a 42-year-old woman referred to our hospital. Case presentation A 42-year-old Caucasian woman admitted to our institute in August 1999, presented with a nodule in the left breast of 3.0 × 2.5 cm, and, in the right breast, one of 1.0 cm, suspected of malignancy and with a clinically negative armpit. Biopsies had revealed invasive mammary carcinoma (right breast and sarcoma (left breast. She was submitted to bilateral modified radical mastectomy. A histological study showed an invasive mammary carcinoma degree II lobular pleomorphic type with invasion of seven of the 19 excised axillary nodes in the right breast and, in the left breast, a sarcoma of the mammary stroma, for which the immunohistochemistry study was negative for epithelial biomarkers and positive for vimentin. Later, she was submitted for chemotherapy (six cycles of 75 mg/m2 5-fluorouracil, epirubicin and cyclophosphamide followed by radiotherapy of the thoracic wall and axillary nodes on the left. Hormone receptors were positive in the tumor of the right breast, and tamoxifen, 20 mg, was prescribed on a daily basis (five years followed by letrozole, 2.5 mg, also daily (five years. She presented no sign of negative evolution in the last consultation. Conclusion The risk of development of bilateral breast cancer is about 1% each year within a similar histological type, but it is higher in tumors with lobular histology. In this case, the patient presented, simultaneously, two histologically distinct tumors, thus evidencing a rare situation.

  19. Eugenia jambolana Lam. Berry Extract Inhibits Growth and Induces Apoptosis of Human Breast Cancer but not Non-Tumorigenic Breast Cells

    Science.gov (United States)

    Li, Liya; Adams, Lynn S.; Chen, Shiuan; Killian, Caroline; Ahmed, Aftab; Seeram, Navindra P.

    2009-01-01

    The ripe purple berries of the native Indian plant, Eugenia jambolana Lam., known as Jamun, are popularly consumed and available in the United States in Florida and Hawaii. Despite the growing body of data on the chemopreventive potential of edible berry extracts, there is paucity of such data for Jamun fruit. Therefore our laboratory initiated the current study with the following objectives:1) to prepare a standardized Jamun fruit extract (JFE) for biological studies and, 2) to investigate the anti-proliferative and pro-apoptotic effects of JFE in estrogen dependent/aromatase positive (MCF-7aro), and estrogen independent (MDA-MB-231) breast cancer cells, and in a normal/non-tumorigenic (MCF-10A) breast cell line. JFE was standardized to anthocyanin content using the pH differential method, and individual anthocyanins were identified by high performance liquid chromatography with ultraviolet (HPLC-UV) and tandem mass spectrometry (LC-MS/MS) methods. JFE contained 3.5% anthocyanins (as cyanidin-3-glucoside equivalents) which occur as diglucosides of five anthocyanidins/aglycons: delphinidin, cyanidin, petunidin, peonidin and malvidin. In the proliferation assay, JFE was most effective against MCF-7aro (IC50=27 µg/mL), followed by MDA-MB-231 (IC50=40 µg/mL) breast cancer cells. Importantly, JFE exhibited only mild antiproliferative effects against the normal MCF-10A (IC50>100 µg/mL) breast cells. Similarly, JFE (at 200 µg/mL) exhibited pro-apoptotic effects against the MCF-7aro (p≤0.05) and the MDA-MB-231 (p≤0.01) breast cancer cells, but not towards the normal MCF-10A breast cells. These studies suggest that JFE may have potential beneficial effects against breast cancer. PMID:19166352

  20. The diagnostic capability of laser induced fluorescence in the characterization of excised breast tissues

    Science.gov (United States)

    Galmed, A. H.; Elshemey, Wael M.

    2017-08-01

    Differentiating between normal, benign and malignant excised breast tissues is one of the major worldwide challenges that need a quantitative, fast and reliable technique in order to avoid personal errors in diagnosis. Laser induced fluorescence (LIF) is a promising technique that has been applied for the characterization of biological tissues including breast tissue. Unfortunately, only few studies have adopted a quantitative approach that can be directly applied for breast tissue characterization. This work provides a quantitative means for such characterization via introduction of several LIF characterization parameters and determining the diagnostic accuracy of each parameter in the differentiation between normal, benign and malignant excised breast tissues. Extensive analysis on 41 lyophilized breast samples using scatter diagrams, cut-off values, diagnostic indices and receiver operating characteristic (ROC) curves, shows that some spectral parameters (peak height and area under the peak) are superior for characterization of normal, benign and malignant breast tissues with high sensitivity (up to 0.91), specificity (up to 0.91) and accuracy ranking (highly accurate).

  1. Micro/nano-computed tomography technology for quantitative dynamic, multi-scale imaging of morphogenesis.

    Science.gov (United States)

    Gregg, Chelsea L; Recknagel, Andrew K; Butcher, Jonathan T

    2015-01-01

    Tissue morphogenesis and embryonic development are dynamic events challenging to quantify, especially considering the intricate events that happen simultaneously in different locations and time. Micro- and more recently nano-computed tomography (micro/nanoCT) has been used for the past 15 years to characterize large 3D fields of tortuous geometries at high spatial resolution. We and others have advanced micro/nanoCT imaging strategies for quantifying tissue- and organ-level fate changes throughout morphogenesis. Exogenous soft tissue contrast media enables visualization of vascular lumens and tissues via extravasation. Furthermore, the emergence of antigen-specific tissue contrast enables direct quantitative visualization of protein and mRNA expression. Micro-CT X-ray doses appear to be non-embryotoxic, enabling longitudinal imaging studies in live embryos. In this chapter we present established soft tissue contrast protocols for obtaining high-quality micro/nanoCT images and the image processing techniques useful for quantifying anatomical and physiological information from the data sets.

  2. Quantification of local matrix deformations and mechanical properties during capillary morphogenesis in 3D†‡

    Science.gov (United States)

    Kniazeva, Ekaterina; Weidling, John W.; Singh, Rahul; Botvinick, Elliot L.; Digman, Michelle A.; Gratton, Enrico

    2013-01-01

    Reciprocal mechanical interactions between cells and the extracellular matrix (ECM) are thought to play important instructive roles in branching morphogenesis. However, most studies to date have failed to characterize these interactions on a length scale relevant to cells, especially in three-dimensional (3D) matrices. Here we utilized two complementary methods, spatio-temporal image correlation spectroscopy (STICS) and laser optical tweezers-based active microrheology (AMR), to quantify endothelial cell (EC)-mediated deformations of individual ECM elements and the local ECM mechanical properties, respectively, during the process of capillary morphogenesis in a 3D cell culture model. In experiments in which the ECM density was systematically varied, STICS revealed that the rate at which ECs deformed individual ECM fibers on the microscale positively correlated with capillary sprouting on the macroscale. ECs expressing constitutively active V14-RhoA displaced individual matrix fibers at significantly faster rates and displayed enhanced capillary sprouting relative to wild-type cells, while those expressing dominant-negative N19-RhoA behaved in an opposite fashion. In parallel, AMR revealed a local stiffening of the ECM proximal to the tips of sprouting ECs. By quantifying the dynamic physical properties of the cell-ECM interface in both space and time, we identified a correlation linking ECM deformation rates and local ECM stiffening at the microscale with capillary morphogenesis at the macroscale. PMID:22281872

  3. Differences in breast tissue oxygenation following radiotherapy

    International Nuclear Information System (INIS)

    Dornfeld, Ken; Gessert, Charles E.; Renier, Colleen M.; McNaney, David D.; Urias, Rodolfo E.; Knowles, Denise M.; Beauduy, Jean L.; Widell, Sherry L.; McDonald, Bonita L.

    2011-01-01

    Tissue perfusion and oxygenation changes following radiotherapy may result from and/or contribute to the toxicity of treatment. Breast tissue oxygenation levels were determined in the treated and non-treated breast 1 year after radiotherapy for breast conserving treatment. Transcutaneous oxygenation varied between subjects in both treated and non-treated breast. Subjects without diabetes mellitus (n = 16) had an average oxygenation level of 64.8 ± 19.9 mmHg in the irradiated breast and an average of 72.3 ± 18.1 mmHg (p = 0.018) at the corresponding location in the control breast. Patients with diabetes (n = 4) showed a different oxygenation pattern, with lower oxygenation levels in control tissue and no decrease in the irradiated breast. This study suggests oxygenation levels in normal tissues vary between patients and may respond differently after radiotherapy.

  4. Immunoexpression analysis and prognostic value of BLCAP in breast cancer

    DEFF Research Database (Denmark)

    Gromova, Irina; Gromov, Pavel; Kroman, Niels

    2012-01-01

    , such as cervical and renal cancer, as well as human tongue carcinoma and osteosarcoma. Here we report the first study of the expression patterns of BLCAP in breast tissue. We analyzed by immunohistochemistry tissue sections of normal and malignant specimens collected from 123 clinical high-risk breast cancer...... sample matched cohort, that immunostaining intensity for BLCAP was increased in tumors relative to normal tissue, in more than 45% of the cases examined, indicating that BLCAP may be of value as a marker for breast cancer. We also analyzed BLCAP expression and prognostic value using a set of tissue...

  5. Modulating Wnt Signaling Rescues Palate Morphogenesis in Pax9 Mutant Mice.

    Science.gov (United States)

    Li, C; Lan, Y; Krumlauf, R; Jiang, R

    2017-10-01

    Cleft palate is a common birth defect caused by disruption of palatogenesis during embryonic development. Although mutations disrupting components of the Wnt signaling pathway have been associated with cleft lip and palate in humans and mice, the mechanisms involving canonical Wnt signaling and its regulation in secondary palate development are not well understood. Here, we report that canonical Wnt signaling plays an important role in Pax9-mediated regulation of secondary palate development. We found that cleft palate pathogenesis in Pax9-deficient embryos is accompanied by significantly reduced expression of Axin2, an endogenous target of canonical Wnt signaling, in the developing palatal mesenchyme, particularly in the posterior regions of the palatal shelves. We found that expression of Dkk2, encoding a secreted Wnt antagonist, is significantly increased whereas the levels of active β-catenin protein, the essential transcriptional coactivator of canonical Wnt signaling, is significantly decreased in the posterior regions of the palatal shelves in embryonic day 13.5 Pax9-deficent embryos in comparison with control littermates. We show that small molecule-mediated inhibition of Dickkopf (DKK) activity in utero during palatal shelf morphogenesis partly rescued secondary palate development in Pax9-deficient embryos. Moreover, we found that genetic inactivation of Wise, which is expressed in the developing palatal shelves and encodes another secreted antagonist of canonical Wnt signaling, also rescued palate morphogenesis in Pax9-deficient mice. Furthermore, whereas Pax9 del/del embryos exhibit defects in palatal shelf elevation/reorientation and significant reduction in accumulation of hyaluronic acid-a high molecular extracellular matrix glycosaminoglycan implicated in playing an important role in palatal shelf elevation-80% of Pax9 del/del ;Wise -/- double-mutant mouse embryos exhibit rescued palatal shelf elevation/reorientation, accompanied by restored

  6. Org-1 is required for the diversification of circular visceral muscle founder cells and normal midgut morphogenesis.

    Science.gov (United States)

    Schaub, Christoph; Frasch, Manfred

    2013-04-15

    The T-Box family of transcription factors plays fundamental roles in the generation of appropriate spatial and temporal gene expression profiles during cellular differentiation and organogenesis in animals. In this study we report that the Drosophila Tbx1 orthologue optomotor-blind-related-gene-1 (org-1) exerts a pivotal function in the diversification of circular visceral muscle founder cell identities in Drosophila. In embryos mutant for org-1, the specification of the midgut musculature per se is not affected, but the differentiating midgut fails to form the anterior and central midgut constrictions and lacks the gastric caeca. We demonstrate that this phenotype results from the nearly complete loss of the founder cell specific expression domains of several genes known to regulate midgut morphogenesis, including odd-paired (opa), teashirt (tsh), Ultrabithorax (Ubx), decapentaplegic (dpp) and wingless (wg). To address the mechanisms that mediate the regulatory inputs from org-1 towards Ubx, dpp, and wg in these founder cells we genetically dissected known visceral mesoderm specific cis-regulatory-modules (CRMs) of these genes. The analyses revealed that the activities of the dpp and wg CRMs depend on org-1, the CRMs are bound by Org-1 in vivo and their T-Box binding sites are essential for their activation in the visceral muscle founder cells. We conclude that Org-1 acts within a well-defined signaling and transcriptional network of the trunk visceral mesoderm as a crucial founder cell-specific competence factor, in concert with the general visceral mesodermal factor Biniou. As such, it directly regulates several key genes involved in the establishment of morphogenetic centers along the anteroposterior axis of the visceral mesoderm, which subsequently organize the formation of midgut constrictions and gastric caeca and thereby determine the morphology of the midgut. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. T cell receptor sequencing of early-stage breast cancer tumors identifies altered clonal structure of the T cell repertoire.

    Science.gov (United States)

    Beausang, John F; Wheeler, Amanda J; Chan, Natalie H; Hanft, Violet R; Dirbas, Frederick M; Jeffrey, Stefanie S; Quake, Stephen R

    2017-11-28

    Tumor-infiltrating T cells play an important role in many cancers, and can improve prognosis and yield therapeutic targets. We characterized T cells infiltrating both breast cancer tumors and the surrounding normal breast tissue to identify T cells specific to each, as well as their abundance in peripheral blood. Using immune profiling of the T cell beta-chain repertoire in 16 patients with early-stage breast cancer, we show that the clonal structure of the tumor is significantly different from adjacent breast tissue, with the tumor containing ∼2.5-fold greater density of T cells and higher clonality compared with normal breast. The clonal structure of T cells in blood and normal breast is more similar than between blood and tumor, and could be used to distinguish tumor from normal breast tissue in 14 of 16 patients. Many T cell sequences overlap between tissue and blood from the same patient, including ∼50% of T cells between tumor and normal breast. Both tumor and normal breast contain high-abundance "enriched" sequences that are absent or of low abundance in the other tissue. Many of these T cells are either not detected or detected with very low frequency in the blood, suggesting the existence of separate compartments of T cells in both tumor and normal breast. Enriched T cell sequences are typically unique to each patient, but a subset is shared between many different patients. We show that many of these are commonly generated sequences, and thus unlikely to play an important role in the tumor microenvironment. Copyright © 2017 the Author(s). Published by PNAS.

  8. Regulation of cell wall morphogenesis in Bacillus subtilis by recruitment of PBP1 to the MreB helix.

    Science.gov (United States)

    Kawai, Yoshikazu; Daniel, Richard A; Errington, Jeffery

    2009-03-01

    The bacterial actin homologue MreB plays a key role in cell morphogenesis. In Bacillus subtilis MreB is essential under normal growth conditions and mreB mutants are defective in the control of cell diameter. However, the precise role of MreB is still unclear. Analysis of the lethal phenotypic consequences of mreB disruption revealed an unusual bulging phenotype that precedes cell death. A similar phenotype was seen in wild-type cells at very low Mg(2+) concentrations. We found that inactivation of the major bi-functional penicillin-binding protein (PBP) PBP1 of B. subtilis restored the viability of an mreB null mutant as well as preventing bulging in both mutant and wild-type backgrounds. Bulging was associated with delocalization of PBP1. We show that the normal pattern of localization of PBP1 is dependent on MreB and that the proteins can physically interact using in vivo pull-down and bacterial two-hybrid approaches. Interactions between MreB and several other PBPs were also detected. Our results suggest that MreB filaments associate directly with the peptidoglycan biosynthetic machinery in B. subtilis as part of the mechanism that brings about controlled cell elongation.

  9. Alterations in the Immune Cell Composition in Premalignant Breast Tissue that Precede Breast Cancer Development.

    Science.gov (United States)

    Degnim, Amy C; Hoskin, Tanya L; Arshad, Muhammad; Frost, Marlene H; Winham, Stacey J; Brahmbhatt, Rushin A; Pena, Alvaro; Carter, Jodi M; Stallings-Mann, Melody L; Murphy, Linda M; Miller, Erin E; Denison, Lori A; Vachon, Celine M; Knutson, Keith L; Radisky, Derek C; Visscher, Daniel W

    2017-07-15

    Purpose: Little is known about the role of the immune system in the earliest stages of breast carcinogenesis. We studied quantitative differences in immune cell types between breast tissues from normal donors and those from women with benign breast disease (BBD). Experimental Design: A breast tissue matched case-control study was created from donors to the Susan G. Komen for the Cure Tissue Bank (KTB) and from women diagnosed with BBD at Mayo Clinic (Rochester, MN) who either subsequently developed cancer (BBD cases) or remained cancer-free (BBD controls). Serial tissue sections underwent immunostaining and digital quantification of cell number per mm 2 for CD4 + T cells, CD8 + T cells, CD20 + B cells, and CD68 + macrophages and quantification of positive pixel measure for CD11c (dendritic cells). Results: In 94 age-matched triplets, BBD lobules showed greater densities of CD8 + T cells, CD11c + dendritic cells, CD20 + B cells, and CD68 + macrophages compared with KTB normals. Relative to BBD controls, BBD cases had lower CD20 + cell density ( P = 0.04). Nearly 42% of BBD cases had no CD20 + B cells in evaluated lobules compared with 28% of BBD controls ( P = 0.02). The absence of CD20 + cells versus the presence in all lobules showed an adjusted OR of 5.7 (95% confidence interval, 1.4-23.1) for subsequent breast cancer risk. Conclusions: Elevated infiltration of both innate and adaptive immune effectors in BBD tissues suggests an immunogenic microenvironment. The reduced B-cell infiltration in women with later breast cancer suggests a role for B cells in preventing disease progression and as a possible biomarker for breast cancer risk. Clin Cancer Res; 23(14); 3945-52. ©2017 AACR . ©2017 American Association for Cancer Research.

  10. Hand-held and automated breast ultrasound

    International Nuclear Information System (INIS)

    Bassett, L.W.; Gold, R.H.; Kimme-Smith, C.

    1985-01-01

    The book is a guide for physicians and technologists who use US as an adjunct to mammography; it carefully outlines the pros and cons of US of the breast and its role in the diagnosis of benign and malignant diseases. After an introduction that discusses the philosophy of breast US, the chapters cover the physics of US and instrumentation (both hand-held transducers as well as automated water path scanners), then proceed to a discussion of the normal breast. Sections on benign disorders, malignant lesions, and pitfalls of diagnosis are followed by quiz cases

  11. Rapid Discrimination of Malignant Breast Lesions from Normal Tissues Utilizing Raman Spectroscopy System: A Systematic Review and Meta-Analysis of In Vitro Studies.

    Directory of Open Access Journals (Sweden)

    Ke Deng

    Full Text Available The aim of this study is to evaluate the diagnostic accuracy of Raman spectroscopy system in the detection of malignant breast lesions through a systemic review and meta-analysis of published studies.We conducted a comprehensive literature search of PubMed and Embase from 2000 to June 2015. Published studies that evaluated the diagnostic performance of Raman spectroscopy in distinguishing malignant breast lesions from benign lesions and normal tissues were included in our study. The pooled sensitivity, specificity, diagnostic odds ratio, and the area under the curve of summary receiver-operating characteristic curves was derived. A Revised Tool for the Quality Assessment of Diagnostic Accuracy Studies guidelines was used to assess the quality of included studies.The initial search produced a total of 157 articles after removing duplicates. Nine studies (8 in vitro and 1 in vivo were eligible in this meta-analysis. We analyzed the eight in vitro studies with 1756 lesions, the pooled sensitivity and specificity of Raman spectroscopy system for the diagnosis of malignant breast lesions were 0.92 (95% CI 0.86-0.96 and 0.97 (97% CI 0.93-0.98, respectively. Diagnostic odds ratio was 266.70 (95% CI 89.38-795.79, and the area under the curve of summary receiver-operating characteristic curves was 0.98 (95% CI 0.97-0.99. Significant heterogeneity was found between studies. There was no evidence of considerable publication bias.Raman spectroscopy system is an optical diagnostic technology with great value for detecting malignant breast lesions. At the same time, it has advantages of being non-invasive, real-time, and easy to use. Thus it deserves to be further explored for intra-operatory breast tumor margin detection.

  12. Breast Pain: Clinical pattern and aetiology in a breast clinic in Eastern Nigeria

    Directory of Open Access Journals (Sweden)

    Ochonma A Egwuonwu

    2016-01-01

    Full Text Available Background: Patients with breast pain are likely to be very worried because some consider pain in the breast as an indication of malignancy. Objective: To highlight the causes of pain in the patients are presenting to our breast clinic. Materials and Methods: A prospective study of all consenting patients with breast disease presenting to the breast clinic was conducted from January 2004 to December 2008. Results: A total of 664 patients presented to the breast clinic during the study period. Of this number, 127 presented with breast pain either as the sole symptom or in association with other symptoms. The presenting complaints were a pain, pain with lump, and pain with nipple discharge in 63 (49.6%, 59 (46.4%, and 5 (4.0% patients, respectively. The pain was noncyclical in 96 (75.6% patients. The site of the pain was whole breast in 87 (68.5% patients and a lump in 40 (31.5%. The clinical diagnosis in 31 (24.4% cases was fibrocystic disease, 28 (22.0% cancer, 23 (18.1% unknown, 10 (7.9% fibroadenoma, 8 (6.3% duct ectasia, 6 (4.7% normal breast, and others 21 (16.5% cases benign diseases were diagnosed. The histological diagnosis was fibrocystic changes, carcinoma, and fibroadenoma in 15 (42.9%, 10 (28.6%, and 5 (14.3% patients, respectively. Others were benign phyllodes, abscess, duct ectasia, chronic mastitis, and lipoma, each constituting 1 (2.9% case. Conclusion: Breast pain constitutes a small proportion of complaints to our breast clinic. Fibrocystic changes were the most common cause of breast pain both clinically and histologically.

  13. Changes in ultrasound shear wave elastography properties of normal breast during menstrual cycle.

    Science.gov (United States)

    Rzymski, P; Skórzewska, A; Opala, T

    2011-01-01

    Elastography is a novel technique capable of noninvasively assessing the elastic properties of breast tissue. Because the risk factors for breast cancer include hormonal status and proliferation, the aim of our study was to estimate the intensity of sonoelastographic changes during the menstrual cycle. Eight women aged 20-23 years with regular menstrual cycles underwent B-mode sonography and sonoelastography (ShearWave on Aixplorer, France) on days 3, 10, 17 and 24. Mean values of glandular and fat tissue elasticity did not change statistically significantly during the menstrual cycle as well as glandular to fat tissue ratio. During almost the whole cycle differences between outer and inner quadrants in glandular and fat tissue were statistically significant. The lowest values of elasticity occurred on the 10th day and the highest on the 24th of the menstrual cycle. There were statistically significant differences in elasticity between inner and outer quadrants of both breasts close to day 3 and 17 of the menstrual cycle.

  14. Classification of mass and normal breast tissue: A convolution neural network classifier with spatial domain and texture images

    International Nuclear Information System (INIS)

    Sahiner, B.; Chan, H.P.; Petrick, N.; Helvie, M.A.; Adler, D.D.; Goodsitt, M.M.; Wei, D.

    1996-01-01

    The authors investigated the classification of regions of interest (ROI's) on mammograms as either mass or normal tissue using a convolution neural network (CNN). A CNN is a back-propagation neural network with two-dimensional (2-D) weight kernels that operate on images. A generalized, fast and stable implementation of the CNN was developed. The input images to the CNN were obtained form the ROI's using two techniques. The first technique employed averaging and subsampling. The second technique employed texture feature extraction methods applied to small subregions inside the ROI. Features computed over different subregions were arranged as texture images, which were subsequently used as CNN inputs. The effects of CNN architecture and texture feature parameters on classification accuracy were studied. Receiver operating characteristic (ROC) methodology was used to evaluate the classification accuracy. A data set consisting of 168 ROI's containing biopsy-proven masses and 504 ROI's containing normal breast tissue was extracted from 168 mammograms by radiologists experienced in mammography. This data set was used for training and testing the CNN. With the best combination of CNN architecture and texture feature parameters, the area under the test ROC curve reached 0.87, which corresponded to a true-positive fraction of 90% at a false positive fraction of 31%. The results demonstrate the feasibility of using a CNN for classification of masses and normal tissue on mammograms

  15. Diarrhoea Caused by Diffuse Metastatic Lobular Breast Cancer

    Directory of Open Access Journals (Sweden)

    Sjoerd F. Bakker

    2016-01-01

    Full Text Available A 70-year-old woman with a history of lobular breast cancer presented to our Outpatient Clinic with diarrhoea for the past 3 years. Clinical examination and laboratory research were normal. Colonoscopy showed diffuse mild erythema and a decreased vascular pattern. Biopsies from the ascending colon, transverse colon, and descending colon showed metastases of lobular breast carcinoma. Although gastrointestinal metastases are rare in breast cancer, our case emphasizes the need for further diagnostic efforts in patients with gastrointestinal symptoms and a history of breast carcinoma.

