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Sample records for breast tumor phenotype

  1. Breast tumor copy number aberration phenotypes and genomic instability

    International Nuclear Information System (INIS)

    Genomic DNA copy number aberrations are frequent in solid tumors, although the underlying causes of chromosomal instability in tumors remain obscure. Genes likely to have genomic instability phenotypes when mutated (e.g. those involved in mitosis, replication, repair, and telomeres) are rarely mutated in chromosomally unstable sporadic tumors, even though such mutations are associated with some heritable cancer prone syndromes. We applied array comparative genomic hybridization (CGH) to the analysis of breast tumors. The variation in the levels of genomic instability amongst tumors prompted us to investigate whether alterations in processes/genes involved in maintenance and/or manipulation of the genome were associated with particular types of genomic instability. We discriminated three breast tumor subtypes based on genomic DNA copy number alterations. The subtypes varied with respect to level of genomic instability. We find that shorter telomeres and altered telomere related gene expression are associated with amplification, implicating telomere attrition as a promoter of this type of aberration in breast cancer. On the other hand, the numbers of chromosomal alterations, particularly low level changes, are associated with altered expression of genes in other functional classes (mitosis, cell cycle, DNA replication and repair). Further, although loss of function instability phenotypes have been demonstrated for many of the genes in model systems, we observed enhanced expression of most genes in tumors, indicating that over expression, rather than deficiency underlies instability. Many of the genes associated with higher frequency of copy number aberrations are direct targets of E2F, supporting the hypothesis that deregulation of the Rb pathway is a major contributor to chromosomal instability in breast tumors. These observations are consistent with failure to find mutations in sporadic tumors in genes that have roles in maintenance or manipulation of the genome

  2. Genomic and phenotypic profiles of two Brazilian breast cancer cell lines derived from primary human tumors

    OpenAIRE

    CORRÊA, NATÁSSIA C.R.; Kuasne, Hellen; Faria, Jerusa A. Q. A.; SEIXAS, CIÇA C.S.; SANTOS, IRIA G.D.; ABREU, FRANCINE B.; Nonogaki, Suely; Rocha, Rafael M.; Silva, Gerluza Aparecida Borges; Gobbi, Helenice; Silvia R Rogatto; Alfredo M. Goes; Gomes, Dawidson A

    2013-01-01

    Breast cancer is the most common type of cancer among women worldwide. Research using breast cancer cell lines derived from primary tumors may provide valuable additional knowledge regarding this type of cancer. Therefore, the aim of this study was to investigate the phenotypic profiles of MACL-1 and MGSO-3, the only Brazilian breast cancer cell lines available for comparative studies. We evaluated the presence of hormone receptors, proliferation, differentiation and stem cell markers, using ...

  3. Genomic and phenotypic profiles of two Brazilian breast cancer cell lines derived from primary human tumors

    DEFF Research Database (Denmark)

    Corrêa, Natássia C R; Kuasne, Hellen; Faria, Jerusa A Q A;

    2013-01-01

    and MGSO-3, the only Brazilian breast cancer cell lines available for comparative studies. We evaluated the presence of hormone receptors, proliferation, differentiation and stem cell markers, using immunohistochemical staining of the primary tumor, cultured cells and xenografts implanted...

  4. Fructose as a carbon source induces an aggressive phenotype in MDA-MB-468 breast tumor cells

    Science.gov (United States)

    MONZAVI-KARBASSI, BEHJATOLAH; HINE, R. JEAN; STANLEY, JOSEPH S.; RAMANI, VISHNU PRAKASH; CARCEL-TRULLOLS, JAIME; WHITEHEAD, TRACY L.; KELLY, THOMAS; SIEGEL, ERIC R.; ARTAUD, CECILE; SHAAF, SAEID; SAHA, RINKU; JOUSHEGHANY, FARIBA; HENRY-TILLMAN, RONDA; KIEBER-EMMONS, THOMAS

    2012-01-01

    Aberrant glycosylation is a universal feature of cancer cells, and certain glycan structures are well-known markers for tumor progression. Availability and composition of sugars in the microenvironment may affect cell glycosylation. Recent studies of human breast tumor cell lines indicate their ability to take up and utilize fructose. Here we tested the hypothesis that adding fructose to culture as a carbon source induces phenotypic changes in cultured human breast tumor cells that are associated with metastatic disease. MDA-MB-468 cells were adapted to culture media in which fructose was substituted for glucose. Changes in cell surface glycan structures, expression of genes related to glycan assembly, cytoskeleton F-actin, migration, adhesion and invasion were determined. Cells cultured in fructose expressed distinct cell-surface glycans. The addition of fructose affected sialylation and fucosylation patterns. Fructose feeding also increased binding of leukoagglutinating Phaseolus vulgaris isolectin, suggesting a possible rise in expression of branching β-1, 6 GlcNAc structures. Rhodamine-phalloidin staining revealed an altered F-actin cytoskeletal system. Fructose accelerated cellular migration and increased invasion. These data suggest that changing the carbon source of the less aggressive MDA-MB-468 cell line induced characteristics associated with more aggressive phenotypes. These data could be of fundamental importance due to the markedly increased consumption of sweeteners containing free fructose in recent years, as they suggest that the presence of fructose in nutritional micro-environment of tumor cells may negatively affect the outcome for some breast cancer patients. PMID:20664930