  16. Rho-associated kinase activity is required for proper morphogenesis of the inner cell mass in the mouse blastocyst.

    Science.gov (United States)

    Laeno, Arlene May A; Tamashiro, Dana Ann A; Alarcon, Vernadeth B

    2013-11-01

    The blastocyst consists of the outer layer of trophectoderm and pluripotent inner cell mass (ICM), the precursor of the placenta and fetus, respectively. During blastocyst expansion, the ICM adopts a compact, ovoidal shape, whose proper morphology is crucial for normal embryogenesis. Rho-associated kinase (ROCK), an effector of small GTPase RHO signaling, mediates the diverse cellular processes of morphogenesis, but its role in ICM morphogenesis is unclear. Here, we demonstrate that ROCK is required for cohesion of ICM cells and formation of segregated tissues called primitive endoderm (PrE) and epiblast (Epi) in the ICM of the mouse blastocyst. Blastocyst treatment with ROCK inhibitors Y-27632 and Fasudil caused widening or spreading of the ICM, and intermingling of PrE and Epi. Widening of ICM was independent of trophectoderm because isolated ICMs as well as colonies of mouse embryonic stem cells (mESC) also spread upon Y-27632 treatment. PrE, Epi, and trophectoderm cell numbers were similar between control and treated blastocysts, suggesting that ROCK inhibition affected ICM morphology but not lineage differentiation. Rock1 and Rock2 knockdown via RNA interference in mESC also induced spreading, supporting the conclusion that morphological defects caused by the pharmacological inhibitors were due to ROCK inactivation. When blastocysts were transferred into surrogates, implantation efficiencies were unaffected by ROCK inhibition, but treated blastocysts yielded greater fetal loss. These results show that proper ICM morphology is dependent on ROCK activity and is crucial for fetal development. Our studies have wider implication for improving efficiencies of human assisted reproductive technologies that diminish pregnancy loss and promote successful births.

  17. Evaluation of monoclonal antibodies for the development of breast cancer immunotoxins

    International Nuclear Information System (INIS)

    Bjorn, M.J.; Ring, D.; Frankel, A.

    1985-01-01

    Eighty-five antibodies recognizing breast cancer-selective antigens were conjugated to ricin toxin A-chain using a disulfide linkage. The cytotoxicities of the resulting immunotoxins were determined on breast cancer cells and normal human fibroblasts. Twenty-four antibodies formed immunotoxins that were toxic to at least one breast cancer cell line at concentrations of 10 nM or less but were nontoxic to human fibroblast lines used as negative controls. Some of the breast tumor-selective immunotoxins were as toxic as a conjugate between monoclonal anti-transferrin receptor and ricin toxin A-chain (50% inhibition of cellular protein synthesis at approximately 0.1 nM). Another set of four immunotoxins were indiscriminately toxic to human breast tumor cell lines, two human fibroblast cell lines, and a human lymphoblastoid line. Several of the antibodies the toxin conjugates of which specifically killed breast cancer cell lines may be useful in cancer therapy, since they show a wide range of binding to individual breast tumors and cell lines and a limited range of binding to normal tissue types

  18. Repositioning of antibiotic levofloxacin as a mitochondrial biogenesis inhibitor to target breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Min [Galactophore Department, JingZhou Central Hospital, JingZhou (China); Li, Ruishu, E-mail: liruishu2016@yahoo.com [Forensic Surgery Department, JingZhou Traditional Chinese Medicine Hospital, JingZhou (China); Zhang, Juan [Endocrinology Department, JingZhou Central Hospital, JingZhou (China)

    2016-03-18

    Targeting mitochondrial biogenesis has become a potential therapeutic strategy in cancer due to their unique metabolic dependencies. In this study, we show that levofloxacin, a FDA-approved antibiotic, is an attractive candidate for breast cancer treatment. This is achieved by the inhibition of proliferation and induction of apoptosis in a panel of breast cancer cell lines while sparing normal breast cells. It also acts synergistically with conventional chemo drug in two independent in vivo breast xenograft mouse models. Importantly, levofloxacin inhibits mitochondrial biogenesis as shown by the decreased level of mitochondrial respiration, membrane potential and ATP. In addition, the anti-proliferative and pro-apoptotic effects of levofloxacin are reversed by acetyl-L-Carnitine (ALCAR, a mitochondrial fuel), confirming that levofloxacin's action in breast cancer cells is through inhibition of mitochondrial biogenesis. A consequence of mitochondrial biogenesis inhibition by levofloxacin in breast cancer cells is the deactivation of PI3K/Akt/mTOR and MAPK/ERK pathways. We further demonstrate that breast cancer cells have increased mitochondrial biogenesis than normal breast cells, and this explains their different sensitivity to levofloxacin. Our work suggest that levofloxacin is a useful addition to breast cancer treatment. Our work also establish the essential role of mitochondrial biogenesis on the activation of PI3K/Akt/mTOR and MAPK/ERK pathways in breast cancer cells. - Highlights: • Levofloxacin targets a panel of breast cancer cell lines in vitro and in vivo. • Levofloxacin acts synergistically with 5-Fluorouracil in breast cancer. • Levofloxacin targets breast cancer cells via inhibiting mitochondrial biogenesis. • Breast cancer cells have increased mitochondrial biogenesis than normal cells. • Mitochondrial biogenesis inhibition lead to deactivation of PI3K/Akt/mTOR pathway.

  19. Repositioning of antibiotic levofloxacin as a mitochondrial biogenesis inhibitor to target breast cancer

    International Nuclear Information System (INIS)

    Yu, Min; Li, Ruishu; Zhang, Juan

    2016-01-01

    Targeting mitochondrial biogenesis has become a potential therapeutic strategy in cancer due to their unique metabolic dependencies. In this study, we show that levofloxacin, a FDA-approved antibiotic, is an attractive candidate for breast cancer treatment. This is achieved by the inhibition of proliferation and induction of apoptosis in a panel of breast cancer cell lines while sparing normal breast cells. It also acts synergistically with conventional chemo drug in two independent in vivo breast xenograft mouse models. Importantly, levofloxacin inhibits mitochondrial biogenesis as shown by the decreased level of mitochondrial respiration, membrane potential and ATP. In addition, the anti-proliferative and pro-apoptotic effects of levofloxacin are reversed by acetyl-L-Carnitine (ALCAR, a mitochondrial fuel), confirming that levofloxacin's action in breast cancer cells is through inhibition of mitochondrial biogenesis. A consequence of mitochondrial biogenesis inhibition by levofloxacin in breast cancer cells is the deactivation of PI3K/Akt/mTOR and MAPK/ERK pathways. We further demonstrate that breast cancer cells have increased mitochondrial biogenesis than normal breast cells, and this explains their different sensitivity to levofloxacin. Our work suggest that levofloxacin is a useful addition to breast cancer treatment. Our work also establish the essential role of mitochondrial biogenesis on the activation of PI3K/Akt/mTOR and MAPK/ERK pathways in breast cancer cells. - Highlights: • Levofloxacin targets a panel of breast cancer cell lines in vitro and in vivo. • Levofloxacin acts synergistically with 5-Fluorouracil in breast cancer. • Levofloxacin targets breast cancer cells via inhibiting mitochondrial biogenesis. • Breast cancer cells have increased mitochondrial biogenesis than normal cells. • Mitochondrial biogenesis inhibition lead to deactivation of PI3K/Akt/mTOR pathway.

  20. DMBT1 expression is down-regulated in breast cancer

    DEFF Research Database (Denmark)

    Braidotti, P; Nuciforo, P G; Mollenhauer, J

    2004-01-01

    and hyperplastic mammary cells positive with DMBTh12 were also MCM5-positive. CONCLUSIONS: The redistribution and up-regulation of DMBT1 in normal and hyperplastic tissues flanking malignant tumours and its down-regulation in carcinomas suggests a potential role in breast cancer. Moreover, the concomitant......BACKGROUND: We studied the expression of DMBT1 (deleted in malignant brain tumor 1), a putative tumor suppressor gene, in normal, proliferative, and malignant breast epithelium and its possible relation to cell cycle. METHODS: Sections from 17 benign lesions and 55 carcinomas were immunostained...... expression was down-regulated in the cancerous lesions compared to the normal and/or hyperplastic epithelium adjacent to carcinomas (3/55 positive carcinomas versus 33/42 positive normal/hyperplastic epithelia; p = 0.0001). In 72% of cases RT-PCR confirmed immunohistochemical results. Most of normal...

  1. SU-F-T-314: Estimation of Dose Distributions with Different Types of Breast Implants in Various Radiation Treatment Techniques for Breast Cancer

    International Nuclear Information System (INIS)

    Lee, M; Lee, S; Suh, T; Jung, J; Kim, S; Cho, Y; Lee, I

    2016-01-01

    Purpose: This study investigates the effects of different kinds and designs of commercialized breast implants on the dose distributions in breast cancer radiotherapy under a variety of conditions. Methods: The dose for the clinical conventional tangential irradiation, Intensity Modulated Radiation Therapy (IMRT), volumetric modulated arc therapy (VMAT) breast plans was measured using radiochromic films and stimulated luminescence dosimeter (OSLD). The radiochromic film was used as an integrating dosimeter, while the OSLDs were used for real-time dosimetry to isolate the contribution of dose from individual segment. The films were placed at various slices in the Rando phantom and between the body and breast surface OSLDs were used to measure skin dose at 18 positions spaced on the two (right/left) breast. The implant breast was placed on the left side and the phantom breast was remained on the right side. Each treatment technique was performed on different size of the breasts and different shape of the breast implant. The PTV dose was prescribed 50.4 Gy and V47.88≥95%. Results: In different shapes of the breast implant, because of the shadow formed extensive around the breast implant, dose variation was relatively higher that of prescribed dose. As the PTV was delineated on the whole breast, maximum 5% dose error and average 3% difference was observed averagely. VMAT techniques largely decrease the contiguous hot spot in the skin by an average of 25% compared with IMRT. The both IMRT and VMAT techniques resulted in lower doses to normal critical structures than tangential plans for nearly all dose analyzation. Conclusion: Compared to the other technique, IMRT reduced radiation dose exposure to normal tissues and maintained reasonable target homogeneity and for the same target coverage, VMAT can reduce the skin dose in all the regions of the body.

  2. SU-F-T-314: Estimation of Dose Distributions with Different Types of Breast Implants in Various Radiation Treatment Techniques for Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lee, M; Lee, S; Suh, T [Department of Biomedical Engineering, College of Medicine, The Catholic University of Korea, Seoul (Korea, Republic of); Research Institute of Biomedical Engineering, College of Medicine, The Catholic University of Korea, Seoul (Korea, Republic of); Jung, J [Department of Biomedical Engineering, College of Medicine, The Catholic University of Korea, Seoul (Korea, Republic of); Research Institute of Biomedical Engineering, College of Medicine, The Catholic University of Korea, Seoul (Korea, Republic of); Department of Radiation Oncology, College of Medicine, Soonchunhyang University Bucheon Hospital, Bucheon (Korea, Republic of); Kim, S; Cho, Y; Lee, I [Department of Radiation Oncology, Gangnam Severance Hospital, Seoul (Korea, Republic of)

    2016-06-15

    Purpose: This study investigates the effects of different kinds and designs of commercialized breast implants on the dose distributions in breast cancer radiotherapy under a variety of conditions. Methods: The dose for the clinical conventional tangential irradiation, Intensity Modulated Radiation Therapy (IMRT), volumetric modulated arc therapy (VMAT) breast plans was measured using radiochromic films and stimulated luminescence dosimeter (OSLD). The radiochromic film was used as an integrating dosimeter, while the OSLDs were used for real-time dosimetry to isolate the contribution of dose from individual segment. The films were placed at various slices in the Rando phantom and between the body and breast surface OSLDs were used to measure skin dose at 18 positions spaced on the two (right/left) breast. The implant breast was placed on the left side and the phantom breast was remained on the right side. Each treatment technique was performed on different size of the breasts and different shape of the breast implant. The PTV dose was prescribed 50.4 Gy and V47.88≥95%. Results: In different shapes of the breast implant, because of the shadow formed extensive around the breast implant, dose variation was relatively higher that of prescribed dose. As the PTV was delineated on the whole breast, maximum 5% dose error and average 3% difference was observed averagely. VMAT techniques largely decrease the contiguous hot spot in the skin by an average of 25% compared with IMRT. The both IMRT and VMAT techniques resulted in lower doses to normal critical structures than tangential plans for nearly all dose analyzation. Conclusion: Compared to the other technique, IMRT reduced radiation dose exposure to normal tissues and maintained reasonable target homogeneity and for the same target coverage, VMAT can reduce the skin dose in all the regions of the body.

  3. Ph.D. Post-Doctoral Training Program in Breast Cancer Research

    National Research Council Canada - National Science Library

    Edwards, Dean

    2002-01-01

    .... The curriculum of the Breast Cancer Training Program extends beyond that of the normal Ph.D. requirements to include didactic classroom teaching, journal clubs, seminars, workshops and mini-symposiums on relevant topics in breast cancer...

  4. Ph.D. Post-Doctoral Training Program in Breast Cancer Research

    National Research Council Canada - National Science Library

    Edwards, Dean

    2001-01-01

    .... The curriculum of the Breast Cancer Training Program extends beyond that of the normal Ph.D. requirements to include didactic classroom teaching, journal clubs, seminars, workshops and mini-symposiums on relevant topics in breast cancer...

  5. Ph.D. Post-Doctoral Training Program in Breast Cancer Research

    National Research Council Canada - National Science Library

    Edwards, Dean

    2004-01-01

    .... The curriculum of the Breast Cancer Training Program extends beyond that of the normal Ph.D. requirements to include didactic classroom teaching, journal clubs, seminars, workshops and mini-symposiums on relevant topics in breast cancer...

  6. Proliferation and apoptosis in early molar morphogenesis - voles as models in odontogenesis

    Czech Academy of Sciences Publication Activity Database

    Šetková, Jana; Lesot, H.; Matalová, Eva; Witter, K.; Matulová, Petra; Míšek, Ivan

    2006-01-01

    Roč. 50, 5 (2006), s. 481-489 ISSN 0214-6282 R&D Projects: GA ČR GA304/04/0101; GA MŠk OC B23.001 Grant - others:COST STSM B23-00981 Institutional research plan: CEZ:AV0Z50450515 Keywords : tooth development * morphogenesis * Microtus Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.577, year: 2006

  7. Digital histologic analysis reveals morphometric patterns of age-related involution in breast epithelium and stroma.

    Science.gov (United States)

    Sandhu, Rupninder; Chollet-Hinton, Lynn; Kirk, Erin L; Midkiff, Bentley; Troester, Melissa A

    2016-02-01

    Complete age-related regression of mammary epithelium, often termed postmenopausal involution, is associated with decreased breast cancer risk. However, most studies have qualitatively assessed involution. We quantitatively analyzed epithelium, stroma, and adipose tissue from histologically normal breast tissue of 454 patients in the Normal Breast Study. High-resolution digital images of normal breast hematoxylin and eosin-stained slides were partitioned into epithelium, adipose tissue, and nonfatty stroma. Percentage area and nuclei per unit area (nuclear density) were calculated for each component. Quantitative data were evaluated in association with age using linear regression and cubic spline models. Stromal area decreased (P = 0.0002), and adipose tissue area increased (P epithelium. Epithelial nuclear density is a quantitative measure of age-related breast involution that begins to decline in the early premenopausal period. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Homeostasis 5: nurses as external agents of control in breast cancer.

    Science.gov (United States)

    Clancy, John; McVicar, Andrew

    Breast cancer is caused by a homeostatic imbalance of cell division. Healthcare practitioners need to understand cellular activities to appreciate the physiological basis of health (homeostasis), the pathophysiological basis of illness and the physiological rationale of healthcare. Cells are the 'basic unit of life' (Clancy and McVicar, 2011a). This article describes normal cell division and the anatomy and physiology of the breast and, using a case study, will show how breast cancer is a homeostatic imbalance of cell division. There are analogies between the components of homeostasis and the components of the nursing (healthcare) process (Clancy and McVicar, 2011b) in the condition of breast cancer. After reading this article, nurses should be able to: understand that breast cancer is a cellular hence chemical imbalance that causes uncontrollable mitotic division of breast cells; understand how the cell cycle of cancer cells differs from that of normal cells; identify nature-nurture interactions involved in the aetiology of breast cancer; understand that when caring for people with breast cancer, health professionals including oncology nurses are acting as external agents of homeostatic control as the patient 'recovers' from breast cancer, and also to some extent when reducing signs and symptoms, hence quality of life, by providing palliative care.

  9. Breast phantom for mammary tissue characterization by near infrared spectroscopy

    International Nuclear Information System (INIS)

    Miranda, D A; Cristiano, K L; Gutiérrez, J C

    2013-01-01

    Breast cancer is a disease associated to a high morbidity and mortality in the entire world. In the study of early detection of breast cancer the development of phantom is so important. In this research we fabricate a breast phantom using a ballistic gel with special modifications to simulate a normal and abnormal human breast. Optical properties of woman breast in the near infrared region were modelled with the phantom we developed. The developed phantom was evaluated with near infrared spectroscopy in order to study its relation with breast tissue. A good optical behaviour was achieved with the model fabricated

  10. The distribution of lectin receptor sites in human breast lesions.

    Science.gov (United States)

    Skutelsky, E; Hoenig, S; Griffel, B; Alroy, J

    1988-08-01

    Conflicting data regarding the status of A, B, H and T antigens in epithelium of normal, mastopathies, fibroadenomas and carcinomas of the breast stimulated us to re-examine the carbohydrate residues in these condition. Currently, we extended the number of carbohydrate residues studied by using ten different biotinylated lectins as probes and avidin-biotin-peroxidase complex (ABC) as a visualant. In addition, the pattern of lectin staining of cancerous cells in primary and metastatic sites was compared. In primary and metastatic breast carcinomas, lectin receptor sites were stained more intensely with Concanavalia ensiformi agglutinin (*Con A), Ricinus communis agglutinin-I (RCA-I) and wheat germ agglutinin (WGA), than in normal breast, in mastopathies or in fibroadenomas. Cryptic receptor sites for peanut agglutinin (PNA) were stained in all cases of breast carcinomas, while free PNA sites stained only in a few cases of well-differentiated carcinomas. Receptors sites for Ulex europaeus agglutinin-I (UEA-I) stained non-malignant epithelium of patients with blood group H but did not stain malignant cells. The results show significant differences in lectin-binding patterns and staining intensities between normal and non-malignant, and malignant epithelial breast cells. Furthermore, these results indicate that in malignant cells, there is an increased content of sialic acid-rich carbohydrates but not of asialylated glycoconjugates.

  11. Interaction between APC and Fen1 during breast carcinogenesis.

    Science.gov (United States)

    Narayan, Satya; Jaiswal, Aruna S; Law, Brian K; Kamal, Mohammad A; Sharma, Arun K; Hromas, Robert A

    2016-05-01

    Aberrant DNA base excision repair (BER) contributes to malignant transformation. However, inter-individual variations in DNA repair capacity plays a key role in modifying breast cancer risk. We review here emerging evidence that two proteins involved in BER - adenomatous polyposis coli (APC) and flap endonuclease 1 (Fen1) - promote the development of breast cancer through novel mechanisms. APC and Fen1 expression and interaction is increased in breast tumors versus normal cells, APC interacts with and blocks Fen1 activity in Pol-β-directed LP-BER, and abrogation of LP-BER is linked with cigarette smoke condensate-induced transformation of normal breast epithelial cells. Carcinogens increase expression of APC and Fen1 in spontaneously immortalized human breast epithelial cells, human colon cancer cells, and mouse embryonic fibroblasts. Since APC and Fen1 are tumor suppressors, an increase in their levels could protect against carcinogenesis; however, this does not seem to be the case. Elevated Fen1 levels in breast and lung cancer cells may reflect the enhanced proliferation of cancer cells or increased DNA damage in cancer cells compared to normal cells. Inactivation of the tumor suppressor functions of APC and Fen1 is due to their interaction, which may act as a susceptibility factor for breast cancer. The increased interaction of APC and Fen1 may occur due to polypmorphic and/or mutational variation in these genes. Screening of APC and Fen1 polymorphic and/or mutational variations and APC/Fen1 interaction may permit assessment of individual DNA repair capability and the risk for breast cancer development. Such individuals might lower their breast cancer risk by reducing exposure to carcinogens. Stratifying individuals according to susceptibility would greatly assist epidemiologic studies of the impact of suspected environmental carcinogens. Additionally, a mechanistic understanding of the interaction of APC and Fen1 may provide the basis for developing new and

  12. Overexpression of SERBP1 (Plasminogen activator inhibitor 1 RNA binding protein) in human breast cancer is correlated with favourable prognosis

    International Nuclear Information System (INIS)

    Serce, Nuran Bektas; Knuechel, Ruth; Beckmann, Matthias W; Fasching, Peter A; Dahl, Edgar; Boesl, Andreas; Klaman, Irina; Serényi, Sonja von; Noetzel, Erik; Press, Michael F; Dimmler, Arno; Hartmann, Arndt; Sehouli, Jalid

    2012-01-01

    Plasminogen activator inhibitor 1 (PAI-1) overexpression is an important prognostic and predictive biomarker in human breast cancer. SERBP1, a protein that is supposed to regulate the stability of PAI-1 mRNA, may play a role in gynaecological cancers as well, since upregulation of SERBP1 was described in ovarian cancer recently. This is the first study to present a systematic characterisation of SERBP1 expression in human breast cancer and normal breast tissue at both the mRNA and the protein level. Using semiquantitative realtime PCR we analysed SERBP1 expression in different normal human tissues (n = 25), and in matched pairs of normal (n = 7) and cancerous breast tissues (n = 7). SERBP1 protein expression was analysed in two independent cohorts on tissue microarrays (TMAs), an initial evaluation set, consisting of 193 breast carcinomas and 48 normal breast tissues, and a second large validation set, consisting of 605 breast carcinomas. In addition, a collection of benign (n = 2) and malignant (n = 6) mammary cell lines as well as breast carcinoma lysates (n = 16) were investigated for SERBP1 expression by Western blot analysis. Furthermore, applying non-radioisotopic in situ hybridisation a subset of normal (n = 10) and cancerous (n = 10) breast tissue specimens from the initial TMA were analysed for SERBP1 mRNA expression. SERBP1 is not differentially expressed in breast carcinoma compared to normal breast tissue, both at the RNA and protein level. However, recurrence-free survival analysis showed a significant correlation (P = 0.008) between abundant SERBP1 expression in breast carcinoma and favourable prognosis. Interestingly, overall survival analysis also displayed a tendency (P = 0.09) towards favourable prognosis when SERBP1 was overexpressed in breast cancer. The RNA-binding protein SERBP1 is abundantly expressed in human breast cancer and may represent a novel breast tumour marker with prognostic significance. Its potential involvement in the

  13. Bilateral symmetry analysis of breast MRI

    International Nuclear Information System (INIS)

    Alterson, Robert; Plewes, Donald B

    2003-01-01

    Mammographic interpretation often uses symmetry between left and right breasts to indicate the site of potential tumour masses. This approach has not been applied to breast images obtained from MRI. We present an automatic technique for breast symmetry detection based on feature extraction techniques which does not require any efforts to co-register breast MRI data. The approach applies computer-vision techniques to detect natural biological symmetries in breast MR scans based on three objective measures of similarity: multiresolution non-orthogonal wavelet representation, three-dimensional intensity distributions and co-occurrence matrices. Statistical distributions that are invariant to feature localization are computed for each of the extracted image features. These distributions are later compared against each other to account for perceptual similarity. Studies based on 51 normal MRI scans of randomly selected patients showed that the sensitivity of symmetry detection rate approached 94%. The symmetry analysis procedure presented in this paper can be applied as an aid in detecting breast tissue changes arising from disease

  14. Differentiating the two main histologic categories of fibroadenoma tissue from normal breast tissue by using multiphoton microscopy.

    Science.gov (United States)

    Nie, Y T; Wu, Y; Fu, F M; Lian, Y E; Zhuo, S M; Wang, C; Chen, J X

    2015-04-01

    Multiphoton microscopy has become a novel biological imaging technique that allows cellular and subcellular microstructure imaging based on two-photon excited fluorescence and second harmonic generation. In this work, we used multiphoton microscopy to obtain the high-contrast images of human normal breast tissue and two main histologic types of fibroadenoma (intracanalicular, pericanalicular). Moreover, quantitative image analysis was performed to characterize the changes of collagen morphology (collagen content, collagen orientation). The results show that multiphoton microscopy combined with quantitative method has the ability to identify the characteristics of fibroadenoma including changes of the duct architecture and collagen morphology in stroma. With the advancement of multiphoton microscopy, we believe that the technique has great potential to be a real-time histopathological diagnostic tool for intraoperative detection of fibroadenoma in the future. © 2015 The Authors Journal of Microscopy © 2015 Royal Microscopical Society.

  15. Imaging of human breast tissue using polarization sensitive optical coherence tomography

    Science.gov (United States)

    Verma, Y.; Gautam, M.; Divakar Rao, K.; Swami, M. K.; Gupta, P. K.

    2011-12-01

    We report a study on the use of polarization sensitive optical coherence tomography (PSOCT) for discriminating malignant (invasive ductal carcinoma), benign (fibroadenoma) and normal (adipocytes) breast tissue sites. The results show that while conventional OCT, that utilizes only the intensity of light back-scattered from tissue microstructures, is able to discriminate breast tissues as normal (adipocytes) and abnormal (malignant and benign) tissues, PS-OCT helps in discriminating between malignant and benign tissue sites also. The estimated values of birefringence obtained from the PSOCT imaging show that benign breast tissue samples have significantly higher birefringence as compared to the malignant tissue samples.

  16. Turing mechanism underlying a branching model for lung morphogenesis.

    Science.gov (United States)

    Xu, Hui; Sun, Mingzhu; Zhao, Xin

    2017-01-01

    The mammalian lung develops through branching morphogenesis. Two primary forms of branching, which occur in order, in the lung have been identified: tip bifurcation and side branching. However, the mechanisms of lung branching morphogenesis remain to be explored. In our previous study, a biological mechanism was presented for lung branching pattern formation through a branching model. Here, we provide a mathematical mechanism underlying the branching patterns. By decoupling the branching model, we demonstrated the existence of Turing instability. We performed Turing instability analysis to reveal the mathematical mechanism of the branching patterns. Our simulation results show that the Turing patterns underlying the branching patterns are spot patterns that exhibit high local morphogen concentration. The high local morphogen concentration induces the growth of branching. Furthermore, we found that the sparse spot patterns underlie the tip bifurcation patterns, while the dense spot patterns underlies the side branching patterns. The dispersion relation analysis shows that the Turing wavelength affects the branching structure. As the wavelength decreases, the spot patterns change from sparse to dense, the rate of tip bifurcation decreases and side branching eventually occurs instead. In the process of transformation, there may exists hybrid branching that mixes tip bifurcation and side branching. Since experimental studies have reported that branching mode switching from side branching to tip bifurcation in the lung is under genetic control, our simulation results suggest that genes control the switch of the branching mode by regulating the Turing wavelength. Our results provide a novel insight into and understanding of the formation of branching patterns in the lung and other biological systems.

  17. Serum insulin-like growth factor (IGF)-I and IGF binding protein-3 in relation to terminal duct lobular unit involution of the normal breast in Caucasian and African American women: The Susan G. Komen Tissue Bank.

    Science.gov (United States)

    Oh, Hannah; Pfeiffer, Ruth M; Falk, Roni T; Horne, Hisani N; Xiang, Jackie; Pollak, Michael; Brinton, Louise A; Storniolo, Anna Maria V; Sherman, Mark E; Gierach, Gretchen L; Figueroa, Jonine D

    2018-02-22

    Lesser degrees of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini/TDLU, are associated with elevated breast cancer risk. In rodent models, the insulin-like growth factor (IGF) system regulates involution of the mammary gland. We examined associations of circulating IGF measures with TDLU involution in normal breast tissues among women without precancerous lesions. Among 715 Caucasian and 283 African American (AA) women who donated normal breast tissue samples to the Komen Tissue Bank between 2009 and 2012 (75% premenopausal), serum concentrations of IGF-I and binding protein (IGFBP)-3 were quantified using enzyme-linked immunosorbent assay. Hematoxilyn and eosin-stained tissue sections were assessed for numbers of TDLUs ("TDLU count"). Zero-inflated Poisson regression models with a robust variance estimator were used to estimate relative risks (RRs) for association of IGF measures (tertiles) with TDLU count by race and menopausal status, adjusting for potential confounders. AA (vs. Caucasian) women had higher age-adjusted mean levels of serum IGF-I (137 vs. 131 ng/mL, p = 0.07) and lower levels of IGFBP-3 (4165 vs. 4684 ng/mL, p IGF-I:IGFBP-3 ratios were associated with higher TDLU count in Caucasian (RR T3vs.T1 =1.33, 95% CI = 1.02-1.75, p-trend = 0.04), but not in AA (RR T3vs.T1 =0.65, 95% CI = 0.42-1.00, p-trend = 0.05), women. Our data suggest a role of the IGF system, particularly IGFBP-3, in TDLU involution of the normal breast, a breast cancer risk factor, among Caucasian and AA women. © 2018 UICC.

  18. Hepatocyte growth factor signaling in intrapancreatic ductal cells drives pancreatic morphogenesis.

    Directory of Open Access Journals (Sweden)

    Ryan M Anderson

    Full Text Available In a forward genetic screen for regulators of pancreas development in zebrafish, we identified donut(s908 , a mutant which exhibits failed outgrowth of the exocrine pancreas. The s908 mutation leads to a leucine to arginine substitution in the ectodomain of the hepatocyte growth factor (HGF tyrosine kinase receptor, Met. This missense mutation impedes the proteolytic maturation of the receptor, its trafficking to the plasma membrane, and diminishes the phospho-activation of its kinase domain. Interestingly, during pancreatogenesis, met and its hgf ligands are expressed in pancreatic epithelia and mesenchyme, respectively. Although Met signaling elicits mitogenic and migratory responses in varied contexts, normal proliferation rates in donut mutant pancreata together with dysmorphic, mislocalized ductal cells suggest that met primarily functions motogenically in pancreatic tail formation. Treatment with PI3K and STAT3 inhibitors, but not with MAPK inhibitors, phenocopies the donut pancreatic defect, further indicating that Met signals through migratory pathways during pancreas development. Chimera analyses showed that Met-deficient cells were excluded from the duct, but not acinar, compartment in the pancreatic tail. Conversely, wild-type intrapancreatic duct and "tip cells" at the leading edge of the growing pancreas rescued the donut phenotype. Altogether, these results reveal a novel and essential role for HGF signaling in the intrapancreatic ducts during exocrine morphogenesis.

  19. Homology with vesicle fusion mediator syntaxin-1a predicts determinants ofepimorphin/syntaxin-2 function in mammary epithelial morphogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Connie S.; Nelson, Celeste M.; Khauv, Davitte; Bennett, Simone; Radisky, Evette S.; Hirai, Yohei; Bissell, Mina J.; Radisky, Derek C.

    2009-06-03

    We have shown that branching morphogenesis of mammary ductal structures requires the action of the morphogen epimorphin/syntaxin-2. Epimorphin, originally identified as an extracellular molecule, is identical to syntaxin-2, an intracellular molecule that is a member of the extensively investigated syntaxin family of proteins that mediate vesicle trafficking. We show here that although epimorphin/syntaxin-2 is highly homologous to syntaxin-1a, only epimorphin/syntaxin-2 can stimulate mammary branching morphogenesis. We construct a homology model of epimorphin/syntaxin-2 based on the published structure of syntaxin-1a, and we use this model to identify the structural motif responsible for the morphogenic activity. We identify four residues located within the cleft between helices B and C that differ between syntaxin-1a and epimorphin/syntaxin-2; through site-directed mutagenesis of these four amino acids, we confer the properties of epimorphin for cell adhesion, gene activation, and branching morphogenesis onto the inactive syntaxin-1a template. These results provide a dramatic demonstration of the use of structural information about one molecule to define a functional motif of a second molecule that is related at the sequence level but highly divergent functionally.

  20. The morphogenesis of feathers.

    Science.gov (United States)

    Yu, Mingke; Wu, Ping; Widelitz, Randall B; Chuong, Cheng-Ming

    2002-11-21

    Feathers are highly ordered, hierarchical branched structures that confer birds with the ability of flight. Discoveries of fossilized dinosaurs in China bearing 'feather-like' structures have prompted interest in the origin and evolution of feathers. However, there is uncertainty about whether the irregularly branched integumentary fibres on dinosaurs such as Sinornithosaurus are truly feathers, and whether an integumentary appendage with a major central shaft and notched edges is a non-avian feather or a proto-feather. Here, we use a developmental approach to analyse molecular mechanisms in feather-branching morphogenesis. We have used the replication-competent avian sarcoma retrovirus to deliver exogenous genes to regenerating flight feather follicles of chickens. We show that the antagonistic balance between noggin and bone morphogenetic protein 4 (BMP4) has a critical role in feather branching, with BMP4 promoting rachis formation and barb fusion, and noggin enhancing rachis and barb branching. Furthermore, we show that sonic hedgehog (Shh) is essential for inducing apoptosis of the marginal plate epithelia, which results in spaces between barbs. Our analyses identify the molecular pathways underlying the topological transformation of feathers from cylindrical epithelia to the hierarchical branched structures, and provide insights on the possible developmental mechanisms in the evolution of feather forms.

  1. Quantification and normalization of x-ray mammograms

    International Nuclear Information System (INIS)

    Tromans, Christopher E; Cocker, Mary R; Brady, Michael

    2012-01-01

    The analysis of (x-ray) mammograms remains qualitative, relying on the judgement of clinicians. We present a novel method to compute a quantitative, normalized measure of tissue radiodensity traversed by the primary beam incident on each pixel of a mammogram, a measure we term the standard attenuation rate (SAR). SAR enables: the estimation of breast density which is linked to cancer risk; direct comparison between images; the full potential of computer aided diagnosis to be utilized; and a basis for digital breast tomosynthesis reconstruction. It does this by removing the effects of the imaging conditions under which the mammogram is acquired. First, the x-ray spectrum incident upon the breast is calculated, and from this, the energy exiting the breast is calculated. The contribution of scattered radiation is calculated and subtracted. The SAR measure is the scaling factor that must be applied to the reference material in order to match the primary attenuation of the breast. Specifically, this is the scaled reference material attenuation which when traversed by an identical beam to that traversing the breast, and when subsequently detected, results in the primary component of the pixel intensity observed in the breast image. We present results using two tissue equivalent phantoms, as well as a sensitivity analysis to detector response changes over time and possible errors in compressed thickness measurement. (paper)

  2. Breast cancer in atomic bomb survivors

    International Nuclear Information System (INIS)

    Tokunga, M.; Land, C.E.; Tokuoka, S.

    1986-01-01

    Thirty eight years after the atomic bombings, studies of the Radiation Effects Research Foundation (RERF) on the extended Life Span Study (LSS) sample have continued to provide important information on radiation carcinogenesis. The third breast cancer survey among this sample revealed 564 cases during the period 1950-80, of which 412 were reviewed microscopically. The following statements reflect the conclusions from the current investigation; 1) the relationship between radiation dose and breast cancer incidence was consistent with linearity and did not differ markedly between the Hiroshima and Nagasaki survivors, 2) a dose-related breast cancer risk was observed among women who were in their first decade of life at the time of exposure, 3) the relative risk of radiationinduced breast cancer decreased with increasing age at exposure, 4) the pattern over time of age-specific breast cancer incidence is similar for exposed and control women (that is, exposed women have more breast cancer than control women but the excess risk closely follows normal risk as expressed by age-specific population rates), and 5) radiation-induced breast cancer appears to be morphologically similar to other breast cancer

  3. Breast cancer in atomic bomb survivors

    International Nuclear Information System (INIS)

    Tokunaga, Masayoshi; Tokuoka, Shoji; Land, C.E.

    1986-01-01

    Thirty eight years after the atomic bombings, studies of the Radiation Effects Research Foundation (RERF) on the extended Life Span Study (LSS) sample have continued to provide important information on radiation carcinogenesis. The third breast cancer survey among this sample revealed 564 cases during the period 1950 - 80, of which 412 were reviewed microscopically. The following statements reflect the conclusions from the current investigation; 1) the relationship between radiation dose and breast cancer incidence was consistent with linearity and did not differ markedly between the Hiroshima and Nagasaki survivors, 2) a dose-related breast cancer risk was observed among women who were in their first decade of life at the time of exposure, 3) the relative risk of radiation-induced breast cancer decreased with increasing age at exposure, 4) the pattern over time of age-specific breast cancer incidence is similar for exposed and control women (that is, exposed women have more breast cancer than control women but the excess risk closely follows normal risk as expressed by age-specific population rates), and 5) radiation-induced breast cancer appears to be morphologically similar to other breast cancer. (author)

  4. Ceramide species are elevated in human breast cancer and are associated with less aggressiveness

    Science.gov (United States)

    Moro, Kazuki; Kawaguchi, Tsutomu; Tsuchida, Junko; Gabriel, Emmanuel; Qi, Qianya; Yan, Li; Wakai, Toshifumi; Takabe, Kazuaki; Nagahashi, Masayuki

    2018-01-01

    Sphingolipids have emerged as key regulatory molecules in cancer cell survival and death. Although important roles of sphingolipids in breast cancer progression have been reported in experimental models, their roles in human patients are yet to be revealed. The aim of this study was to investigate the ceramide levels and its biosynthesis pathways in human breast cancer patients. Breast cancer, peri-tumor and normal breast tissue samples were collected from surgical specimens from a series of 44 patients with breast cancer. The amount of sphingolipid metabolites in the tissue were determined by mass spectrometry. The Cancer Genome Atlas was used to analyze gene expression related to the sphingolipid metabolism. Ceramide levels were higher in breast cancer tissue compared to both normal and peri-tumor breast tissue. Substrates and enzymes that generate ceramide were significantly increased in all three ceramide biosynthesis pathways in cancer. Further, higher levels of ceramide in breast cancer were associated with less aggressive cancer biology presented by Ki-67 index and nuclear grade of the cancer. Interestingly, patients with higher gene expressions of enzymes in the three major ceramide synthesis pathways showed significantly worse prognosis. This is the first study to reveal the clinical relevance of ceramide metabolism in breast cancer patients. We demonstrated that ceramide levels in breast cancer tissue were significantly higher than those in normal tissue, with activation of the three ceramide biosynthesis pathways. We also identified that ceramide levels have a significant association with aggressive phenotype and its enzymes have prognostic impact on breast cancer patients. PMID:29731990

  5. Infrared absorption of human breast tissues in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Liu Chenglin [Department of Physics, Surface Physics Laboratory (National Key laboratory), Synchrotron Radiation Research Center, Fudan University, Shanghai 200433 (China); Physics Department of Yancheng Teachers' College, Yancheng 224002 (China); Zhang Yuan [Department of Physics, Surface Physics Laboratory (National Key laboratory), Synchrotron Radiation Research Center, Fudan University, Shanghai 200433 (China); Yan Xiaohui [Department of Physics, Surface Physics Laboratory (National Key laboratory), Synchrotron Radiation Research Center, Fudan University, Shanghai 200433 (China); Zhang Xinyi [Department of Physics, Surface Physics Laboratory (National Key laboratory), Synchrotron Radiation Research Center, Fudan University, Shanghai 200433 (China) and Shanghai Research Center of Acupuncture and Meridian, Pudong, Shanghai 201203 (China)]. E-mail: xy-zhang@fudan.edu.cn; Li Chengxiang [National Synchrotron Radiation Laboratory, University of Science and Technology of China, Hefei 230029 (China); Yang Wentao [Cancer Hospital, Medical Center, Fudan University, Shanghai 200032 (China); Shi Daren [Cancer Hospital, Medical Center, Fudan University, Shanghai 200032 (China)

    2006-07-15

    The spectral characteristics of human breast tissues in normal status and during different cancerous stages have been investigated by synchrotron radiation based Fourier transform infrared (SR-FTIR) absorption spectroscopy. Thanks to the excellent synchrotron radiation infrared (IR) source, higher resolving power is achieved in SR-FTIR absorption spectra than in conventional IR absorption measurements. Obvious variations in IR absorption spectrum of breast tissues were found as they change from healthy to diseased, or say in progression to cancer. On the other hand, some specific absorption peaks were found in breast cancer tissues by SR-FTIR spectroscopic methods. These spectral characteristics of breast tissue may help us in early diagnosis of breast cancer.

  6. Breast Hypertrophy, Reduction Mammaplasty, and Body Image.

    Science.gov (United States)

    Fonseca, Cristiane Costa; Veiga, Daniela Francescato; Garcia, Edgard da Silva; Cabral, Isaías Vieira; de Carvalho, Monique Maçais; de Brito, Maria José Azevedo; Ferreira, Lydia Masako

    2018-02-07

    Body image dissatisfaction is one of the major factors that motivate patients to undergo plastic surgery. However, few studies have associated body satisfaction with reduction mammaplasty. The aim of this study was to evaluate the impact of breast hypertrophy and reduction mammaplasty on body image. Breast hypertrophy patients, with reduction mammaplasty already scheduled between June 2013 and December 2015 (mammaplasty group, MG), were prospectively evaluated through the body dysmorphic disorder examination (BDDE), body investment scale (BIS), and breast evaluation questionnaire (BEQ55) tools. Women with normal-sized breasts were also evaluated as study controls (normal-sized breast group, NSBG). All the participants were interviewed at the initial assessment and after six months. Data were analyzed before and after six months. Each group consisted of 103 women. The MG group had a significant improvement in BDDE, BIS, and BEQ55 scores six months postoperatively (P ≤ 0.001 for the three instruments), whereas the NSBG group showed no alteration in results over time (P = 0.876; P = 0.442; and P = 0.184, respectively). In the intergroup comparison it was observed that the MG group began to invest more in the body, similarly to the NSBG group, and surpassed the level of satisfaction and body image that the women of the NSBG group had after the surgery. Reduction mammaplasty promoted improvement in body image of women with breast hypertrophy. © 2018 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com

  7. Mammary Development and Breast Cancer: A Wnt Perspective

    Science.gov (United States)

    Yu, Qing Cissy; Verheyen, Esther M.; Zeng, Yi Arial

    2016-01-01

    The Wnt pathway has emerged as a key signaling cascade participating in mammary organogenesis and breast oncogenesis. In this review, we will summarize the current knowledge of how the pathway regulates stem cells and normal development of the mammary gland, and discuss how its various components contribute to breast carcinoma pathology. PMID:27420097

  8. Application of Raman Spectroscopy and Infrared Spectroscopy in the Identification of Breast Cancer.

    Science.gov (United States)

    Depciuch, Joanna; Kaznowska, Ewa; Zawlik, Izabela; Wojnarowska, Renata; Cholewa, Marian; Heraud, Philip; Cebulski, Józef

    2016-02-01

    Raman spectroscopy and infrared (IR) spectroscopy are both techniques that allow for the investigation of vibrating chemical particles. These techniques provide information not only about chemical particles through the identification of functional groups and spectral analysis of so-called "fingerprints", these methods allow for the qualitative and quantitative analyses of chemical substances in the sample. Both of these spectral techniques are frequently being used in biology and medicine in diagnosing illnesses and monitoring methods of therapy. The type of breast cancer found in woman is often a malignant tumor, causing 1.38 million new cases of breast cancer and 458 000 deaths in the world in 2013. The most important risk factors for breast cancer development are: sex, age, family history, specific benign breast conditions in the breast, ionizing radiation, and lifestyle. The main purpose of breast cancer screening tests is to establish early diagnostics and to apply proper treatment. Diagnoses of breast cancer are based on: (1) physical techniques (e.g., ultrasonography, mammography, elastography, magnetic resonance, positron emission tomography [PET]); (2) histopathological techniques; (3) biological techniques; and (4) optical techniques (e.g., photo acoustic imaging, fluorescence tomography). However, none of these techniques provides unique or especially revealing answers. The aim of our study is comparative spectroscopic measurements on patients with the following: normal non-cancerous breast tissue; breast cancer tissues before chemotherapy; breast cancer tissues after chemotherapy; and normal breast tissues received around the cancerous breast region. Spectra collected from breast cancer patients shows changes in amounts of carotenoids and fats. We also observed changes in carbohydrate and protein levels (e.g., lack of amino acids, changes in the concentration of amino acids, structural changes) in comparison with normal breast tissues. This fact

  9. NUCKS overexpression in breast cancer

    Directory of Open Access Journals (Sweden)

    Kittas Christos

    2009-08-01

    Full Text Available Abstract Background NUCKS (Nuclear, Casein Kinase and Cyclin-dependent Kinase Substrate is a nuclear, DNA-binding and highly phosphorylated protein. A number of reports show that NUCKS is highly expressed on the level of mRNA in several human cancers, including breast cancer. In this work, NUCKS expression on both RNA and protein levels was studied in breast tissue biopsies consisted of invasive carcinomas, intraductal proliferative lesions, benign epithelial proliferations and fibroadenomas, as well as in primary cultures derived from the above biopsies. Specifically, in order to evaluate the level of NUCKS protein in correlation with the histopathological features of breast disease, immunohistochemistry was employed on paraffin sections of breast biopsies of the above types. In addition, NUCKS expression was studied by means of Reverse Transcription PCR (RT-PCR, real-time PCR (qRT-PCR and Western immunoblot analyses in the primary cell cultures developed from the same biopsies. Results The immunohistochemical Results showed intense NUCKS staining mostly in grade I and II breast carcinomas compared to normal tissues. Furthermore, NUCKS was moderate expressed in benign epithelial proliferations, such as adenosis and sclerosing adenosis, and highly expressed in intraductal lesions, specifically in ductal carcinomas in situ (DCIS. It is worth noting that all the fibroadenoma tissues examined were negative for NUCKS staining. RT-PCR and qRT-PCR showed an increase of NUCKS expression in cells derived from primary cultures of proliferative lesions and cancerous tissues compared to the ones derived from normal breast tissues and fibroadenomas. This increase was also confirmed by Western immunoblot analysis. Although NUCKS is a cell cycle related protein, its expression does not correlate with Ki67 expression, neither in tissue sections nor in primary cell cultures. Conclusion The results show overexpression of the NUCKS protein in a number of non

  10. Foetal antigen 2 (FA2) in the stromal reaction induced by breast carcinoma

    DEFF Research Database (Denmark)

    Rasmussen, H B; Teisner, B; Andersen, J A

    1992-01-01

    An indirect immunoperoxidase technique was used to examine the distribution of foetal antigen 2 (FA2), a recently described basement membrane (BM)-associated antigen, in invasive breast carcinoma (n = 34), fibroadenoma (n = 5) and normal breast tissue (n = 5), and to compare its distribution...... with that of laminin and collagen type IV. In normal breast tissue, FA2 was detected in the intralobular stroma as a broad band around acini and ducts, but was not present in the interlobular stroma. In areas of carcinoma in situ, FA2 was present diffusely around and in close contact with the glandular elements......, the staining being more intense than that found around normal glandular structures. Two distinct patterns of FA2 distribution were found in adenocarcinomas of the breast. In the fibroblast reaction type, fibroblast staining dominated, whilst in the stromal reaction type, intense and extensive staining...

  11. Variability of non-Gaussian diffusion MRI and intravoxel incoherent motion (IVIM) measurements in the breast.

    Science.gov (United States)

    Iima, Mami; Kataoka, Masako; Kanao, Shotaro; Kawai, Makiko; Onishi, Natsuko; Koyasu, Sho; Murata, Katsutoshi; Ohashi, Akane; Sakaguchi, Rena; Togashi, Kaori

    2018-01-01

    We prospectively examined the variability of non-Gaussian diffusion magnetic resonance imaging (MRI) and intravoxel incoherent motion (IVIM) measurements with different numbers of b-values and excitations in normal breast tissue and breast lesions. Thirteen volunteers and fourteen patients with breast lesions (seven malignant, eight benign; one patient had bilateral lesions) were recruited in this prospective study (approved by the Internal Review Board). Diffusion-weighted MRI was performed with 16 b-values (0-2500 s/mm2 with one number of excitations [NEX]) and five b-values (0-2500 s/mm2, 3 NEX), using a 3T breast MRI. Intravoxel incoherent motion (flowing blood volume fraction [fIVIM] and pseudodiffusion coefficient [D*]) and non-Gaussian diffusion (theoretical apparent diffusion coefficient [ADC] at b value of 0 sec/mm2 [ADC0] and kurtosis [K]) parameters were estimated from IVIM and Kurtosis models using 16 b-values, and synthetic apparent diffusion coefficient (sADC) values were obtained from two key b-values. The variabilities between and within subjects and between different diffusion acquisition methods were estimated. There were no statistical differences in ADC0, K, or sADC values between the different b-values or NEX. A good agreement of diffusion parameters was observed between 16 b-values (one NEX), five b-values (one NEX), and five b-values (three NEX) in normal breast tissue or breast lesions. Insufficient agreement was observed for IVIM parameters. There were no statistical differences in the non-Gaussian diffusion MRI estimated values obtained from a different number of b-values or excitations in normal breast tissue or breast lesions. These data suggest that a limited MRI protocol using a few b-values might be relevant in a clinical setting for the estimation of non-Gaussian diffusion MRI parameters in normal breast tissue and breast lesions.

  12. Effect of adjuvant systemic treatment on cosmetic outcome and late normal-tissue reactions after breast conservation

    DEFF Research Database (Denmark)

    Johansen, Jørgen; Overgaard, Jens; Overgaard, Marie

    2007-01-01

    To investigate whether adjuvant treatment with CMF or tamoxifen predisposes to an unfavorable cosmetic outcome or increased breast morbidity after radiotherapy in breast conservation. Data from 266 patients who entered a randomized breast conservation trial (DBCG-82TM protocol) was analyzed......-risk patients: premenopausal patients (n = 67) received eight cycles of CMF intravenously (600/40/600 mg per m(2)) every fourth week; postmenopausal patients (n = 27) received 30 mg of tamoxifen daily for one year. Clinical assessments included cosmetic outcome, breast fibrosis, skin telangiectasia....... In premenopausal patients, systemic treatment with CMF independently predicted a fair/poor cosmetic outcome, RR = 2.2 (95% CI 1.2-4.2), as well as increased skin telangiectasia, RR = 3.3 (1.4-8.2). There was no impact of tamoxifen treatment on cosmetic outcome in postmenopausal patients (p = 0.32). However...

  13. Combination of Hypomorphic Mutations of the Drosophila Homologues of Aryl Hydrocarbon Receptor and Nucleosome Assembly Protein Family Genes Disrupts Morphogenesis, Memory and Detoxification

    OpenAIRE

    Kuzin, Boris A.; Nikitina, Ekaterina A.; Cherezov, Roman O.; Vorontsova, Julia E.; Slezinger, Mikhail S.; Zatsepina, Olga G.; Simonova, Olga B.; Enikolopov, Grigori N.; Savvateeva-Popova, Elena V.

    2014-01-01

    Aryl hydrocarbon receptor is essential for biological responses to endogenous and exogenous toxins in mammals. Its Drosophila homolog spineless plays an important role in fly morphogenesis. We have previously shown that during morphogenesis spineless genetically interacts with CG5017 gene, which encodes a nucleosome assembly factor and may affect cognitive function of the fly. We now demonstrate synergistic interactions of spineless and CG5017 in pathways controlling oxidative stress response...

  14. Dedicated breast CT: radiation dose for circle-plus-line trajectory

    International Nuclear Information System (INIS)

    Vedantham, Srinivasan; Shi, Linxi; Karellas, Andrew; Noo, Frederic

    2012-01-01

    Purpose: Dedicated breast CT prototypes used in clinical investigations utilize single circular source trajectory and cone-beam geometry with flat-panel detectors that do not satisfy data-sufficiency conditions and could lead to cone beam artifacts. Hence, this work investigated the glandular dose characteristics of a circle-plus-line trajectory that fulfills data-sufficiency conditions for image reconstruction in dedicated breast CT. Methods: Monte Carlo-based computer simulations were performed using the GEANT4 toolkit and was validated with previously reported normalized glandular dose coefficients for one prototype breast CT system. Upon validation, Monte Carlo simulations were performed to determine the normalized glandular dose coefficients as a function of x-ray source position along the line scan. The source-to-axis of rotation distance and the source-to-detector distance were maintained constant at 65 and 100 cm, respectively, in all simulations. The ratio of the normalized glandular dose coefficient at each source position along the line scan to that for the circular scan, defined as relative normalized glandular dose coefficient (RD g N), was studied by varying the diameter of the breast at the chest wall, chest-wall to nipple distance, skin thickness, x-ray beam energy, and glandular fraction of the breast. Results: The RD g N metric when stated as a function of source position along the line scan, relative to the maximum length of line scan needed for data sufficiency, was found to be minimally dependent on breast diameter, chest-wall to nipple distance, skin thickness, glandular fraction, and x-ray photon energy. This observation facilitates easy estimation of the average glandular dose of the line scan. Polynomial fit equations for computing the RD g N and hence the average glandular dose are provided. Conclusions: For a breast CT system that acquires 300-500 projections over 2π for the circular scan, the addition of a line trajectory with equal

  15. Role of Notch Signaling in Human Breast Cancer Pathogenesis

    Science.gov (United States)

    2006-11-01

    transform HMLE cells. Similarly, overexpression of ErbB2, a receptor tyrosine kinase upstream of Ras normally found overexpressed in many breast cancers ...Assess Notch-Ras cooperation in breast cancers in vivo: Since the major observation in this project has been the cooperation of Notch and Ras in HMLE ...metastasis. The in vitro cooperation between Notch and Ras in HMLE cells is mimicked in naturally arising breast cancers in vivo. Further dissection of the

  16. Benign Breast Problems and Conditions

    Science.gov (United States)

    ... Hyperplasia: A condition in which cells in the breast ducts or lobes are increasing in number and do not look normal under a microscope. Benign: Not cancer. Biopsy: A minor surgical procedure to remove a small ...

  17. Role of MRI in differentiating benign from malignant breast lesions ...

    African Journals Online (AJOL)

    Mohamed Ahmed Youssef

    2017-02-15

    Feb 15, 2017 ... detecting breast lesions than either T1- or T2-weighted imaging, but it is better to be performed in con- junction with contrast ... of MRI in several aspects of breast cancer diagnosis and management.2 ..... Hayes DF.: Normal ...

  18. Diagnosing breast cancer by using Raman spectroscopy

    Science.gov (United States)

    Haka, Abigail S.; Shafer-Peltier, Karen E.; Fitzmaurice, Maryann; Crowe, Joseph; Dasari, Ramachandra R.; Feld, Michael S.

    2005-08-01

    We employ Raman spectroscopy to diagnose benign and malignant lesions in human breast tissue based on chemical composition. In this study, 130 Raman spectra are acquired from ex vivo samples of human breast tissue (normal, fibrocystic change, fibroadenoma, and infiltrating carcinoma) from 58 patients. Data are fit by using a linear combination model in which nine basis spectra represent the morphologic and chemical features of breast tissue. The resulting fit coefficients provide insight into the chemical/morphological makeup of the tissue and are used to develop diagnostic algorithms. The fit coefficients for fat and collagen are the key parameters in the resulting diagnostic algorithm, which classifies samples according to their specific pathological diagnoses, attaining 94% sensitivity and 96% specificity for distinguishing cancerous tissues from normal and benign tissues. The excellent results demonstrate that Raman spectroscopy has the potential to be applied in vivo to accurately classify breast lesions, thereby reducing the number of excisional breast biopsies that are performed. Author contributions: M.F., J.C., R.R.D., and M.S.F. designed research; A.S.H. and K.E.S.-P. performed research; A.S.H. and M.F. analyzed data; and A.S.H. wrote the paper.This paper was submitted directly (Track II) to the PNAS office.Abbreviations: DEH, ductal epithelial hyperplasia; ROC, receiver operating characteristic; N/C, nuclear-to-cytoplasm.

  19. The integrative epigenomic-transcriptomic landscape of ER positive breast cancer.

    Science.gov (United States)

    Gao, Yang; Jones, Allison; Fasching, Peter A; Ruebner, Matthias; Beckmann, Matthias W; Widschwendter, Martin; Teschendorff, Andrew E

    2015-01-01

    While recent integrative analyses of copy number and gene expression data in breast cancer have revealed a complex molecular landscape with multiple subtypes and many oncogenic/tumour suppressor driver events, much less is known about the role of DNA methylation in shaping breast cancer taxonomy and defining driver events. Here, we applied a powerful integrative network algorithm to matched DNA methylation and RNA-Seq data for 724 estrogen receptor (ER)-positive (ER+) breast cancers and 111 normal adjacent tissue specimens from The Cancer Genome Atlas (TCGA) project, in order to identify putative epigenetic driver events and to explore the resulting molecular taxonomy. This revealed the existence of nine functionally deregulated epigenetic hotspots encompassing a total of 146 genes, which we were able to validate in independent data sets encompassing over 1000 ER+ breast cancers. Integrative clustering of the matched messenger RNA (mRNA) and DNA methylation data over these genes resulted in only two clusters, which correlated very strongly with the luminal-A and luminal B subtypes. Overall, luminal-A and luminal-B breast cancers shared the same epigenetically deregulated hotspots but with luminal-B cancers exhibiting increased aberrant DNA methylation patterns relative to normal tissue. We show that increased levels of DNA methylation and mRNA expression deviation from the normal state define a marker of poor prognosis. Our data further implicates epigenetic silencing of WNT signalling antagonists and bone morphogenetic proteins (BMP) as key events underlying both luminal subtypes but specially of luminal-B breast cancer. Finally, we show that DNA methylation changes within the identified epigenetic interactome hotspots do not exhibit mutually exclusive patterns within the same cancer sample, instead exhibiting coordinated changes within the sample. Our results indicate that the integrative DNA methylation and transcriptomic landscape of ER+ breast cancer is

  20. CDKL5, a protein associated with rett syndrome, regulates neuronal morphogenesis via Rac1 signaling.

    Science.gov (United States)

    Chen, Qian; Zhu, Yong-Chuan; Yu, Jing; Miao, Sheng; Zheng, Jing; Xu, Li; Zhou, Yang; Li, Dan; Zhang, Chi; Tao, Jiong; Xiong, Zhi-Qi

    2010-09-22

    Mutations in cyclin-dependent kinase-like 5 (CDKL5), also known as serine/threonine kinase 9 (STK9), have been identified in patients with Rett syndrome (RTT) and X-linked infantile spasm. However, the function of CDKL5 in the brain remains unknown. Here, we report that CDKL5 is a critical regulator of neuronal morphogenesis. We identified a neuron-specific splicing variant of CDKL5 whose expression was markedly induced during postnatal development of the rat brain. Downregulating CDKL5 by RNA interference (RNAi) in cultured cortical neurons inhibited neurite growth and dendritic arborization, whereas overexpressing CDKL5 had opposite effects. Furthermore, knocking down CDKL5 in the rat brain by in utero electroporation resulted in delayed neuronal migration, and severely impaired dendritic arborization. In contrast to its proposed function in the nucleus, we found that CDKL5 regulated dendrite development through a cytoplasmic mechanism. In fibroblasts and in neurons, CDKL5 colocalized and formed a protein complex with Rac1, a critical regulator of actin remodeling and neuronal morphogenesis. Overexpression of Rac1 prevented the inhibition of dendrite growth caused by CDKL5 knockdown, and the growth-promoting effect of ectopically expressed CDKL5 on dendrites was abolished by coexpressing a dominant-negative form of Rac1. Moreover, CDKL5 was required for brain-derived neurotrophic factor (BDNF)-induced activation of Rac1. Together, these results demonstrate a critical role of CDKL5 in neuronal morphogenesis and identify a Rho GTPase signaling pathway which may contribute to CDKL5-related disorders.

  1. Effect of adjuvant systemic treatment on cosmetic outcome and late normal-tissue reactions after breast conservation

    International Nuclear Information System (INIS)

    Johansen, Joergen; Overgaard, Jens; Overgaard, Marie

    2007-01-01

    To investigate whether adjuvant treatment with CMF or tamoxifen predisposes to an unfavorable cosmetic outcome or increased breast morbidity after radiotherapy in breast conservation. Data from 266 patients who entered a randomized breast conservation trial (DBCG-82TM protocol) was analyzed. The patients were treated with lumpectomy and axillary dissection followed by external beam radiotherapy to the residual breast. High-risk patients (n 94), as well as 31 low-risk patients, received additional radiation to the regional lymph nodes. Adjuvant systemic treatment was given to all high-risk patients: premenopausal patients (n = 67) received eight cycles of CMF intravenously (600/40/600 mg/m 2 ) every fourth week; postmenopausal patients (n = 27) received 30 mg of tamoxifen daily for one year. Clinical assessments included cosmetic outcome, breast fibrosis, skin telangiectasia, and dyspigmentation which were scored on a 4-point categorical scale after median 6.6 years. The observations were analyzed in multivariate logistic regression analysis which included potential risk factors on outcome related to systemic treatment, surgery, radiation technique, tumor, and patient characteristics. In premenopausal patients, systemic treatment with CMF independently predicted a fair/poor cosmetic outcome, RR = 2.2 (95% CI 1.2-4.2), as well as increased skin telangiectasia, RR = 3.3 (1.4-8.2). There was no impact of tamoxifen treatment on cosmetic outcome in postmenopausal patients (p 0.32). However, univariate analysis showed that tamoxifen was significantly associated with breast fibrosis (p <0.004), as was radiation to the regional lymph nodes (p <0.0001). A strong interaction between axillary irradiation and tamoxifen treatment occurred since 26 of 27 high-risk postmenopausal patients had received both tamoxifen and axillary irradiation. In multivariate regression analysis, axillary irradiation independently predicted moderate/severe breast fibrosis with a relative risk of 5

  2. Expression of Progesterone and Androgen Receptors in the Breast of Premenopausal Women, Considering Menstrual Phase.

    Science.gov (United States)

    Fahlén, Mia; Zhang, Hua; Löfgren, Lars; Masironi, Britt; VON Schoultz, Eva; VON Schoultz, B O; Sahlin, Lena

    2018-03-01

    Progesterone and androgens are important for normal development and tumorigenesis of the breast. Breast tissue samples from 49 premenopausal women were obtained. The progesterone receptors (PRA, PRB, PGRMC1 and PGRMC2) and the androgen receptor (AR) were determined in malignant and benign breast tumors and control tissues. The PRB and AR mRNA levels were highest in tumors. PGRMC1 and PGRMC2 mRNA levels were higher in malignant tumors compared to their paired normal tissues. PRA protein showed most immunostaining in benign tumors. PRB immunostaining varied according to menstrual phase. AR immunostaining was highest in the glands of malignant tumors. Progesterone and androgen receptors are differently regulated in tumors compared to normal breast tissues. A malignant breast tumor could appear PR-negative if collected in the luteal phase, but positive in the follicular phase. This finding may have clinical implications. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  3. Myoepithelioma breast: clinically masquerading as breast carcinoma

    Directory of Open Access Journals (Sweden)

    Vishal Dhingra

    2012-10-01

    Full Text Available Pure myoepithelioma of breast is an extremely rare tumor. Only a few cases have been reported in the literature so far. A 30-year old female presented with a large fungating mass arising from the areolar region of her right breast of six months duration. A clinical diagnosis of breast carcinoma was made and a mastectomy was performed. The specimen measured 23x22x9 cm with attached skin, and showed a large white ulcerated growth with areas of necrosis and hemorrhage. No normal breast tissue, nipple or areolar region was seen. Histopathological examination showed oval to spindle cells arranged in fascicles and bundles with whorling pattern in places showing mild pleomorphism with oval to spindle-shaped vesicular nuclei, prominent eosinophilic nucleoli, eosinophilic cytoplasm and clear cell changes in places, along with perivascular hyalinization and collagenization. Differential diagnosis of pleomorphic hyalinizing angiectatic tumor, solitary fibrous tumor, perivascular epithelioid cell tumor, mammary type myofibroblastic tumor and myoepitheliomawereallconsidered.Immunohistochemistry for vimentin, smooth muscle actin, calponin, caldesmon, p63, epithelial membrane antigen, S-100, CD-31, CD-34, muscle specific antigen, myogenin, desmin, and pancytokeratin was carried out. On the basis of positive staining for vimentin, actin, p63 (nuclear, calponin and caldesmon (focal, a final diagnosis of myoepithelioma was considered; however, cytokeratin negativity was an unusual finding. This case was considered worthy of documentation because of its rarity, and because it highlights the importance of proper clinical examination and radiological examination to prevent misdiagnosis.

  4. Quality indicators for breast cancer

    DEFF Research Database (Denmark)

    Poortmans, Philip; Aznar, Marianne; Bartelink, Harry

    2012-01-01

    Radiation therapy for breast cancer has considerably changed over the years, from simple simulator-based 2-dimensional techniques to sophisticated image-guided individualized treatments, with maximally protected normal structures. This has led to a substantial improvement in the outcome of breast...... cancer patients in terms of disease control, survival, and quality of life. This progress is based on clinical research and paralleled by progress in delivering sophisticated radiation treatment. Clinical trials resulted in identifying patients groups who will benefit from radiation treatment. They also...

  5. Transcript profiling of Wilms tumors reveals connections to kidney morphogenesis and expression patterns associated with anaplasia.

    Science.gov (United States)

    Li, Wenliang; Kessler, Patricia; Williams, Bryan R G

    2005-01-13

    Anaplasia (unfavorable histology) is associated with therapy resistance and poor prognosis of Wilms tumor, but the molecular basis for this phenotype is unclear. Here, we used a cDNA array with 9240 clones relevant to cancer biology and/or kidney development to examine the expression profiles of 54 Wilms tumors, five normal kidneys and fetal kidney. By linking genes differentially expressed between fetal kidney and Wilms tumors to kidney morphogenesis, we found that genes expressed at a higher level in Wilms tumors tend to be expressed more in uninduced metanephrogenic mesenchyme or blastema than in their differentiated structures. Conversely, genes expressed at a lower level in Wilms tumors tend to be expressed less in uninduced metanephrogenic mesenchyme or blastema. We also identified 97 clones representing 76 Unigenes or unclustered ESTs that clearly separate anaplastic Wilms tumors from tumors with favorable histology. Genes in this set provide insight into the nature of the abnormal nuclear morphology of anaplastic tumors and may facilitate identification of molecular targets to improve their responsiveness to treatment.

  6. Meat quality of broiler breast fillets with white striping and woody breast muscle myopathies.

    Science.gov (United States)

    Tijare, V V; Yang, F L; Kuttappan, V A; Alvarado, C Z; Coon, C N; Owens, C M

    2016-09-01

    The global poultry industry has been faced with emerging broiler breast meat quality issues including conditions known as white striping (WS, white striations parallel to muscle fibers) and woody breast (WB, hardness of raw fillet). Experiments were conducted to evaluate effects of WS and WB hardness on meat quality traits in broiler breast fillets. In Exp. 1, birds were processed at approximately 9 wk of age and deboned at 4 h postmortem (PM); in Exp. 2, birds were processed at approximately 6 and 9 wk of age and deboned at 2 h PM. Fillets were categorized as: normal for both white striping and woody breast (NORM); moderate for white striping and mild for woody breast (MILD); severe for white striping and mild for woody breast (WS); severe for woody breast and moderate for white striping (WB); or severe for both white striping and woody breast (BOTH). Sarcomere length, gravimetric fragmentation index, marination uptake, cook loss, and Meullenet-Owens razor shear energy (MORSE) values on non-marinated and marinated fillets were assessed. Sarcomeres tended to be longer (P = 0.07) with increasing severity of WS and WB in both experiments and gravimetric fragmentation index did not differ (P > 0.05) among categories. Marinade uptake decreased (P  0.05) in non-marinated fillets, the marinated BOTH fillets had greater MORSE values (P  0.05) among categories of marinated breasts. At 9 wk, WS and BOTH were higher (P white striping and woody breast, individually or in combination, negatively impact meat quality, especially water holding capacity attributes such as marinade uptake and cook loss. © 2016 Poultry Science Association Inc.

  7. Radiography of the male breast in gynecomastia

    Energy Technology Data Exchange (ETDEWEB)

    Rissanen, T.J.; Maekaeraeinen, H.P.; Kallioinen, M.J.; Kiviniemi, H.O.; Salmela, P.I. (Oulu Univ. Central Hospital (Finland). Depts. of Diagnostic Radiology, Pathology, Surgery, and Internal Medicine)

    1992-03-01

    In order to investigate the role of imaging methods in the evaluation of the male breast we reviewed the mammograms and ultrasonograms (US) performed in 40 men with breast enlargement or pain. The patients, whose breasts were examined by either mammography or US or both, ranged in age from 14 to 83 years. The final diagnoses were gynecomastia in 35 patients, lipomas in one, abscess or sequelae to abscess in 2, and normal in 2. In gynecomastia the subareolar density was of varying shape and size or showed a diffuse pattern of heterogeneous density occupying the whole breast on mammography, and a retromammillar hypoechoic focus, a diffuse heterogeneous area, or a combination of these was observed at US. Mammography is recommended for the evaluation of the male breast if the differential diagnosis between gynecomastia and fatty enlargement is not clinically evident, and in all cases of unilateral breast symptoms. US is a complementary method to mammography. (orig.).

  8. Radiography of the male breast in gynecomastia

    International Nuclear Information System (INIS)

    Rissanen, T.J.; Maekaeraeinen, H.P.; Kallioinen, M.J.; Kiviniemi, H.O.; Salmela, P.I.

    1992-01-01

    In order to investigate the role of imaging methods in the evaluation of the male breast we reviewed the mammograms and ultrasonograms (US) performed in 40 men with breast enlargement or pain. The patients, whose breasts were examined by either mammography or US or both, ranged in age from 14 to 83 years. The final diagnoses were gynecomastia in 35 patients, lipomas in one, abscess or sequelae to abscess in 2, and normal in 2. In gynecomastia the subareolar density was of varying shape and size or showed a diffuse pattern of heterogeneous density occupying the whole breast on mammography, and a retromammillar hypoechoic focus, a diffuse heterogeneous area, or a combination of these was observed at US. Mammography is recommended for the evaluation of the male breast if the differential diagnosis between gynecomastia and fatty enlargement is not clinically evident, and in all cases of unilateral breast symptoms. US is a complementary method to mammography. (orig.)

  9. NASA SMART Probe: Breast Cancer Application

    Science.gov (United States)

    Mah, Robert W.; Norvig, Peter (Technical Monitor)

    2000-01-01

    There is evidence in breast cancer and other malignancies that the physiologic environment within a tumor correlates with clinical outcome. We are developing a unique percutaneous Smart Probe to be used at the time of needle biopsy of the breast. The Smart Probe will simultaneously measure multiple physiologic parameters within a breast tumor. Direct and indirect measurements of tissue oxygen levels, blood flow, pH, and tissue fluid pressure will be analyzed in real-time. These parameters will be interpreted individually and collectively by innovative neural network techniques using advanced intelligent software. The goals are 1) develop a pecutaneous Smart Probe with multiple sensor modalities and applying advanced Information Technologies to provide real time diagnostic information of the tissue at tip of the probe, 2) test the percutaneous Smart Probe in women with benign and malignant breast masses who will be undergoing surgical biopsy, 3) correlate probe sensor data with benign and malignant status of breast masses, 4) determine whether the probe can detect physiologic differences within a breast tumor, and its margins, and in adjacent normal breast tissue, 5) correlate probe sensor data with known prognostic factors for breast caner, including tumor size, tumor grade, axillary lymph node metastases, estrogen receptor and progesterone receptor status.

  10. CRIM1 complexes with ß-catenin and cadherins, stabilizes cell-cell junctions and is critical for neural morphogenesis.

    Directory of Open Access Journals (Sweden)

    Virgilio G Ponferrada

    Full Text Available In multicellular organisms, morphogenesis is a highly coordinated process that requires dynamically regulated adhesion between cells. An excellent example of cellular morphogenesis is the formation of the neural tube from the flattened epithelium of the neural plate. Cysteine-rich motor neuron protein 1 (CRIM1 is a single-pass (type 1 transmembrane protein that is expressed in neural structures beginning at the neural plate stage. In the frog Xenopus laevis, loss of function studies using CRIM1 antisense morpholino oligonucleotides resulted in a failure of neural development. The CRIM1 knockdown phenotype was, in some cases, mild and resulted in perturbed neural fold morphogenesis. In severely affected embryos there was a dramatic failure of cell adhesion in the neural plate and complete absence of neural structures subsequently. Investigation of the mechanism of CRIM1 function revealed that it can form complexes with ß-catenin and cadherins, albeit indirectly, via the cytosolic domain. Consistent with this, CRIM1 knockdown resulted in diminished levels of cadherins and ß-catenin in junctional complexes in the neural plate. We conclude that CRIM1 is critical for cell-cell adhesion during neural development because it is required for the function of cadherin-dependent junctions.

  11. Comparison of breast cancer detection by diffusion-weighted magnetic resonance imaging and mammography

    International Nuclear Information System (INIS)

    Yoshikawa, Miho I.; Kikuchi, Keiichi; Mochizuki, Teruhito; Ohsumi, Shozo; Sugata, Shigenori; Kataoka, Masaaki; Takashima, Shigemitsu

    2007-01-01

    Breast cancer-detecting ability of diffusion-weighted magnetic resonance imaging (DW-MRI) was investigated by comparing the breast cancer detection rates of DW-MRI and mammography (MMG). The subjects were 48 women who had breast cancer (53 cancer lesions) who underwent DW-MRI before surgery. Altogether, 41 lesions were invasive ductal carcinoma (IDC), 7 were noninvasive ductal carcinoma (NIDC) and 5 were ''others.'' The breast cancer detection rates by MMG and DW-MRI were 84.9% and 94.3% (P -3 , 1.50±0.24 x 10 -3 , 1.12±0.25 x 10 -3 , and 2.01±0.29 x 10 -3 mm 2 /s for IDC, NIDC, others, and normal breast, respectively, showing that the values of IDC and NIDC were significantly different from that of the normal breast (P<0.001 each). A significant difference was also noted between IDC and NIDC (P<0.001). DW-MRI may be useful for detecting breast cancer in a wide age group of women, including young women with dense mammary glands. (author)

  12. Overexpression of a novel cell cycle regulator ecdysoneless in breast cancer: a marker of poor prognosis in HER2/neu-overexpressing breast cancer patients.

    Science.gov (United States)

    Zhao, Xiangshan; Mirza, Sameer; Alshareeda, Alaa; Zhang, Ying; Gurumurthy, Channabasavaiah Basavaraju; Bele, Aditya; Kim, Jun Hyun; Mohibi, Shakur; Goswami, Monica; Lele, Subodh M; West, William; Qiu, Fang; Ellis, Ian O; Rakha, Emad A; Green, Andrew R; Band, Hamid; Band, Vimla

    2012-07-01

    Uncontrolled proliferation is one of the hallmarks of breast cancer. We have previously identified the human Ecd protein (human ortholog of Drosophila Ecdysoneless, hereafter called Ecd) as a novel promoter of mammalian cell cycle progression, a function related to its ability to remove the repressive effects of Rb-family tumor suppressors on E2F transcription factors. Given the frequent dysregulation of cell cycle regulatory components in human cancer, we used immunohistochemistry of paraffin-embedded tissues to examine Ecd expression in normal breast tissue versus tissues representing increasing breast cancer progression. Initial studies of a smaller cohort without outcomes information showed that Ecd expression was barely detectable in normal breast tissue and in hyperplasia of breast, but high levels of Ecd were detected in benign breast hyperplasia, ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDCs) of the breast. In this cohort of 104 IDC patients, Ecd expression levels showed a positive correlation with higher grade (P=0.04). Further analyses of Ecd expression using a larger, independent cohort (954) confirmed these results, with a strong positive correlation of elevated Ecd expression with higher histological grade (P=0.013), mitotic index (P=0.032), and Nottingham Prognostic Index score (P=0.014). Ecd expression was positively associated with HER2/neu (P=0.002) overexpression, a known marker of poor prognosis in breast cancer. Significantly, increased Ecd expression showed a strong positive association with shorter breast cancer specific survival (BCSS) (P=0.008) and disease-free survival (DFS) (P=0.003) in HER2/neu overexpressing patients. Taken together, our results reveal Ecd as a novel marker for breast cancer progression and show that levels of Ecd expression predict poorer survival in Her2/neu overexpressing breast cancer patients.

  13. The Role of Notch Signaling Pathway in Breast Cancer Pathogenesis

    Science.gov (United States)

    2005-07-01

    breast cancer cells, I tested whether ErbB2 overexpression will cooperate with Notch in HMLE cells. While overexpression of activated Notch1 failed to...tyrosine kinase upstream of Ras normally found overexpressed in many breast cancers , also failed to transform HMLE cells. These observations suggested...cooperation between Notch1IC and ErbB2 signaling in transforming HMLE cells. Breast cancers typically do not harbor oncogenic Ras mutations; nevertheless

  14. Identification of Differentially Expressed IGFBP5-Related Genes in Breast Cancer Tumor Tissues Using cDNA Microarray Experiments.

    Science.gov (United States)

    Akkiprik, Mustafa; Peker, İrem; Özmen, Tolga; Amuran, Gökçe Güllü; Güllüoğlu, Bahadır M; Kaya, Handan; Özer, Ayşe

    2015-11-10

    IGFBP5 is an important regulatory protein in breast cancer progression. We tried to identify differentially expressed genes (DEGs) between breast tumor tissues with IGFBP5 overexpression and their adjacent normal tissues. In this study, thirty-eight breast cancer and adjacent normal breast tissue samples were used to determine IGFBP5 expression by qPCR. cDNA microarrays were applied to the highest IGFBP5 overexpressed tumor samples compared to their adjacent normal breast tissue. Microarray analysis revealed that a total of 186 genes were differentially expressed in breast cancer compared with normal breast tissues. Of the 186 genes, 169 genes were downregulated and 17 genes were upregulated in the tumor samples. KEGG pathway analyses showed that protein digestion and absorption, focal adhesion, salivary secretion, drug metabolism-cytochrome P450, and phenylalanine metabolism pathways are involved. Among these DEGs, the prominent top two genes (MMP11 and COL1A1) which potentially correlated with IGFBP5 were selected for validation using real time RT-qPCR. Only COL1A1 expression showed a consistent upregulation with IGFBP5 expression and COL1A1 and MMP11 were significantly positively correlated. We concluded that the discovery of coordinately expressed genes related with IGFBP5 might contribute to understanding of the molecular mechanism of the function of IGFBP5 in breast cancer. Further functional studies on DEGs and association with IGFBP5 may identify novel biomarkers for clinical applications in breast cancer.

  15. Aberrantly methylated DNA as a biomarker in breast cancer

    DEFF Research Database (Denmark)

    Kristiansen, Søren; Jørgensen, Lars Mønster; Guldberg, Per

    2013-01-01

    hypermethylation events, their use as tumor biomarkers is usually not hampered by analytical signals from normal cells, which is a general problem for existing protein tumor markers used for clinical assessment of breast cancer. There is accumulating evidence that DNA-methylation changes in breast cancer patients...... occur early during tumorigenesis. This may open up for effective screening, and analysis of blood or nipple aspirate may later help in diagnosing breast cancer. As a more detailed molecular characterization of different types of breast cancer becomes available, the ability to divide patients...... as a versatile biomarker tool for screening, diagnosis, prognosis and monitoring of breast cancer. Standardization of methods and biomarker panels will be required to fully exploit this clinical potential....

  16. Roentgenological structural types of the unaltered breast

    International Nuclear Information System (INIS)

    Kolganova, I.P.; Zal'tsman, I.N.

    1981-01-01

    The authors present a roentgenoanatomical analysis of normal breast specimens and mammograms of 324 healthy women aged 31 to 60. Four roentgenological structural types of the unaltered breast have been singled out: linear-reticular, lamellar-cellular, large focal, and a single polygonal shadow. These structural types were detected in age groups from 31 to 40, from 41 to 50, and from 51 to 60 with various frequency. Each type corresponds to a certain morphological and functional state of the breast. The frequency of the 2nd and 4th types decreases and of the 1st type increases with advancing age [ru

  17. Roentgenological structural types of the unaltered breast

    Energy Technology Data Exchange (ETDEWEB)

    Kolganova, I P; Zal' tsman, I N [Akademiya Meditsinskikh Nauk RSFSR, Moscow. Pervyj Moskovskij Meditsinskij Inst.

    1981-11-01

    The authors present a roentgenoanatomical analysis of normal breast specimens and mammograms of 324 healthy women aged 31 to 60. Four roentgenological structural types of the unaltered breast have been singled out: linear-reticular, lamellar-cellular, large focal, and a single polygonal shadow. These structural types were detected in age groups from 31 to 40, from 41 to 50, and from 51 to 60 with various frequency. Each type corresponds to a certain morphological and functional state of the breast. The frequency of the 2nd and 4th types decreases and of the 1st type increases with advancing age.

  18. Growth and morphogenesis of shoot initials of Douglas fir, Pseudotsuga menziesii (Mirb.) Franco, in vitro

    NARCIS (Netherlands)

    Evers, P.W.

    1984-01-01

    An optimalized method of micropropagation of Douglas fir is described. Seasonal changes were found in optima for nitrate and sucrose in the medium and in the optimum for the light intensity during the culture of shoot initials. Differences in morphogenesis were obtained from shoot initials that had

  19. Diagnosing Breast Cancer Using Protease Fingerprint

    National Research Council Canada - National Science Library

    Chen, Emily

    2002-01-01

    .... An activity-based probe, FP-biotin, was used to analyze the global activity pattern of a class of disease-relevant enzymes, serine hydrolases, in normal epithelial cells and several breast cancer cells...

  20. Local curvature analysis for classifying breast tumors: Preliminary analysis in dedicated breast CT

    International Nuclear Information System (INIS)

    Lee, Juhun; Nishikawa, Robert M.; Reiser, Ingrid; Boone, John M.; Lindfors, Karen K.

    2015-01-01

    Purpose: The purpose of this study is to measure the effectiveness of local curvature measures as novel image features for classifying breast tumors. Methods: A total of 119 breast lesions from 104 noncontrast dedicated breast computed tomography images of women were used in this study. Volumetric segmentation was done using a seed-based segmentation algorithm and then a triangulated surface was extracted from the resulting segmentation. Total, mean, and Gaussian curvatures were then computed. Normalized curvatures were used as classification features. In addition, traditional image features were also extracted and a forward feature selection scheme was used to select the optimal feature set. Logistic regression was used as a classifier and leave-one-out cross-validation was utilized to evaluate the classification performances of the features. The area under the receiver operating characteristic curve (AUC, area under curve) was used as a figure of merit. Results: Among curvature measures, the normalized total curvature (C_T) showed the best classification performance (AUC of 0.74), while the others showed no classification power individually. Five traditional image features (two shape, two margin, and one texture descriptors) were selected via the feature selection scheme and its resulting classifier achieved an AUC of 0.83. Among those five features, the radial gradient index (RGI), which is a margin descriptor, showed the best classification performance (AUC of 0.73). A classifier combining RGI and C_T yielded an AUC of 0.81, which showed similar performance (i.e., no statistically significant difference) to the classifier with the above five traditional image features. Additional comparisons in AUC values between classifiers using different combinations of traditional image features and C_T were conducted. The results showed that C_T was able to replace the other four image features for the classification task. Conclusions: The normalized curvature measure

  1. Transgelin gene is frequently downregulated by promoter DNA hypermethylation in breast cancer.

    Science.gov (United States)

    Sayar, Nilufer; Karahan, Gurbet; Konu, Ozlen; Bozkurt, Betul; Bozdogan, Onder; Yulug, Isik G

    2015-01-01

    CpG hypermethylation in gene promoters is a frequent mechanism of tumor suppressor gene silencing in various types of cancers. It usually occurs at early steps of cancer progression and can be detected easily, giving rise to development of promising biomarkers for both detection and progression of cancer, including breast cancer. 5-aza-2'-deoxycytidine (AZA) is a DNA demethylating and anti-cancer agent resulting in induction of genes suppressed via DNA hypermethylation. Using microarray expression profiling of AZA- or DMSO-treated breast cancer and non-tumorigenic breast (NTB) cells, we identified for the first time TAGLN gene as a target of DNA hypermethylation in breast cancer. TAGLN expression was significantly and frequently downregulated via promoter DNA hypermethylation in breast cancer cells compared to NTB cells, and also in 13/21 (61.9 %) of breast tumors compared to matched normal tissues. Analyses of public microarray methylation data showed that TAGLN was also hypermethylated in 63.02 % of tumors compared to normal tissues; relapse-free survival of patients was worse with higher TAGLN methylation; and methylation levels could discriminate between tumors and healthy tissues with 83.14 % sensitivity and 100 % specificity. Additionally, qRT-PCR and immunohistochemistry experiments showed that TAGLN expression was significantly downregulated in two more independent sets of breast tumors compared to normal tissues and was lower in tumors with poor prognosis. Colony formation was increased in TAGLN silenced NTB cells, while decreased in overexpressing BC cells. TAGLN gene is frequently downregulated by DNA hypermethylation, and TAGLN promoter methylation profiles could serve as a future diagnostic biomarker, with possible clinical impact regarding the prognosis in breast cancer.

  2. Programmed Cell-to-Cell Variability in Ras Activity Triggers Emergent Behaviors during Mammary Epithelial Morphogenesis

    Directory of Open Access Journals (Sweden)

    Jennifer S. Liu

    2012-11-01

    Full Text Available Variability in signaling pathway activation between neighboring epithelial cells can arise from local differences in the microenvironment, noisy gene expression, or acquired genetic changes. To investigate the consequences of this cell-to-cell variability in signaling pathway activation on coordinated multicellular processes such as morphogenesis, we use DNA-programmed assembly to construct three-dimensional MCF10A microtissues that are mosaic for low-level expression of activated H-Ras. We find two emergent behaviors in mosaic microtissues: cells with activated H-Ras are basally extruded or lead motile multicellular protrusions that direct the collective motility of their wild-type neighbors. Remarkably, these behaviors are not observed in homogeneous microtissues in which all cells express the activated Ras protein, indicating that heterogeneity in Ras activity, rather than the total amount of Ras activity, is critical for these processes. Our results directly demonstrate that cell-to-cell variability in pathway activation within local populations of epithelial cells can drive emergent behaviors during epithelial morphogenesis.

  3. Gibberellin influence on the morphogenesis of the moss Bryum argenteum Hedw. in in vitro conditions

    Directory of Open Access Journals (Sweden)

    Sabovljević Aneta

    2010-01-01

    Full Text Available The moss Bryum argenteum Hedw. was treated with gibberellins as well as some inhibitors of gibberellin biosynthesis in order to investigate their influence on B. argenteum morphogenesis. Generally, gibberellins have not been chemically identified in bryophytes, while other groups of classical phytohormones (auxins, cytokinins, abscisic acid and ethylene have been chemically identified in these plants. The in vitro culture of the moss Bryum argenteum was established from sterilized spores. The apical shoots of untreated gametophytes grown in vitro were used to investigate the influence of different substances on secondary protonema and on the growth and multiplication of the gametophytes. B. argenteum reacts differently to the growth regulators applied. Both gibberellins applied in vitro (GA3 and GA7 have a positive effect on B. argenteum morphogenesis. Shoot multiplication was negatively affected by three tested growth retardants (ancymidol, BX-112 and chlorocholine chloride, while these substances did not have such strong effects on the moss protonema development.

  4. Biochemical study on some tumour angiogenesis factors and inhibitors in breast cancer

    International Nuclear Information System (INIS)

    Mohamed, N.M.E

    2007-01-01

    This pilot study was undertaken to investigate the significance of some tumour angiogenic factors (e.g. MMP, ADAM-12 and VEGF) and tumour angiogenic inhibitors (endostatin and TIMP-1) in the aetiology of breast cancer and their responsiveness to cancer treatment as well . We also sought to assess the significance of these angiogenic and antiangiogenic factors in the prognosis and diagnosis of breast cancer. The cases were allocated into five groups: Normal control group (Gr.l), fibroadenoma (Gr.l l), breast cancer (invasive duct carcinoma type grade l l) (Gr.lll) , breast cancer + chemo hormonal therapy (Gr.IV), and breast cancer + chemo hormonal and radiotherapy (Gr.V).Results obtained from this study reported absence of matrix metalloproteinase-9 (MMP-9)activity in the urine and serum of normal subjects and fibroadenoma patients and its significant depression in the urine and serum of breast cancer patients treated with chemo hormonal therapy alone or followed by radiotherapy, compared to breast cancer group as reference. A significantly mild elevation in urinary MMP-2 activity and a non significant change in its activity in the serum of fibroadenoma patients, compared to the dramatic rise in the urine and serum of breast cancer patients were observed

  5. A novel cell binding site in the coiled‐coil domain of laminin involved in capillary morphogenesis

    DEFF Research Database (Denmark)

    Sanz, Laura; García-Bermejo, Laura; Blanco, Francisco J

    2003-01-01

    Recently, we reported the isolation and characterization of an anti‐laminin antibody that modulates the extracellular matrix‐dependent morphogenesis of endothelial cells. Here we use this antibody to precisely map the binding site responsible for mediating this biologically important interaction....

  6. Cell-based multi-parametric model of cleft progression during submandibular salivary gland branching morphogenesis.

    Directory of Open Access Journals (Sweden)

    Shayoni Ray

    Full Text Available Cleft formation during submandibular salivary gland branching morphogenesis is the critical step initiating the growth and development of the complex adult organ. Previous experimental studies indicated requirements for several epithelial cellular processes, such as proliferation, migration, cell-cell adhesion, cell-extracellular matrix (matrix adhesion, and cellular contraction in cleft formation; however, the relative contribution of each of these processes is not fully understood since it is not possible to experimentally manipulate each factor independently. We present here a comprehensive analysis of several cellular parameters regulating cleft progression during branching morphogenesis in the epithelial tissue of an early embryonic salivary gland at a local scale using an on lattice Monte-Carlo simulation model, the Glazier-Graner-Hogeweg model. We utilized measurements from time-lapse images of mouse submandibular gland organ explants to construct a temporally and spatially relevant cell-based 2D model. Our model simulates the effect of cellular proliferation, actomyosin contractility, cell-cell and cell-matrix adhesions on cleft progression, and it was used to test specific hypotheses regarding the function of these parameters in branching morphogenesis. We use innovative features capturing several aspects of cleft morphology and quantitatively analyze clefts formed during functional modification of the cellular parameters. Our simulations predict that a low epithelial mitosis rate and moderate level of actomyosin contractility in the cleft cells promote cleft progression. Raising or lowering levels of contractility and mitosis rate resulted in non-progressive clefts. We also show that lowered cell-cell adhesion in the cleft region and increased cleft cell-matrix adhesions are required for cleft progression. Using a classifier-based analysis, the relative importance of these four contributing cellular factors for effective cleft

  7. SU-F-P-46: Comparative Study Between Two Normalization Prescriptions for Accelerated Partial Breast Irradiation: A Dosimetric Study

    Energy Technology Data Exchange (ETDEWEB)

    Agarwal, P; Sharma, D; Gandhi, A; Binjola, A; Subramani, V; Chander, S [All India Institute of Medical Sciences, New Delhi, New Delhi, Delhi (India)

    2016-06-15

    Purpose: To compare the Accelerated Partial Breast Irradiation (APBI) plan with the normalized basal dose points and 5mm box prescription. Methods: Five patients of APBI were planned twice in Oncentra Master planning TPS (Version 4.3) using TG-43 algorithm. The number of catheters for all the patients was 10 to 16 and implant plane 2 to 3. For planning all catheters were reconstructed. Source loading was done as per HR-CTV contoured. The HR-CTV volume range was from 75cc to 182cc. Plans were normalized in two methods. First all plans were normalized on Basal dose points (PlanA) and second all the plan were normalized on 5mm box (PlanB). The prescription dose (PD) was 35Gy in 10 fractions. All the plans were completely based on normalization and without optimization. Plan evaluation was based on certain parameters coverage Index (CI), dose homogeneity index (DHI), conformity index (COIN), over dose volume index (OI). Results: The average and median of CI for planA was 0.835 and 0.8154, for planB 0.82 and 0.799 respectively. The median and average of DHI for planA was 0.66 and 0.6062, for planB 0.67 and 0.62 respectively. The range of COIN for planA and planB was from 0.58 to 0.65 respectively. The range of OI was from 0.083 to 0.169 for planA and planB. The treatment time in planA was in average 1.13 times more than planB as V150% of HR-CTV in planA was 4–6% more. The ipsilateral lung was getting 30% of PD which was 0.6% to 3.5%. Conclusion: Treatment Planning should be individualized based on implants characteristics. Planning with prescription to basal dose points should be preferred to 5mm box prescription, in order to achieve better DHI and less treatment time.

  8. Role of Estrogen Receptor Signaling in Breast Cancer Metastasis

    International Nuclear Information System (INIS)

    Roy, S.S.; Vadlamudi, R.K.

    2012-01-01

    Metastatic breast cancer is a life-threatening stage of cancer and is the leading cause of death in advanced breast cancer patients. Estrogen signaling and the estrogen receptor (ER) are implicated in breast cancer progression, and the majority of the human breast cancers start out as estrogen dependent. Accumulating evidence suggests that ER signaling is complex, involving coregulatory proteins and extranuclear actions. ER-coregualtory proteins are tightly regulated under normal conditions with miss expression primarily reported in cancer. Deregulation of ER coregualtors or ER extranuclear signaling has potential to promote metastasis in ER-positive breast cancer cells. This review summarizes the emerging role of ER signaling in promoting metastasis of breast cancer cells, discusses the molecular mechanisms by which ER signaling contributes to metastasis, and explores possible therapeutic targets to block ER-driven metastasis

  9. Gene expression profiling of human breast tissue samples using SAGE-Seq.

    Science.gov (United States)

    Wu, Zhenhua Jeremy; Meyer, Clifford A; Choudhury, Sibgat; Shipitsin, Michail; Maruyama, Reo; Bessarabova, Marina; Nikolskaya, Tatiana; Sukumar, Saraswati; Schwartzman, Armin; Liu, Jun S; Polyak, Kornelia; Liu, X Shirley

    2010-12-01

    We present a powerful application of ultra high-throughput sequencing, SAGE-Seq, for the accurate quantification of normal and neoplastic mammary epithelial cell transcriptomes. We develop data analysis pipelines that allow the mapping of sense and antisense strands of mitochondrial and RefSeq genes, the normalization between libraries, and the identification of differentially expressed genes. We find that the diversity of cancer transcriptomes is significantly higher than that of normal cells. Our analysis indicates that transcript discovery plateaus at 10 million reads/sample, and suggests a minimum desired sequencing depth around five million reads. Comparison of SAGE-Seq and traditional SAGE on normal and cancerous breast tissues reveals higher sensitivity of SAGE-Seq to detect less-abundant genes, including those encoding for known breast cancer-related transcription factors and G protein-coupled receptors (GPCRs). SAGE-Seq is able to identify genes and pathways abnormally activated in breast cancer that traditional SAGE failed to call. SAGE-Seq is a powerful method for the identification of biomarkers and therapeutic targets in human disease.

  10. Background enhancement in breast MR: Correlation with breast density in mammography and background echotexture in ultrasound

    International Nuclear Information System (INIS)

    Ko, Eun Sook; Lee, Byung Hee; Choi, Hye Young; Kim, Rock Bum; Noh, Woo-Chul

    2011-01-01

    Objective: This study aimed to determine whether background enhancement on MR was related to mammographic breast density or ultrasonographic background echotexture in premenopausal and postmenopausal women. Materials and methods: We studied 142 patients (79 premenopausal, 63 postmenopausal) who underwent mammography, ultrasonography, and breast MR. We reviewed the mammography for overall breast density of the contralateral normal breast according to the four-point scale of the BI-RADS classification. Ultrasound findings were classified as homogeneous or heterogeneous background echotexture according to the BI-RADS lexicon. We rated background enhancement on a contralateral breast MR into four categories based on subtraction images: absent, mild, moderate, and marked. All imaging findings were interpreted independently by two readers without knowledge of menstrual status, imaging findings of other modalities. Results: There were significant differences between the premenopausal and postmenopausal group in distribution of mammographic breast density, ultrasonographic background echotexture, and degree of background enhancement. Regarding the relationship between mammographic density and background enhancement, there was no significant correlation. There was significant relationship between ultrasonographic background echotexture and background enhancement in both premenopausal and postmenopausal groups. Conclusion: There is a significant correlation between ultrasonographic background echotexture and background enhancement in MR regardless of menopausal status. Interpreting breast MR, or scheduling for breast MR of women showing heterogeneous background echotexture needs more caution.

  11. [Ectopic breast fibroadenoma. Case report].

    Science.gov (United States)

    Senatore, G; Zanotti, S; Cambrini, P; Montroni, I; Pellegrini, A; Montanari, E; Santini, D; Taffurelli, M

    2010-03-01

    Among the rare anomalies of the breast development, polythelia is the most common, between 1% and 5% of women and men present supernumerary nipples. Polymastia, usually presenting as ectopic breast tissue without areola-nipple complex, is seen mostly along the milk line, extending from the axilla to the pubic region. Ectopic breast tissue is functionally analogous to mammary gland and it is subjected to the same alterations and diseases, whether benign or malignant, that affect normal breast tissue. We report the case of a 21 years-old female evaluated by the medical staff after founding a solid nodular mass by suspect axillary lymphadenopathy. Differential diagnosis with lymphoma is the major problem in these cases. The mass was removed and the intraoperative histological examination showed fibroadenoma in axillary supernumerary breast. Presence of ectopic breast tissue is a rare condition; development of benign mass or malignant degeneration is possible, but it is very unusual. In case of polymastia diagnosis is simple; in case of isolated nodule, without local inflammation or infection, there are greater difficulties. Ultrasonography is diagnostic in case of breast fibroadenoma, but it might be inadequate in ectopic localizations owing to the shortage of mammary tissue around the mass. Preoperative diagnosis is important to plan an adequate surgical treatment; lumpectomy is indicated in case of benign tissue; in case of malignancy, therapy is based on the standard treatment used for breast cancer (surgery, chemotherapy and radiation therapy).

  12. The neurotensin receptor-1 pathway contributes to human ductal breast cancer progression.

    Science.gov (United States)

    Dupouy, Sandra; Viardot-Foucault, Véronique; Alifano, Marco; Souazé, Frédérique; Plu-Bureau, Geneviève; Chaouat, Marc; Lavaur, Anne; Hugol, Danielle; Gespach, Christian; Gompel, Anne; Forgez, Patricia

    2009-01-01

    The neurotensin (NTS) and its specific high affinity G protein coupled receptor, the NT1 receptor (NTSR1), are considered to be a good candidate for one of the factors implicated in neoplastic progression. In breast cancer cells, functionally expressed NT1 receptor coordinates a series of transforming functions including cellular migration and invasion. we investigated the expression of NTS and NTSR1 in normal human breast tissue and in invasive ductal breast carcinomas (IDCs) by immunohistochemistry and RT-PCR. NTS is expressed and up-regulated by estrogen in normal epithelial breast cells. NTS is also found expressed in the ductal and invasive components of IDCs. The high expression of NTSR1 is associated with the SBR grade, the size of the tumor, and the number of metastatic lymph nodes. Furthermore, the NTSR1 high expression is an independent factor of prognosis associated with the death of patients. these data support the activation of neurotensinergic deleterious pathways in breast cancer progression.

  13. THE EXPRESSION AND CLINICAL VALUE OF APOPTOSIS CONTROL GENE Bcl-2 AND Bax IN BREAST CANCER

    Institute of Scientific and Technical Information of China (English)

    ZHENG Jun; YAO Zhen-xiang; ZHANG Jing

    1999-01-01

    Objective: To study the expression and clinical value of apoptosis control gene bcl-2 and bax in breast cancer.Methods: Protein bax and bcl-2 in 41 breast cancers obtained from operations in our hospital in 1996 were detected using ABC immunohistochemical stain assay and compared with 10 cases with normal breast tissues.Results: The positive rate of bax in normal breast tissue was 90% and in breast cancer was 59%, with a significant statistical difference between them (P<0.05), but there was no statistical difference in bcl-2 protein expression. Among the 41 breast cancer, the group with lymph node metastasis (21 cases) had obviously low bax expression (43%) and high bcl-2 expression (76%), showing significant difference to the group without lymph node metastasis (P<0.05).Conclusion: The antiapoptosis function of bcl-2 was stronger than bax in breast cancer. Protein bax and bcl-2 assay may be useful in understanding the biological behaviors of breast cancer.

  14. Delineating an Epigenetic Continuum for Initiation, Transformation and Progression to Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Kang Mei; Stephen, Josena K. [Department of Otolaryngology/Head and Neck Surgery, Henry Ford Hospital, 1 Ford Place, 1D, Detroit, MI 48202 (United States); Raju, Usha [Department of Pathology, Henry Ford Hospital, Detroit, 1 Ford Place, 1D, Detroit, MI 48202 (United States); Worsham, Maria J., E-mail: mworsha1@hfhs.org [Department of Otolaryngology/Head and Neck Surgery, Henry Ford Hospital, 1 Ford Place, 1D, Detroit, MI 48202 (United States)

    2011-03-29

    Aberrant methylation of promoter CpG islands is a hallmark of human cancers and is an early event in carcinogenesis. We examined whether promoter hypermethylation contributes to the pathogenesis of benign breast lesions along a progression continuum to invasive breast cancer. The exploratory study cohort comprised 17 breast cancer patients with multiple benign and/or in situ lesions concurrently present with invasive carcinoma within a tumor biopsy. DNA from tumor tissue, normal breast epithelium when present, benign lesions (fibroadenoma, hyperplasia, papilloma, sclerosing adenosis, apocrine metaplasia, atypical lobular hyperplasia or atypical ductal hyperplasia), and in situ lesions of lobular carcinoma and ductal carcinoma were interrogated for promoter methylation status in 22 tumor suppressor genes using the multiplex ligation-dependent probe amplification assay (MS-MLPA). Methylation specific PCR was performed to confirm hypermethylation detected by MS-MLPA. Promoter methylation was detected in 11/22 tumor suppressor genes in 16/17 cases. Hypermethylation of RASSF1 was most frequent, present in 14/17 cases, followed by APC in 12/17, and GSTP1 in 9/17 cases with establishment of an epigenetic monocloncal progression continuum to invasive breast cancer. Hypermethylated promoter regions in normal breast epithelium, benign, and premalignant lesions within the same tumor biopsy implicate RASSF1, APC, GSTP1, TIMP3, CDKN2B, CDKN2A, ESR1, CDH13, RARB, CASP8, and TP73 as early events. DNA hypermethylation underlies the pathogenesis of step-wise transformation along a monoclonal continuum from normal to preneoplasia to invasive breast cancer.

  15. Delineating an Epigenetic Continuum for Initiation, Transformation and Progression to Breast Cancer

    International Nuclear Information System (INIS)

    Chen, Kang Mei; Stephen, Josena K.; Raju, Usha; Worsham, Maria J.

    2011-01-01

    Aberrant methylation of promoter CpG islands is a hallmark of human cancers and is an early event in carcinogenesis. We examined whether promoter hypermethylation contributes to the pathogenesis of benign breast lesions along a progression continuum to invasive breast cancer. The exploratory study cohort comprised 17 breast cancer patients with multiple benign and/or in situ lesions concurrently present with invasive carcinoma within a tumor biopsy. DNA from tumor tissue, normal breast epithelium when present, benign lesions (fibroadenoma, hyperplasia, papilloma, sclerosing adenosis, apocrine metaplasia, atypical lobular hyperplasia or atypical ductal hyperplasia), and in situ lesions of lobular carcinoma and ductal carcinoma were interrogated for promoter methylation status in 22 tumor suppressor genes using the multiplex ligation-dependent probe amplification assay (MS-MLPA). Methylation specific PCR was performed to confirm hypermethylation detected by MS-MLPA. Promoter methylation was detected in 11/22 tumor suppressor genes in 16/17 cases. Hypermethylation of RASSF1 was most frequent, present in 14/17 cases, followed by APC in 12/17, and GSTP1 in 9/17 cases with establishment of an epigenetic monocloncal progression continuum to invasive breast cancer. Hypermethylated promoter regions in normal breast epithelium, benign, and premalignant lesions within the same tumor biopsy implicate RASSF1, APC, GSTP1, TIMP3, CDKN2B, CDKN2A, ESR1, CDH13, RARB, CASP8, and TP73 as early events. DNA hypermethylation underlies the pathogenesis of step-wise transformation along a monoclonal continuum from normal to preneoplasia to invasive breast cancer

  16. The hallmarks of breast cancer by Raman spectroscopy

    Science.gov (United States)

    Abramczyk, H.; Surmacki, J.; Brożek-Płuska, B.; Morawiec, Z.; Tazbir, M.

    2009-04-01

    This paper presents new biological results on ex vivo breast tissue based on Raman spectroscopy and demonstrates its power as diagnostic tool with the key advantage in breast cancer research. The results presented here demonstrate the ability of Raman spectroscopy to accurately characterize cancer tissue and distinguish between normal, malignant and benign types. The goal of the paper is to develop the diagnostic ability of Raman spectroscopy in order to find an optical marker of cancer in the breast tissue. Applications of Raman spectroscopy in breast cancer research are in the early stages of development in the world. To the best of our knowledge, this paper is one of the most statistically reliable reports (1100 spectra, 99 patients) on Raman spectroscopy-based diagnosis of breast cancers among the world women population.

  17. Significance of β-tubulin Expression in Breast Premalignant Lesions and Carcinomas

    Institute of Scientific and Technical Information of China (English)

    Yuxia Gao; Yun Niu; Xiumin Ding; Yong Yu

    2008-01-01

    OBJECTIVE To explore the expression of β-tubulin in premalignant lesions and carcinomas of the breast, and to observe the relationship of its expression with breast cancer pathological features.METHODS The expression of β-tubulin was detected immunohistochemically in 50 specimens of premalignant lesions of the breast (ADH and Peri-PM with ADH), 50 specimens of breast in situ ductal carcinomas (DCIS), and 50 specimens of invasive ductal carcinomas (IDC). Thirty specimens of normal breast tissues served as a control group.RESULTS Immunohistochemical analysis showed that: the differences among the 4 groups (normal breast tissues, breast premalignant lesions, DCIS and IDC, P < 0.05) were significant,and there were also statistically significant differences between any 2 groups (P < 0.05) except for the β-tubulin positive expression comparing DCIS versus IDC (P > 0.05). In addition, β-tubulin was expressed at a higher level in Peri-PM with ADH compared to ADH (P < 0.05). Following the degree of breast epithelial hyperplasia involved, and its development into carcinoma, the β-tubulin positive expression displayed an elevating tendency.We also found a significant positive relationship of β-tubulin expression with lymph node metastasis (P < 0.05), but no significant correlation with histological grading and nuclear grade.CONCLUSION Centrosome defects may be an early event in the development of breast cancer and they can also promote tumor progression. Studies of aberrations of centrosomal proteins provide a new way to explore the mechanism of breast tumorigenesis.

  18. Investigation of Epstein-Barr virus DNA in formalin-fixed and paraffin- embedded breast cancer tissues.

    Science.gov (United States)

    Kalkan, Ahmet; Ozdarendeli, Aykut; Bulut, Yasemin; Yekeler, Hayrettin; Cobanoglu, Bengu; Doymaz, Mehmet Z

    2005-01-01

    To investigate etiological role of Epstein-Barr virus (EBV) DNA in breast cancer. The presence of EBV DNA in 57 breast cancer tissues was investigated with a sensitive PCR assay. The breast cancer tissues were from invasive ductular (n=28), lobular (n=20) and other miscellaneous carcinomas (n=9). Tissues from normal breasts and patients with various benign breast diseases (n=55): fibrocystic disease (n=34), fibroadenoma (n=16), hyperplasia, and granulomatous mastitis (n=5), were used as control samples. EBV DNA was detected in 13 (23%) cancerous tissues (7 ductular, 4 lobular, 2 other carcinoma) and 19 (35%) in the control tissues. The difference between EBV presence in malignant and benign tissues was not statistically significant (p>0.05). The presence of EBV DNA was detected almost equally in both breast cancer and normal tissues, which indicates no etiological role for EBV in breast cancer. We suggest further etiological studies. Copyright (c) 2005 S. Karger AG, Basel.

  19. Feeling like me again: a grounded theory of the role of breast reconstruction surgery in self-image.

    Science.gov (United States)

    McKean, L N; Newman, E F; Adair, P

    2013-07-01

    The present study aimed to develop a theoretical understanding of the role of breast reconstruction in women's self-image. Semi-structured interviews were conducted with 10 women from breast cancer support groups who had undergone breast reconstruction surgery. A grounded theory methodology was used to explore their experiences. The study generated a model of 'breast cancer, breast reconstruction and self-image', with a core category entitled 'feeling like me again' and two principal categories of 'normal appearance' and 'normal life'. A further two main categories, 'moving on' and 'image of sick person' were generated. The results indicated a role of breast reconstruction in several aspects of self-image including the restoration of pre-surgery persona, which further promoted adjustment. © 2013 John Wiley & Sons Ltd.

  20. A Breast Tissue Protein Expression Profile Contributing to Early Parity-Induced Protection Against Breast Cancer

    Directory of Open Access Journals (Sweden)

    Christina Marie Gutierrez

    2015-11-01

    Full Text Available Background/Aims: Early parity reduces breast cancer risk, whereas, late parity and nulliparity increase breast cancer risk. Despite substantial efforts to understand the protective effects of early parity, the precise molecular circuitry responsible for these changes is not yet fully defined. Methods: Here, we have conducted the first study assessing protein expression profiles in normal breast tissue of healthy early parous, late parous, and nulliparous women. Breast tissue biopsies were obtained from 132 healthy parous and nulliparous volunteers. These samples were subjected to global protein expression profiling and immunohistochemistry. GeneSpring and MetaCore bioinformatics analysis software were used to identify protein expression profiles associated with early parity (low risk versus late/nulliparity (high risk. Results: Early parity reduces expression of key proteins involved in mitogenic signaling pathways in breast tissue through down regulation of EGFR1/3, ESR1, AKT1, ATF, Fos, and SRC. Early parity is also characterized by greater genomic stability and reduced tissue inflammation based on differential expression of aurora kinases, p53, RAD52, BRCA1, MAPKAPK-2, ATF-1, ICAM1, and NF-kappaB compared to late and nulli parity. Conclusions: Early parity reduces basal cell proliferation in breast tissue, which translates to enhanced genomic stability, reduced cellular stress/inflammation, and thus reduced breast cancer risk.

  1. The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway

    Directory of Open Access Journals (Sweden)

    Zakia A. Abdelhamed

    2015-06-01

    Full Text Available Ciliopathies are a group of developmental disorders that manifest with multi-organ anomalies. Mutations in TMEM67 (MKS3 cause a range of human ciliopathies, including Meckel-Gruber and Joubert syndromes. In this study we describe multi-organ developmental abnormalities in the Tmem67tm1Dgen/H1 knockout mouse that closely resemble those seen in Wnt5a and Ror2 knockout mice. These include pulmonary hypoplasia, ventricular septal defects, shortening of the body longitudinal axis, limb abnormalities, and cochlear hair cell stereociliary bundle orientation and basal body/kinocilium positioning defects. The basal body/kinocilium complex was often uncoupled from the hair bundle, suggesting aberrant basal body migration, although planar cell polarity and apical planar asymmetry in the organ of Corti were normal. TMEM67 (meckelin is essential for phosphorylation of the non-canonical Wnt receptor ROR2 (receptor-tyrosine-kinase-like orphan receptor 2 upon stimulation with Wnt5a-conditioned medium. ROR2 also colocalises and interacts with TMEM67 at the ciliary transition zone. Additionally, the extracellular N-terminal domain of TMEM67 preferentially binds to Wnt5a in an in vitro binding assay. Cultured lungs of Tmem67 mutant mice failed to respond to stimulation of epithelial branching morphogenesis by Wnt5a. Wnt5a also inhibited both the Shh and canonical Wnt/β-catenin signalling pathways in wild-type embryonic lung. Pulmonary hypoplasia phenotypes, including loss of correct epithelial branching morphogenesis and cell polarity, were rescued by stimulating the non-canonical Wnt pathway downstream of the Wnt5a-TMEM67-ROR2 axis by activating RhoA. We propose that TMEM67 is a receptor that has a main role in non-canonical Wnt signalling, mediated by Wnt5a and ROR2, and normally represses Shh signalling. Downstream therapeutic targeting of the Wnt5a-TMEM67-ROR2 axis might, therefore, reduce or prevent pulmonary hypoplasia in ciliopathies and other congenital

  2. YKL-40 expression in benign and malignant lesions of the breast: a methodologic study

    DEFF Research Database (Denmark)

    Roslind, Anne; Johansen, Julia S; Junker, Nanna

    2007-01-01

    as well as in benign and malignant breast lesions. The presence of YKL-40 in breast tissue was verified by in situ hybridization and protein extraction procedures. An immunohistochemical method was developed and 4 different antibodies directed against YKL-40 were tested. Ten patients with normal breast...

  3. Study of human breast tissues biochemistry by FT-Raman spectroscopy

    Science.gov (United States)

    Bitar, Renata A.; Jara, Walter Andres A.; Netto, Mário M.; Martinho, Herculano; Ramalho, Leandra Náira Z.; Martin, Airton A.

    2006-02-01

    In this work we employ the Fourier Transform Raman Spectroscopy to study the human breast tissues, both normal and pathological. In the present study we analyze 194 Raman spectra from breast tissues that were separated into 9 groups according to their corresponding histopathological diagnosis, which are as follows: Normal breast tissue, Fibrocystic condition, In Situ Duct Carcinoma, In Situ Duct Carcinoma with Necrosis, Infiltrating Duct Carcinoma, Infiltrating Duct Inflammatory Carcinoma, Infiltrating Duct Medullar Carcinoma, Infiltrating Duct Colloid Carcinoma, and Infiltrating Lobule Carcinoma. We found a strong lipids Raman band, and this structure was identified as abundant in the normal breast tissue spectra. The primary structure of proteins was identified through the shift of the amine acids bands. The identification of the secondary structure of proteins occurred through the peptide bands (Amide I and Amide III). In relation to the carbohydrates, the spectra of duct infiltrating colloid carcinoma, fibrocystic condition, and infiltrating duct carcinoma have been compared and identified. We observed an increase in the intensity of the 800-1200 cm -1 spectral region. This fact could indicate the presence of liquid cystic. We also notice alterations in the peaks in the region of 500 to 600 cm -1 and 2000 to 2100 cm -1 that may suggest changes in the nucleic acids of the cells.

  4. Correlation of in vitro lymphocyte radiosensitivity and gene expression with late normal tissue reactions following curative radiotherapy for breast cancer

    International Nuclear Information System (INIS)

    Finnon, Paul; Kabacik, Sylwia; MacKay, Alan; Raffy, Claudine; A’Hern, Roger; Owen, Roger; Badie, Christophe; Yarnold, John; Bouffler, Simon

    2012-01-01

    Background and purpose: Identification of mechanisms of late normal tissue responses to curative radiotherapy that discriminate individuals with marked or mild responses would aid response prediction. This study aimed to identify differences in gene expression, apoptosis, residual DNA double strand breaks and chromosomal damage after in vitro irradiation of lymphocytes in a series of patients with marked (31 cases) or mild (28 controls) late adverse reaction to adjuvant breast radiotherapy. Materials and methods: Gene expression arrays, residual γH2AX, apoptosis, G2 chromosomal radiosensitivity and G0 micronucleus assay were used to compare case and control lymphocyte radiation responses. Results: Five hundred and thirty genes were up-regulated and 819 down-regulated by ionising radiation. Irradiated samples were identified with an overall cross-validated error rate of 3.4%. Prediction analyses to classify cases and controls using unirradiated (0 Gy), irradiated (4 Gy) or radiation response (4–0 Gy) expression profiles correctly identified samples with, respectively, 25%, 22% or 18.5% error rates. Significant inter-sample variation was observed for all cellular endpoints but cases and controls could not be distinguished. Conclusions: Variation in lymphocyte radiosensitivity does not necessarily correlate with normal tissue response to radiotherapy. Gene expression analysis can predict of radiation exposure and may in the future help prediction of normal tissue radiosensitivity.

  5. Collective cell migration drives morphogenesis of the kidney nephron.

    Directory of Open Access Journals (Sweden)

    Aleksandr Vasilyev

    2009-01-01

    Full Text Available Tissue organization in epithelial organs is achieved during development by the combined processes of cell differentiation and morphogenetic cell movements. In the kidney, the nephron is the functional organ unit. Each nephron is an epithelial tubule that is subdivided into discrete segments with specific transport functions. Little is known about how nephron segments are defined or how segments acquire their distinctive morphology and cell shape. Using live, in vivo cell imaging of the forming zebrafish pronephric nephron, we found that the migration of fully differentiated epithelial cells accounts for both the final position of nephron segment boundaries and the characteristic convolution of the proximal tubule. Pronephric cells maintain adherens junctions and polarized apical brush border membranes while they migrate collectively. Individual tubule cells exhibit basal membrane protrusions in the direction of movement and appear to establish transient, phosphorylated Focal Adhesion Kinase-positive adhesions to the basement membrane. Cell migration continued in the presence of camptothecin, indicating that cell division does not drive migration. Lengthening of the nephron was, however, accompanied by an increase in tubule cell number, specifically in the most distal, ret1-positive nephron segment. The initiation of cell migration coincided with the onset of fluid flow in the pronephros. Complete blockade of pronephric fluid flow prevented cell migration and proximal nephron convolution. Selective blockade of proximal, filtration-driven fluid flow shifted the position of tubule convolution distally and revealed a role for cilia-driven fluid flow in persistent migration of distal nephron cells. We conclude that nephron morphogenesis is driven by fluid flow-dependent, collective epithelial cell migration within the confines of the tubule basement membrane. Our results establish intimate links between nephron function, fluid flow, and morphogenesis.

  6. Distinct subsets of Eve-positive pericardial cells stabilise cardiac outflow and contribute to Hox gene-triggered heart morphogenesis in Drosophila.

    Science.gov (United States)

    Zmojdzian, Monika; de Joussineau, Svetlana; Da Ponte, Jean Philippe; Jagla, Krzysztof

    2018-01-17

    The Drosophila heart, composed of discrete subsets of cardioblasts and pericardial cells, undergoes Hox-triggered anterior-posterior morphogenesis, leading to a functional subdivision into heart proper and aorta, with its most anterior part forming a funnel-shaped cardiac outflow. Cardioblasts differentiate into Tin-positive 'working myocytes' and Svp-expressing ostial cells. However, developmental fates and functions of heart-associated pericardial cells remain elusive. Here, we show that the pericardial cells that express the transcription factor Even Skipped adopt distinct fates along the anterior-posterior axis. Among them, the most anterior Antp-Ubx-AbdA - negative cells form a novel cardiac outflow component we call the outflow hanging structure, whereas the Antp-expressing cells differentiate into wing heart precursors. Interestingly, Hox gene expression in the Even Skipped-positive cells not only underlies their antero-posterior diversification, but also influences heart morphogenesis in a non-cell-autonomous way. In brief, we identify a new cardiac outflow component derived from a subset of Even Skipped-expressing cells that stabilises the anterior heart tip, and demonstrate non-cell-autonomous effects of Hox gene expression in the Even Skipped-positive cells on heart morphogenesis. © 2018. Published by The Company of Biologists Ltd.

  7. The impact of dose calculation algorithms on partial and whole breast radiation treatment plans

    International Nuclear Information System (INIS)

    Basran, Parminder S; Zavgorodni, Sergei; Berrang, Tanya; Olivotto, Ivo A; Beckham, Wayne

    2010-01-01

    This paper compares the calculated dose to target and normal tissues when using pencil beam (PBC), superposition/convolution (AAA) and Monte Carlo (MC) algorithms for whole breast (WBI) and accelerated partial breast irradiation (APBI) treatment plans. Plans for 10 patients who met all dosimetry constraints on a prospective APBI protocol when using PBC calculations were recomputed with AAA and MC, keeping the monitor units and beam angles fixed. Similar calculations were performed for WBI plans on the same patients. Doses to target and normal tissue volumes were tested for significance using the paired Student's t-test. For WBI plans the average dose to target volumes when using PBC calculations was not significantly different than AAA calculations, the average PBC dose to the ipsilateral breast was 10.5% higher than the AAA calculations and the average MC dose to the ipsilateral breast was 11.8% lower than the PBC calculations. For ABPI plans there were no differences in dose to the planning target volume, ipsilateral breast, heart, ipsilateral lung, or contra-lateral lung. Although not significant, the maximum PBC dose to the contra-lateral breast was 1.9% higher than AAA and the PBC dose to the clinical target volume was 2.1% higher than AAA. When WBI technique is switched to APBI, there was significant reduction in dose to the ipsilateral breast when using PBC, a significant reduction in dose to the ipsilateral lung when using AAA, and a significant reduction in dose to the ipsilateral breast and lung and contra-lateral lung when using MC. There is very good agreement between PBC, AAA and MC for all target and most normal tissues when treating with APBI and WBI and most of the differences in doses to target and normal tissues are not clinically significant. However, a commonly used dosimetry constraint, as recommended by the ASTRO consensus document for APBI, that no point in the contra-lateral breast volume should receive >3% of the prescribed dose needs

  8. 99MTC Alpha-Fetoprotein: A Novel, Specific Agent for the Detection of Human Breast Cancer

    National Research Council Canada - National Science Library

    Line, Bruce

    1998-01-01

    .... We have demonstrated that technetium-99m radiolabeled human alpha-fetoprotein (99mTc AFP) localizes in human breast cancer cells in-vivo, most likely concentrating in breast cancer cells due to a specific receptor not found in normal adult breast tissue...

  9. 99MTC Alpha-Fetoprotein: A Novel, Specific Agent for the Detection of Human Breast Cancer

    National Research Council Canada - National Science Library

    Line, Bruce

    1999-01-01

    .... We have demonstrated that technetium-99m radiolabeled human alpha-fetoprotein (99mTc AFP) localizes in human breast cancer cells in-vivo, most likely concentrating in breast cancer cells due to a specific receptor not found in normal adult breast tissue...

  10. Breast cancer detection using time reversal

    Science.gov (United States)

    Sheikh Sajjadieh, Mohammad Hossein

    Breast cancer is the second leading cause of cancer death after lung cancer among women. Mammography and magnetic resonance imaging (MRI) have certain limitations in detecting breast cancer, especially during its early stage of development. A number of studies have shown that microwave breast cancer detection has potential to become a successful clinical complement to the conventional X-ray mammography. Microwave breast imaging is performed by illuminating the breast tissues with an electromagnetic waveform and recording its reflections (backscatters) emanating from variations in the normal breast tissues and tumour cells, if present, using an antenna array. These backscatters, referred to as the overall (tumour and clutter) response, are processed to estimate the tumour response, which is applied as input to array imaging algorithms used to estimate the location of the tumour. Due to changes in the breast profile over time, the commonly utilized background subtraction procedures used to estimate the target (tumour) response in array processing are impractical for breast cancer detection. The thesis proposes a new tumour estimation algorithm based on a combination of the data adaptive filter with the envelope detection filter (DAF/EDF), which collectively do not require a training step. After establishing the superiority of the DAF/EDF based approach, the thesis shows that the time reversal (TR) array imaging algorithms outperform their conventional conterparts in detecting and localizing tumour cells in breast tissues at SNRs ranging from 15 to 30dB.

  11. Mechanical growth and morphogenesis of seashells

    KAUST Repository

    Moulton, D.E.

    2012-10-01

    Seashells grow through the local deposition of mass along the aperture. Many mathematical descriptions of the shapes of shells have been provided over the years, and the basic logarithmic coiling seen in mollusks can be simulated with few parameters. However, the developmental mechanisms underlying shell coiling are largely not understood and the ubiquitous presence of ornamentation such as ribs, tubercles, or spines presents yet another level of difficulty. Here we develop a general model for shell growth based entirely on the local geometry and mechanics of the aperture and mantle. This local description enables us to efficiently describe both arbitrary growth velocities and the evolution of the shell aperture itself. We demonstrate how most shells can be simulated within this framework. We then turn to the mechanics underlying the shell morphogenesis, and develop models for the evolution of the aperture. We demonstrate that the elastic response of the mantle during shell deposition provides a natural mechanism for the formation of three-dimensional ornamentation in shells. © 2012 Elsevier Ltd.

  12. Defining the cellular precursors to human breast cancer

    Science.gov (United States)

    Keller, Patricia J.; Arendt, Lisa M.; Skibinski, Adam; Logvinenko, Tanya; Klebba, Ina; Dong, Shumin; Smith, Avi E.; Prat, Aleix; Perou, Charles M.; Gilmore, Hannah; Schnitt, Stuart; Naber, Stephen P.; Garlick, Jonathan A.; Kuperwasser, Charlotte

    2012-01-01

    Human breast cancers are broadly classified based on their gene-expression profiles into luminal- and basal-type tumors. These two major tumor subtypes express markers corresponding to the major differentiation states of epithelial cells in the breast: luminal (EpCAM+) and basal/myoepithelial (CD10+). However, there are also rare types of breast cancers, such as metaplastic carcinomas, where tumor cells exhibit features of alternate cell types that no longer resemble breast epithelium. Until now, it has been difficult to identify the cell type(s) in the human breast that gives rise to these various forms of breast cancer. Here we report that transformation of EpCAM+ epithelial cells results in the formation of common forms of human breast cancer, including estrogen receptor-positive and estrogen receptor-negative tumors with luminal and basal-like characteristics, respectively, whereas transformation of CD10+ cells results in the development of rare metaplastic tumors reminiscent of the claudin-low subtype. We also demonstrate the existence of CD10+ breast cells with metaplastic traits that can give rise to skin and epidermal tissues. Furthermore, we show that the development of metaplastic breast cancer is attributable, in part, to the transformation of these metaplastic breast epithelial cells. These findings identify normal cellular precursors to human breast cancers and reveal the existence of a population of cells with epidermal progenitor activity within adult human breast tissues. PMID:21940501

  13. Conjugated linoleic acid induces apoptosis through estrogen receptor alpha in human breast tissue

    International Nuclear Information System (INIS)

    Wang, Li-Shu; Huang, Yi-Wen; Liu, Suling; Yan, Pearlly; Lin, Young C

    2008-01-01

    Conjugated linoleic acid (CLA), a naturally occurring fatty acid found in ruminant products such as milk and beef, has been shown to possess anti-cancer activities in in vivo animal models and in vitro cell culture systems. In human breast cancer, the overall duration of estrogen exposure is the most important risk factor for developing estrogen-responsive breast cancer. Accordingly, it has been suggested that estrogen exposure reduces apoptosis through the up-regulation of the anti-apoptosis protein, Bcl-2. Bcl-2, an anti-apoptotic protein, regulates apoptosis and plays a crucial role in the development and growth regulation of normal and cancerous cells. Our research interest is to examine the effects of CLA on the induction of apoptosis in human breast tissues. The localization of Bcl-2 in both normal and cancerous human breast tissues was determined by immunohistochemical staining and the Bcl-2 protein expression was tested by western blot analysis. Co-culture of epithelial cells and stromal cells was carried out in the presence or absence of CLA to evaluate apoptosis in the context of a cell-cell interaction. The results showed that both normal and cancerous breast tissues were positive for Bcl-2 staining, which was higher overall in mammary ducts but very low in the surrounding stromal compartment. Interestingly, by quantifying the western blot data, basal Bcl-2 protein levels were higher in normal breast epithelial cells than in cancerous epithelial cells. Furthermore, treatment with 17β-estradiol (E 2 ) stimulated growth and up-regulated Bcl-2 expression in estrogen responsive breast epithelial cells; however, these carcinogenic effects were diminished by either CLA or 4-Hydroxytamoxifen (Tam) and were suppressed further by the combination of CLA and Tam. In both one cell type cultured and co-culture systems, CLA induced cell apoptosis in ERα transfected MDA-MB-231 cells but not in the wild type MDA-MB-231 cells. These data, therefore, demonstrate that

  14. Conjugated linoleic acid induces apoptosis through estrogen receptor alpha in human breast tissue

    Directory of Open Access Journals (Sweden)

    Liu Suling

    2008-07-01

    Full Text Available Abstract Background Conjugated linoleic acid (CLA, a naturally occurring fatty acid found in ruminant products such as milk and beef, has been shown to possess anti-cancer activities in in vivo animal models and in vitro cell culture systems. In human breast cancer, the overall duration of estrogen exposure is the most important risk factor for developing estrogen-responsive breast cancer. Accordingly, it has been suggested that estrogen exposure reduces apoptosis through the up-regulation of the anti-apoptosis protein, Bcl-2. Bcl-2, an anti-apoptotic protein, regulates apoptosis and plays a crucial role in the development and growth regulation of normal and cancerous cells. Our research interest is to examine the effects of CLA on the induction of apoptosis in human breast tissues. Methods The localization of Bcl-2 in both normal and cancerous human breast tissues was determined by immunohistochemical staining and the Bcl-2 protein expression was tested by western blot analysis. Co-culture of epithelial cells and stromal cells was carried out in the presence or absence of CLA to evaluate apoptosis in the context of a cell-cell interaction. Results The results showed that both normal and cancerous breast tissues were positive for Bcl-2 staining, which was higher overall in mammary ducts but very low in the surrounding stromal compartment. Interestingly, by quantifying the western blot data, basal Bcl-2 protein levels were higher in normal breast epithelial cells than in cancerous epithelial cells. Furthermore, treatment with 17β-estradiol (E2 stimulated growth and up-regulated Bcl-2 expression in estrogen responsive breast epithelial cells; however, these carcinogenic effects were diminished by either CLA or 4-Hydroxytamoxifen (Tam and were suppressed further by the combination of CLA and Tam. In both one cell type cultured and co-culture systems, CLA induced cell apoptosis in ERα transfected MDA-MB-231 cells but not in the wild type MDA

  15. How reassuring is a normal breast ultrasound in assessment of a screen-detected mammographic abnormality? A review of interval cancers after assessment that included ultrasound evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Bennett, M.L. [Breastscreen WA, Perth (Australia); Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Perth (Australia); Welman, C.J. [Breastscreen WA, Perth (Australia); Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Perth (Australia); Department of Radiology, Fremantle Hospital and Health Service, Fremantle (Australia); Celliers, L.M., E-mail: liesl.celliers@health.wa.gov.au [Department of Diagnostic and Interventional Radiology, Royal Perth Hospital, Perth (Australia); Department of Radiology, Fremantle Hospital and Health Service, Fremantle (Australia)

    2011-10-15

    Aim: To review factors resulting in a false-negative outcome or delayed cancer diagnosis in women recalled for further evaluation, including ultrasound, after an abnormal screening mammogram. Materials and methods: Of 646,692 screening mammograms performed between 1 January 1995 and 31 December 2004, 34,533 women were recalled for further assessment. Nine hundred and sixty-four interval cancers were reported in this period. Forty-six of these women had been recalled for further assessment, which specifically included ultrasound evaluation in the preceding 24 months, and therefore, met the inclusion criteria for this study. Screening mammograms, further mammographic views, ultrasound scans, clinical findings, and histopathology results were retrospectively reviewed by two consultant breast radiologists. Results: The interval cancer developed in the contralateral breast (n = 9), ipsilateral breast, but different site (n = 6), and ipsilateral breast at the same site (n = 31) as the abnormality for which they had recently been recalled. In the latter group, 10 were retrospectively classified as a false-negative outcome, nine had a delay in obtaining a biopsy, and 12 had a delay due to a non-diagnostic initial biopsy. Various factors relating to these outcomes are discussed. Conclusion: Out of 34,533 women who attended for an assessment visit and the 46 women who subsequently developed an interval breast cancer, 15 were true interval cancers, 10 had a false-negative assessment outcome, and 21 had a delay to cancer diagnosis on the basis of a number of factors. When there is discrepancy between the imaging and histopathology results, a repeat biopsy rather than early follow-up would have avoided a delay in some cases. A normal ultrasound examination should not deter the radiologist from proceeding to stereotactic biopsy, if the index mammographic lesion is suspicious of malignancy.

  16. Combined SPECT/CT and PET/CT for breast imaging

    Energy Technology Data Exchange (ETDEWEB)

    Russo, Paolo [Università di Napoli Federico II, Dipartimento di Fisica, Via Cintia, Naples I-80126 (Italy); INFN Sezione di Napoli, Via Cintia, Naples I-80126 (Italy); Larobina, Michele [Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, Via Tommaso De Amicis, 95, Naples I-80145 (Italy); Di Lillo, Francesca [Università di Napoli Federico II, Dipartimento di Fisica, Via Cintia, Naples I-80126 (Italy); INFN Sezione di Napoli, Via Cintia, Naples I-80126 (Italy); Del Vecchio, Silvana [Università di Napoli Federico II, Dipartimento di Scienze Biomediche Avanzate, Via Pansini, 5, Naples I-80131 (Italy); Mettivier, Giovanni, E-mail: mettivier@na.infn.it [Università di Napoli Federico II, Dipartimento di Fisica, Via Cintia, Naples I-80126 (Italy); INFN Sezione di Napoli, Via Cintia, Naples I-80126 (Italy)

    2016-02-11

    In the field of nuclear medicine imaging, breast imaging for cancer diagnosis is still mainly based on 2D imaging techniques. Three-dimensional tomographic imaging with whole-body PET or SPECT scanners, when used for imaging the breast, has performance limits in terms of spatial resolution and sensitivity, which can be overcome only with a dedicated instrumentation. However, only few hybrid imaging systems for PET/CT or SPECT/CT dedicated to the breast have been developed in the last decade, providing complementary functional and anatomical information on normal breast tissue and lesions. These systems are still under development and clinical trials on just few patients have been reported; no commercial dedicated breast PET/CT or SPECT/CT is available. This paper reviews combined dedicated breast PET/CT and SPECT/CT scanners described in the recent literature, with focus on their technological aspects.

  17. A Comparison of Behavioral Inhibition/ Activation System, Type D and Optimism in the Breast Cancer Patients and Healthy Controls

    Directory of Open Access Journals (Sweden)

    A Alipoor

    2015-04-01

    Full Text Available Background & aim: Nowadays, the role and importance of psychosocial factors on physical health, as well as the influence of personality characteristics in having psychosomatic diseases such as cancer are of interest to many researchers. In spite of increase in breast cancer in Iran, very few studies have been carried out on risk factors of breast cancer. The aim of this study was to evaluate the comparative Behavioral inhibition / Activation System, type D and optimism in the breast cancer patients and healthy individuals. Methods: In the present casual-comparative study, 190 people (95 Patients and 95 Normal Subjects were selected in Rasht, Iran. Moreover, the groups were matched for demographic characteristics (age, gender and education. All individuals diagnosed with Breast Cancer and Normal Subjects received a Gary-Wilson Personality Questionnaire, Life Orientation Test and Type D Personality Scale. Collected data were analyzed using multivariate analysis of variance and regression. Results: The findings revealed that there were significant differences between cancer and normal groups in behavioral inhibition/activation system, type D Personality and optimism. In this regard, the Breast Cancer group had higher scores subscales of negative affect, social inhibition, passive avoidance, extinction and fight-flight than normal group. In addition, subscales of approach, active avoidance and optimism in the normal group were more than the Breast Cancer group. Conclusion: The present study supported the role of psychological variables in breast cancer patients which is essential for improving patients’ health and quality of life.

  18. BCL-2 family protein, BAD is down-regulated in breast cancer and inhibits cell invasion

    Energy Technology Data Exchange (ETDEWEB)

    Cekanova, Maria, E-mail: mcekanov@utk.edu [Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN (United States); Fernando, Romaine I. [Department of Obstetrics and Gynecology, Graduate School of Medicine, Medical Center, The University of Tennessee, Knoxville, TN (United States); Siriwardhana, Nalin [Department of Animal Science, The University of Tennessee, Knoxville, TN (United States); Sukhthankar, Mugdha [Department of Biomedical and Diagnostics Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN (United States); Parra, Columba de la [Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, PR (United States); Woraratphoka, Jirayus [Department of Obstetrics and Gynecology, Graduate School of Medicine, Medical Center, The University of Tennessee, Knoxville, TN (United States); Malone, Christine [Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC (United States); Ström, Anders [Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX (United States); Baek, Seung J. [Department of Biomedical and Diagnostics Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN (United States); Wade, Paul A. [Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC (United States); Saxton, Arnold M. [Department of Animal Science, The University of Tennessee, Knoxville, TN (United States); Donnell, Robert M. [Department of Biomedical and Diagnostics Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN (United States); Pestell, Richard G. [Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (United States); and others

    2015-02-01

    We have previously demonstrated that the anti-apoptotic protein BAD is expressed in normal human breast tissue and shown that BAD inhibits expression of cyclin D1 to delay cell-cycle progression in breast cancer cells. Herein, expression of proteins in breast tissues was studied by immunohistochemistry and results were analyzed statistically to obtain semi-quantitative data. Biochemical and functional changes in BAD-overexpressing MCF7 breast cancer cells were evaluated using PCR, reporter assays, western blotting, ELISA and extracellular matrix invasion assays. Compared to normal tissues, Grade II breast cancers expressed low total/phosphorylated forms of BAD in both cytoplasmic and nuclear compartments. BAD overexpression decreased the expression of β-catenin, Sp1, and phosphorylation of STATs. BAD inhibited Ras/MEK/ERK and JNK signaling pathways, without affecting the p38 signaling pathway. Expression of the metastasis-related proteins, MMP10, VEGF, SNAIL, CXCR4, E-cadherin and TlMP2 was regulated by BAD with concomitant inhibition of extracellular matrix invasion. Inhibition of BAD by siRNA increased invasion and Akt/p-Akt levels. Clinical data and the results herein suggest that in addition to the effect on apoptosis, BAD conveys anti-metastatic effects and is a valuable prognostic marker in breast cancer. - Highlights: • BAD and p-BAD expressions are decreased in breast cancer compared with normal breast tissue. • BAD impedes breast cancer invasion and migration. • BAD inhibits the EMT and transcription factors that promote cancer cell migration. • Invasion and migration functions of BAD are distinct from the BAD's role in apoptosis.

  19. A rare FANCA gene variation as a breast cancer susceptibility allele in an Iranian population.

    Science.gov (United States)

    Abbasi, Sakineh; Rasouli, Mina

    2017-06-01

    Fanconi Anemia (FA) is an autosomal recessive syndrome characterized by congenital abnormalities, progressive bone marrow failure and Fanconi anemia complementation group A (FANCA) is also a potential breast and ovarian cancer susceptibility gene. A novel allele with tandem duplication of 13 base pair sequence in promoter region was identified. To investigate whether the 13 base pair sequence of tandem duplication in promoter region of the FANCA gene is of high penetrance in patients with breast cancer and to determine if the presence of the duplicated allele was associated with an altered risk of breast cancer, the present study screened DNA in blood samples from 304 breast cancer patients and 295 normal individuals as controls. The duplication allele had a frequency of 35.4 and 21.2% in patients with breast cancer and normal controls, respectively. There was a significant increase in the frequency of the duplication allele in patients with familial breast cancer compared with controls (45.1%, P=0.001). Furthermore, the estimated risk of breast cancer in individuals with a homozygote [odds ratio (OR), 4.093; 95% confidence intervals (CI), 1.957‑8.561] or heterozygote duplicated genotype (OR, 3.315; 95% CI, 1.996‑5.506) was higher compared with the corresponding normal homozygote genotype. In conclusion, the present study indicated that the higher the frequency of the duplicated allele, the higher the risk of breast cancer. To the best of our knowledge, the present study is the first to report FANCA gene duplication in patients with breast cancer.

  20. BCL-2 family protein, BAD is down-regulated in breast cancer and inhibits cell invasion

    International Nuclear Information System (INIS)

    Cekanova, Maria; Fernando, Romaine I.; Siriwardhana, Nalin; Sukhthankar, Mugdha; Parra, Columba de la; Woraratphoka, Jirayus; Malone, Christine; Ström, Anders; Baek, Seung J.; Wade, Paul A.; Saxton, Arnold M.; Donnell, Robert M.; Pestell, Richard G.

    2015-01-01

    We have previously demonstrated that the anti-apoptotic protein BAD is expressed in normal human breast tissue and shown that BAD inhibits expression of cyclin D1 to delay cell-cycle progression in breast cancer cells. Herein, expression of proteins in breast tissues was studied by immunohistochemistry and results were analyzed statistically to obtain semi-quantitative data. Biochemical and functional changes in BAD-overexpressing MCF7 breast cancer cells were evaluated using PCR, reporter assays, western blotting, ELISA and extracellular matrix invasion assays. Compared to normal tissues, Grade II breast cancers expressed low total/phosphorylated forms of BAD in both cytoplasmic and nuclear compartments. BAD overexpression decreased the expression of β-catenin, Sp1, and phosphorylation of STATs. BAD inhibited Ras/MEK/ERK and JNK signaling pathways, without affecting the p38 signaling pathway. Expression of the metastasis-related proteins, MMP10, VEGF, SNAIL, CXCR4, E-cadherin and TlMP2 was regulated by BAD with concomitant inhibition of extracellular matrix invasion. Inhibition of BAD by siRNA increased invasion and Akt/p-Akt levels. Clinical data and the results herein suggest that in addition to the effect on apoptosis, BAD conveys anti-metastatic effects and is a valuable prognostic marker in breast cancer. - Highlights: • BAD and p-BAD expressions are decreased in breast cancer compared with normal breast tissue. • BAD impedes breast cancer invasion and migration. • BAD inhibits the EMT and transcription factors that promote cancer cell migration. • Invasion and migration functions of BAD are distinct from the BAD's role in apoptosis

  1. Saphenous vein grafts for perforator flap salvage in autologous breast reconstruction.

    Science.gov (United States)

    Flores, Jaime I; Rad, Ariel N; Shridharani, Sachin M; Stapleton, Sahael M; Rosson, Gedge D

    2009-01-01

    Although the use of saphenous vein grafts in free-flap salvage and extremity replantation is relatively common, their use in breast reconstruction is rare. These two case reports represent extreme alternatives for breast reconstruction flap salvage. In our normal daily practice, the overwhelming majority of elective breast reconstructions proceed smoothly. However, the occasional patient may require saphenous vein graft flap rescue for completion of the reconstruction. (c) 2008 Wiley-Liss, Inc.

  2. Correlating two-photon excited fluorescence imaging of breast cancer cellular redox state with seahorse flux analysis of normalized cellular oxygen consumption

    Science.gov (United States)

    Hou, Jue; Wright, Heather J.; Chan, Nicole; Tran, Richard; Razorenova, Olga V.; Potma, Eric O.; Tromberg, Bruce J.

    2016-06-01

    Two-photon excited fluorescence (TPEF) imaging of the cellular cofactors nicotinamide adenine dinucleotide and oxidized flavin adenine dinucleotide is widely used to measure cellular metabolism, both in normal and pathological cells and tissues. When dual-wavelength excitation is used, ratiometric TPEF imaging of the intrinsic cofactor fluorescence provides a metabolic index of cells-the "optical redox ratio" (ORR). With increased interest in understanding and controlling cellular metabolism in cancer, there is a need to evaluate the performance of ORR in malignant cells. We compare TPEF metabolic imaging with seahorse flux analysis of cellular oxygen consumption in two different breast cancer cell lines (MCF-7 and MDA-MB-231). We monitor metabolic index in living cells under both normal culture conditions and, for MCF-7, in response to cell respiration inhibitors and uncouplers. We observe a significant correlation between the TPEF-derived ORR and the flux analyzer measurements (R=0.7901, p<0.001). Our results confirm that the ORR is a valid dynamic index of cell metabolism under a range of oxygen consumption conditions relevant for cancer imaging.

  3. Digital breast tomosynthesis versus mammography and breast ultrasound: a multireader performance study

    International Nuclear Information System (INIS)

    Thibault, Fabienne; Malhaire, Caroline; Tardivon, Anne; Dromain, Clarisse; Balleyguier, Corinne S.; Breucq, Catherine; Steyaert, Luc; Baldan, Enrica; Drevon, Harir

    2013-01-01

    To compare the diagnostic performance of single-view breast tomosynthesis (BT) with that of dual-view mammography (MX); to assess the benefit of adding the craniocaudal (CC) mammographic view to BT, and of adding BT to MX plus breast ultrasound, considered to be the reference work-up. One hundred and fifty-five consenting patients with unresolved mammographic and/or ultrasound findings or breast symptoms underwent conventional work-up plus mediolateral oblique-view BT of the affected breast. The final study set in 130 patients resulted in 55 malignant and 76 benign and normal cases. Seven breast radiologists rated the cases through five sequential techniques using a BIRADS-based scale: MX, MX + ultrasound, MX + ultrasound + BT, BT, BT + MX(CC). Multireader, multicase receiver operating characteristic (ROC) analysis was performed and performance of the techniques was assessed from the areas under ROC curves. The performance of BT and of BT + MX(CC) was tested versus MX; the performance of MX + ultrasound + BT tested versus MX + ultrasound. Tomosynthesis was found to be non-inferior to mammography. BT + MX(CC) did not appear to be superior to MX, and MX + ultrasound + BT not superior to MX + ultrasound. Overall, none of the five techniques tested outperformed the others. Further clinical studies are needed to clarify the role of BT as a substitute for traditional work-up in the diagnostic environment. (orig.)

  4. Lewis x is highly expressed in normal tissues: a comparative immunohistochemical study and literature revision.

    Science.gov (United States)

    Croce, María V; Isla-Larrain, Marina; Rabassa, Martín E; Demichelis, Sandra; Colussi, Andrea G; Crespo, Marina; Lacunza, Ezequiel; Segal-Eiras, Amada

    2007-01-01

    An immunohistochemical analysis was employed to determine the expression of carbohydrate antigens associated to mucins in normal epithelia. Tissue samples were obtained as biopsies from normal breast (18), colon (35) and oral cavity mucosa (8). The following carbohydrate epitopes were studied: sialyl-Lewis x, Lewis x, Lewis y, Tn hapten, sialyl-Tn and Thomsen-Friedenreich antigen. Mucins were also studied employing antibodies against MUC1, MUC2, MUC4, MUC5AC, MUC6 and also normal colonic glycolipid. Statistical analysis was performed and Kendall correlations were obtained. Lewis x showed an apical pattern mainly at plasma membrane, although cytoplasmic staining was also found in most samples. TF, Tn and sTn haptens were detected in few specimens, while sLewis x was found in oral mucosa and breast tissue. Also, normal breast expressed MUC1 at a high percentage, whereas MUC4 was observed in a small number of samples. Colon specimens mainly expressed MUC2 and MUC1, while most oral mucosa samples expressed MUC4 and MUC1. A positive correlation between MUC1VNTR and TF epitope (r=0.396) was found in breast samples, while in colon specimens MUC2 and colonic glycolipid versus Lewis x were statistically significantly correlated (r=0.28 and r=0.29, respectively). As a conclusion, a defined carbohydrate epitope expression is not exclusive of normal tissue or a determined localization, and it is possible to assume that different glycoproteins and glycolipids may be carriers of carbohydrate antigens depending on the tissue localization considered.

  5. Differential profiling of breast cancer plasma proteome by isotope-coded affinity tagging method reveals biotinidase as a breast cancer biomarker

    International Nuclear Information System (INIS)

    Kang, Un-Beom; Ahn, Younghee; Lee, Jong Won; Kim, Yong-Hak; Kim, Joon; Yu, Myeong-Hee; Noh, Dong-Young; Lee, Cheolju

    2010-01-01

    Breast cancer is one of the leading causes of women's death worldwide. It is important to discover a reliable biomarker for the detection of breast cancer. Plasma is the most ideal source for cancer biomarker discovery since many cells cross-communicate through the secretion of soluble proteins into blood. Plasma proteomes obtained from 6 breast cancer patients and 6 normal healthy women were analyzed by using the isotope-coded affinity tag (ICAT) labeling approach and tandem mass spectrometry. All the plasma samples used were depleted of highly abundant 6 plasma proteins by immune-affinity column chromatography before ICAT labeling. Several proteins showing differential abundance level were selected based on literature searches and their specificity to the commercially available antibodies, and then verified by immunoblot assays. A total of 155 proteins were identified and quantified by ICAT method. Among them, 33 proteins showed abundance changes by more than 1.5-fold between the plasmas of breast cancer patients and healthy women. We chose 5 proteins for the follow-up confirmation in the individual plasma samples using immunoblot assay. Four proteins, α1-acid glycoprotein 2, monocyte differentiation antigen CD14, biotinidase (BTD), and glutathione peroxidase 3, showed similar abundance ratio to ICAT result. Using a blind set of plasmas obtained from 21 breast cancer patients and 21 normal healthy controls, we confirmed that BTD was significantly down-regulated in breast cancer plasma (Wilcoxon rank-sum test, p = 0.002). BTD levels were lowered in all cancer grades (I-IV) except cancer grade zero. The area under the receiver operating characteristic curve of BTD was 0.78. Estrogen receptor status (p = 0.940) and progesterone receptor status (p = 0.440) were not associated with the plasma BTD levels. Our study suggests that BTD is a potential serological biomarker for the detection of breast cancer

  6. The Complex Interaction of Matrix Metalloproteinases in the Migration of Cancer Cells through Breast Tissue Stroma

    Directory of Open Access Journals (Sweden)

    Kerry J. Davies

    2014-01-01

    Full Text Available Breast cancer mortality is directly linked to metastatic spread. The metastatic cell must exhibit a complex phenotype that includes the capacity to escape from the primary tumour mass, invade the surrounding normal tissue, and penetrate into the circulation before proliferating in the parenchyma of distant organs to produce a metastasis. In the normal breast, cellular structures change cyclically in response to ovarian hormones leading to regulated cell proliferation and apoptosis. Matrix metalloproteinases (MMPs are a family of zinc dependent endopeptidases. Their primary function is degradation of proteins in the extracellular matrix to allow ductal progression through the basement membrane. A complex balance between matrix metalloproteinases and their inhibitors regulate these changes. These proteinases interact with cytokines, growth factors, and tumour necrosis factors to stimulate branching morphologies in normal breast tissues. In breast cancer this process is disrupted facilitating tumour progression and metastasis and inhibiting apoptosis increasing the life of the metastatic cells. This paper highlights the role of matrix metalloproteinases in cell progression through the breast stroma and reviews the complex relationships between the different proteinases and their inhibitors in relation to breast cancer cells as they metastasise.

  7. Comparison between magnetic resonance findings and conventional techniques (ultrasonography and mammography) in breast disease

    International Nuclear Information System (INIS)

    Martin, J.L.; Garofono, J.M.; Berquet, A.; Fernandez, F.J.; Fuentes, P.; Alvarez de Cienfuegos, E.

    1996-01-01

    Although mammography is indisputably the best diagnostic method for detecting breast abnormalities, there are other techniques, such as ultrasonography and magnetic resonance, which are increasingly widely employed as additional indispensable aids. The present work compares mammography, ultrasound and magnetic resonance images of normal breast and of the major pathologies that can be observed in breast, including sclerosing adenosis, giant fibroadenoma, multifocal carcinoma, fibrocystic breast disease, infiltrating duct carcinoma, colloid carcinoma, radical scar, abscess and breast prosthesis. (Author) 10 refs

  8. The expression of Egfl7 in human normal tissues and epithelial tumors.

    Science.gov (United States)

    Fan, Chun; Yang, Lian-Yue; Wu, Fan; Tao, Yi-Ming; Liu, Lin-Sen; Zhang, Jin-Fan; He, Ya-Ning; Tang, Li-Li; Chen, Guo-Dong; Guo, Lei

    2013-04-23

    To investigate the expression of Egfl7 in normal adult human tissues and human epithelial tumors.
 RT-PCR and Western blot were employed to detect Egfl7 expression in normal adult human tissues and 10 human epithelial tumors including hepatocellular carcinoma (HCC), lung cancer, breast cancer, prostate cancer, colorectal cancer, gastric cancer, esophageal cancer, malignant glioma, ovarian cancer and renal cancer. Immunohistochemistry and cytoimmunofluorescence were subsequently used to determine the localization of Egfl7 in human epithelial tumor tissues and cell lines. ELISA was also carried out to examine the serum Egfl7 levels in cancer patients. In addition, correlations between Egfl7 expression and clinicopathological features as well as prognosis of HCC and breast cancer were also analyzed on the basis of immunohistochemistry results.
 Egfl7 was differentially expressed in 19 adult human normal tissues and was overexpressed in all 10 human epithelial tumor tissues. The serum Egfl7 level was also significantly elevated in cancer patients. The increased Egfl7 expression in HCC correlated with vein invasion, absence of capsule formation, multiple tumor nodes and poor prognosis. Similarly, upregulation of Egfl7 in breast cancer correlated strongly with TNM stage, lymphatic metastasis, estrogen receptor positivity, Her2 positivity and poor prognosis. 
 Egfl7 is significantly upregulated in human epithelial tumor tissues, suggesting Egfl7 to be a potential biomarker for human epithelial tumors, especially HCC and breast cancer.

  9. Human Papilloma Viruses and Breast Cancer - Assessment of Causality.

    Science.gov (United States)

    Lawson, James Sutherland; Glenn, Wendy K; Whitaker, Noel James

    2016-01-01

    High risk human papilloma viruses (HPVs) may have a causal role in some breast cancers. Case-control studies, conducted in many different countries, consistently indicate that HPVs are more frequently present in breast cancers as compared to benign breast and normal breast controls (odds ratio 4.02). The assessment of causality of HPVs in breast cancer is difficult because (i) the HPV viral load is extremely low, (ii) HPV infections are common but HPV associated breast cancers are uncommon, and (iii) HPV infections may precede the development of breast and other cancers by years or even decades. Further, HPV oncogenesis can be indirect. Despite these difficulties, the emergence of new evidence has made the assessment of HPV causality, in breast cancer, a practical proposition. With one exception, the evidence meets all the conventional criteria for a causal role of HPVs in breast cancer. The exception is "specificity." HPVs are ubiquitous, which is the exact opposite of specificity. An additional reservation is that the prevalence of breast cancer is not increased in immunocompromised patients as is the case with respect to HPV-associated cervical cancer. This indicates that HPVs may have an indirect causal influence in breast cancer. Based on the overall evidence, high-risk HPVs may have a causal role in some breast cancers.

  10. Targeted overexpression of EZH2 in the mammary gland disrupts ductal morphogenesis and causes epithelial hyperplasia.

    Science.gov (United States)

    Li, Xin; Gonzalez, Maria E; Toy, Katherine; Filzen, Tracey; Merajver, Sofia D; Kleer, Celina G

    2009-09-01

    The Polycomb group protein enhancer of zeste homolog 2 (EZH2), which has roles during development of numerous tissues, is a critical regulator of cell type identity. Overexpression of EZH2 has been detected in invasive breast carcinoma tissue samples and is observed in human breast tissue samples of morphologically normal lobules up to 12 years before the development of breast cancer. The function of EZH2 during preneoplastic progression in the mammary gland is unknown. To investigate the role of EZH2 in the mammary gland, we targeted the expression of EZH2 to mammary epithelial cells using the mouse mammary tumor virus long terminal repeat. EZH2 overexpression resulted in aberrant terminal end bud architecture. By the age of 4 months, 100% of female mouse mammary tumor virus-EZH2 virgin mice developed intraductal epithelial hyperplasia resembling the human counterpart accompanied by premature differentiation of ductal epithelial cells and up-regulation of the luminal marker GATA-3. In addition, remodeling of the mammary gland after parturition was impaired and EZH2 overexpression caused delayed involution. Mechanistically, we found that EZH2 physically interacts with beta-catenin, inducing beta-catenin nuclear accumulation in mammary epithelial cells and activating Wnt/beta-catenin signaling. The biological significance of these data to human hyperplasias is demonstrated by EZH2 up-regulation and colocalization with beta-catenin in human intraductal epithelial hyperplasia, the earliest histologically identifiable precursor of breast carcinoma.

  11. Identification and pathway analysis of microRNAs with no previous involvement in breast cancer.

    Directory of Open Access Journals (Sweden)

    Sandra Romero-Cordoba

    Full Text Available microRNA expression signatures can differentiate normal and breast cancer tissues and can define specific clinico-pathological phenotypes in breast tumors. In order to further evaluate the microRNA expression profile in breast cancer, we analyzed the expression of 667 microRNAs in 29 tumors and 21 adjacent normal tissues using TaqMan Low-density arrays. 130 miRNAs showed significant differential expression (adjusted P value = 0.05, Fold Change = 2 in breast tumors compared to the normal adjacent tissue. Importantly, the role of 43 of these microRNAs has not been previously reported in breast cancer, including several evolutionary conserved microRNA*, showing similar expression rates to that of their corresponding leading strand. The expression of 14 microRNAs was replicated in an independent set of 55 tumors. Bioinformatic analysis of mRNA targets of the altered miRNAs, identified oncogenes like ERBB2, YY1, several MAP kinases, and known tumor-suppressors like FOXA1 and SMAD4. Pathway analysis identified that some biological process which are important in breast carcinogenesis are affected by the altered microRNA expression, including signaling through MAP kinases and TP53 pathways, as well as biological processes like cell death and communication, focal adhesion and ERBB2-ERBB3 signaling. Our data identified the altered expression of several microRNAs whose aberrant expression might have an important impact on cancer-related cellular pathways and whose role in breast cancer has not been previously described.

  12. Prognostic breast cancer signature identified from 3D culture model accurately predicts clinical outcome across independent datasets

    Energy Technology Data Exchange (ETDEWEB)

    Martin, Katherine J.; Patrick, Denis R.; Bissell, Mina J.; Fournier, Marcia V.

    2008-10-20

    One of the major tenets in breast cancer research is that early detection is vital for patient survival by increasing treatment options. To that end, we have previously used a novel unsupervised approach to identify a set of genes whose expression predicts prognosis of breast cancer patients. The predictive genes were selected in a well-defined three dimensional (3D) cell culture model of non-malignant human mammary epithelial cell morphogenesis as down-regulated during breast epithelial cell acinar formation and cell cycle arrest. Here we examine the ability of this gene signature (3D-signature) to predict prognosis in three independent breast cancer microarray datasets having 295, 286, and 118 samples, respectively. Our results show that the 3D-signature accurately predicts prognosis in three unrelated patient datasets. At 10 years, the probability of positive outcome was 52, 51, and 47 percent in the group with a poor-prognosis signature and 91, 75, and 71 percent in the group with a good-prognosis signature for the three datasets, respectively (Kaplan-Meier survival analysis, p<0.05). Hazard ratios for poor outcome were 5.5 (95% CI 3.0 to 12.2, p<0.0001), 2.4 (95% CI 1.6 to 3.6, p<0.0001) and 1.9 (95% CI 1.1 to 3.2, p = 0.016) and remained significant for the two larger datasets when corrected for estrogen receptor (ER) status. Hence the 3D-signature accurately predicts breast cancer outcome in both ER-positive and ER-negative tumors, though individual genes differed in their prognostic ability in the two subtypes. Genes that were prognostic in ER+ patients are AURKA, CEP55, RRM2, EPHA2, FGFBP1, and VRK1, while genes prognostic in ER patients include ACTB, FOXM1 and SERPINE2 (Kaplan-Meier p<0.05). Multivariable Cox regression analysis in the largest dataset showed that the 3D-signature was a strong independent factor in predicting breast cancer outcome. The 3D-signature accurately predicts breast cancer outcome across multiple datasets and holds prognostic

  13. The Potential Role of Hedgehog Signaling in the Luminal/Basal Phenotype of Breast Epithelia and in Breast Cancer Invasion and Metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Flemban, Arwa [Department of Biological, Biomedical and Analytical Sciences, Faculty of Health and Applied Sciences, University of West of England, Bristol BS16 1QY (United Kingdom); Department of Pathology, Faculty of Medicine, Umm Al-Qura University, Makkah 24382 (Saudi Arabia); Qualtrough, David, E-mail: david.qualtrough@uwe.ac.uk [Department of Biological, Biomedical and Analytical Sciences, Faculty of Health and Applied Sciences, University of West of England, Bristol BS16 1QY (United Kingdom)

    2015-09-16

    The epithelium of the lactiferous ducts in the breast is comprised of luminal epithelial cells and underlying basal myoepithelial cells. The regulation of cell fate and transit of cells between these two cell types remains poorly understood. This relationship becomes of greater importance when studying the subtypes of epithelial breast carcinoma, which are categorized according to their expression of luminal or basal markers. The epithelial mesenchymal transition (EMT) is a pivotal event in tumor invasion. It is important to understand mechanisms that regulate this process, which bears relation to the normal dynamic of epithelial/basal phenotype regulation in the mammary gland. Understanding this process could provide answers for the regulation of EMT in breast cancer, and thereby identify potential targets for therapy. Evidence points towards a role for hedgehog signaling in breast tissue homeostasis and also in mammary neoplasia. This review examines our current understanding of role of the hedgehog-signaling (Hh) pathway in breast epithelial cells both during breast development and homeostasis and to assess the potential misappropriation of Hh signals in breast neoplasia, cancer stem cells and tumor metastasis via EMT.

  14. The Potential Role of Hedgehog Signaling in the Luminal/Basal Phenotype of Breast Epithelia and in Breast Cancer Invasion and Metastasis

    International Nuclear Information System (INIS)

    Flemban, Arwa; Qualtrough, David

    2015-01-01

    The epithelium of the lactiferous ducts in the breast is comprised of luminal epithelial cells and underlying basal myoepithelial cells. The regulation of cell fate and transit of cells between these two cell types remains poorly understood. This relationship becomes of greater importance when studying the subtypes of epithelial breast carcinoma, which are categorized according to their expression of luminal or basal markers. The epithelial mesenchymal transition (EMT) is a pivotal event in tumor invasion. It is important to understand mechanisms that regulate this process, which bears relation to the normal dynamic of epithelial/basal phenotype regulation in the mammary gland. Understanding this process could provide answers for the regulation of EMT in breast cancer, and thereby identify potential targets for therapy. Evidence points towards a role for hedgehog signaling in breast tissue homeostasis and also in mammary neoplasia. This review examines our current understanding of role of the hedgehog-signaling (Hh) pathway in breast epithelial cells both during breast development and homeostasis and to assess the potential misappropriation of Hh signals in breast neoplasia, cancer stem cells and tumor metastasis via EMT

  15. Lack of independent prognostic and predictive value of centromere 17 copy number changes in breast cancer patients with known HER2 and TOP2A status

    DEFF Research Database (Denmark)

    Nielsen, Kirsten Vang; Ejlertsen, Bent; Møller, Susanne

    2011-01-01

    hybridization (FISH) with centromere 17 (CEN-17) and TOP2A was performed on 120 normal breast specimens. The diploid CEN-17 copy number was reduced from the expected two signals in whole nuclei to an average of 1.68 signals per nucleus in cut sections of normal breast. Ploidy levels determined in normal breast...

  16. Dicer activity in neural crest cells is essential for craniofacial organogenesis and pharyngeal arch artery morphogenesis

    Science.gov (United States)

    Nie, Xuguang; Wang, Qin; Jiao, Kai

    2014-01-01

    MicroRNAs (miRNAs) play important roles in regulating gene expression during numerous biological/pathological processes. Dicer encodes an RNase III endonuclease that is essential for generating most, if not all, functional miRNAs. In this work, we applied a conditional gene inactivation approach to examine the function of Dicer during neural crest cell (NCC) development. Mice with NCC-specific inactivation of Dicer died perinatally. Cranial and cardiac NCC migration into target tissues was not affected by Dicer disruption, but their subsequent development was disturbed. NCC derivatives and their associated mesoderm-derived cells displayed massive apoptosis, leading to severe abnormalities during craniofacial morphogenesis and organogenesis. In addition, the 4th pharyngeal arch artery (PAA) remodeling was affected, resulting in interrupted aortic arch artery type B (IAA-B) in mutant animals. Taken together, our results show that Dicer activity in NCCs is essential for craniofacial development and pharyngeal arch artery morphogenesis. PMID:21256960

  17. Thermogram breast cancer prediction approach based on Neutrosophic sets and fuzzy c-means algorithm.

    Science.gov (United States)

    Gaber, Tarek; Ismail, Gehad; Anter, Ahmed; Soliman, Mona; Ali, Mona; Semary, Noura; Hassanien, Aboul Ella; Snasel, Vaclav

    2015-08-01

    The early detection of breast cancer makes many women survive. In this paper, a CAD system classifying breast cancer thermograms to normal and abnormal is proposed. This approach consists of two main phases: automatic segmentation and classification. For the former phase, an improved segmentation approach based on both Neutrosophic sets (NS) and optimized Fast Fuzzy c-mean (F-FCM) algorithm was proposed. Also, post-segmentation process was suggested to segment breast parenchyma (i.e. ROI) from thermogram images. For the classification, different kernel functions of the Support Vector Machine (SVM) were used to classify breast parenchyma into normal or abnormal cases. Using benchmark database, the proposed CAD system was evaluated based on precision, recall, and accuracy as well as a comparison with related work. The experimental results showed that our system would be a very promising step toward automatic diagnosis of breast cancer using thermograms as the accuracy reached 100%.

  18. Radiation doses in volume-of-interest breast computed tomography—A Monte Carlo simulation study

    Energy Technology Data Exchange (ETDEWEB)

    Lai, Chao-Jen, E-mail: cjlai3711@gmail.com; Zhong, Yuncheng; Yi, Ying; Wang, Tianpeng; Shaw, Chris C. [Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009 (United States)

    2015-06-15

    measurements were 0.97 ± 0.03 and 1.10 ± 0.13, respectively, indicating that the accuracy of the Monte Carlo simulation was adequate. The normalized AGD with VOI field scans was substantially reduced by a factor of about 2 over the VOI region and by a factor of 18 over the entire breast for both 25% and 50% VGF simulated breasts compared with the normalized AGD with full field scans. The normalized AGD for the VOI breast CT technique can be kept the same as or lower than that for a full field scan with the exposure level for the VOI field scan increased by a factor of as much as 12. Conclusions: The authors’ Monte Carlo estimates of normalized AGDs for the VOI breast CT technique show that this technique can be used to markedly increase the dose to the breast and thus the visibility of the VOI region without increasing the dose to the breast. The results of this investigation should be helpful for those interested in using VOI breast CT technique to image small calcifications with dose concern.

  19. Regulation of in situ to invasive breast carcinoma transition

    Energy Technology Data Exchange (ETDEWEB)

    Polyak, Kornelia; Hu, Min; Yao, Jun; Carroll, Danielle K.; Weremowicz, Stanislawa; Chen, Haiyan; Carrasco, Daniel; Richardson, Andrea; Violette, Shelia; Gelman, Rebecca S.; Bissell, Mina J.; Schnitt, Stuart; Polyak, Kornelia

    2008-05-07

    The transition of ductal carcinoma in situ (DCIS) to invasive carcinoma is a key event in breast tumor progression that is poorly understood. Comparative molecular analysis of tumor epithelial cells from in situ and invasive tumors has failed to identify consistent tumor stage-specific differences. However, the myoepithelial cell layer, present only in DCIS, is a key distinguishing and diagnostic feature. To determine the contribution of non-epithelial cells to tumor progression, we analyzed the role of myoepithelial cells and fibroblasts in the progression of in situ carcinomas using a xenograft model of human DCIS. Progression to invasion was promoted by fibroblasts, but inhibited by normal myoepithelial cells. The invasive tumor cells from these progressed lesions formed DCIS rather than invasive cancers when re-injected into naive mice. Molecular profiles of myoepithelial and epithelial cells isolated from primary normal and cancerous human breast tissue samples corroborated findings obtained in the xenograft model. These results provide the proof of principle that breast tumor progression could occur in the absence of additional genetic alterations and that tumor growth and progression could be controlled by replacement of normal myoepithelial inhibitory signals.

  20. Regulation of In Situ to Invasive Breast CarcinomaTransition

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Min; Carroll, Danielle K.; Weremowicz, Stanislawa; Chen,Haiyan; Carrasco, Daniel; Richardson, Andrea; Bissell, Mina; Violette,Shelia; Gelman, Rebecca S.; Schnitt, Stuart; Polyak, Kornelia

    2007-03-13

    The transition of ductal carcinoma in situ (DCIS) to invasive carcinoma is a key event in breast tumor progression that is poorly understood. Comparative molecular analysis of tumor epithelial cells from in situ and invasive tumors has failed to identify consistent tumor stage-specific differences. However, the myoepithelial cell layer, present only in DCIS, is a key distinguishing and diagnostic feature. To determine the contribution of non-epithelial cells to tumor progression, we analyzed the role of myoepithelial cells and fibroblasts in the progression of in situ carcinomas using a xenograft model of human DCIS. Progression to invasion was promoted by fibroblasts, but inhibited by normal myoepithelial cells. The invasive tumor cells from these progressed lesions formed DCIS rather than invasive cancers when re-injected into naive mice. Molecular profiles of myoepithelial and epithelial cells isolated from primary normal and cancerous human breast tissue samples corroborated findings obtained in the xenograft model. These results provide the proof of principle that breast tumor progression could occur in the absence of additional genetic alterations and that tumor growth and progression could be controlled by replacement of normal myoepithelial inhibitory signals.