  5. Tumor-derived CCL-2 and CXCL-8 as possible prognostic markers of breast cancer: correlation with estrogen and progestrone receptor phenotyping.

    Science.gov (United States)

    Ghoneim, H M; Maher, Sara; Abdel-Aty, Asmaa; Saad, A; Kazem, A; Demian, S R

    2009-01-01

    Prognosis of breast cancer is believed to be a multifactorial process best achieved by complex factors including host and tumor-derived biomarkers together with traditional clinicopathological parameters and tumor histologic markers. The present study aimed at evaluating the prognostic significance of chemokine ligand-2 (CCL-2) and interleukin-8 (CXCL-8) expression in extracts of breast carcinomas through correlation with clinicopathological aspects as well as estrogen receptor (ER) and progesterone receptor (PR) phenotyping. The study was conducted on 30 Egyptian breast cancer patients diagnosed by fine needle aspiration cytology (FNAC) and subjected to modified radical mastectomy. Excised tissues were used to prepare tissue sections and extracts for histopathological and immunohistochemical studies. Expression of CCL-2 and CXCL-8 was determined by enzyme-linked immunosorbent assay (ELISA). 26 patients had invasive ductal carcinoma, grades II and III with metastasis to axillary lymph nodes and ER and PR positive phenotype. Expression of CCL-2 and CXCL-8 was significantly influenced by patient's age, menopausal status, nodal involvement, tumor grade and the ER phenotype. In contrast, it was not affected by either tumor size or PR staining pattern. Both chemokines correlated positively to each other and to tumor grade and negatively to age, menopausal status of patients and ER phenotyping. It is concluded that the angiogenic chemokine CXCL-8 and the macrophage chemoattractant CCL-2 might be useful prognostic markers where their routine follow up might be of importance in assessment of tumor aggressiveness in clinical settings. PMID:22059352

  6. Tumor-derived CCL-2 and CXCL-8 as possible prognostic markers of breast cancer: correlation with estrogen and progestrone receptor phenotyping.

    Science.gov (United States)

    Ghoneim, H M; Maher, Sara; Abdel-Aty, Asmaa; Saad, A; Kazem, A; Demian, S R

    2009-01-01

    Prognosis of breast cancer is believed to be a multifactorial process best achieved by complex factors including host and tumor-derived biomarkers together with traditional clinicopathological parameters and tumor histologic markers. The present study aimed at evaluating the prognostic significance of chemokine ligand-2 (CCL-2) and interleukin-8 (CXCL-8) expression in extracts of breast carcinomas through correlation with clinicopathological aspects as well as estrogen receptor (ER) and progesterone receptor (PR) phenotyping. The study was conducted on 30 Egyptian breast cancer patients diagnosed by fine needle aspiration cytology (FNAC) and subjected to modified radical mastectomy. Excised tissues were used to prepare tissue sections and extracts for histopathological and immunohistochemical studies. Expression of CCL-2 and CXCL-8 was determined by enzyme-linked immunosorbent assay (ELISA). 26 patients had invasive ductal carcinoma, grades II and III with metastasis to axillary lymph nodes and ER and PR positive phenotype. Expression of CCL-2 and CXCL-8 was significantly influenced by patient's age, menopausal status, nodal involvement, tumor grade and the ER phenotype. In contrast, it was not affected by either tumor size or PR staining pattern. Both chemokines correlated positively to each other and to tumor grade and negatively to age, menopausal status of patients and ER phenotyping. It is concluded that the angiogenic chemokine CXCL-8 and the macrophage chemoattractant CCL-2 might be useful prognostic markers where their routine follow up might be of importance in assessment of tumor aggressiveness in clinical settings.

  7. Sleep Duration and Breast Cancer Phenotype

    OpenAIRE

    Ali Khawaja; Santosh Rao; Li Li; Thompson, Cheryl L.

    2013-01-01

    Emerging evidence suggests that short sleep is associated with an increased risk of cancer; however, little has been done to study the role of sleep on tumor characteristics. In this study, we evaluated the relationship between sleep duration and tumor phenotype in 972 breast cancer patients. Sleep duration was inversely associated with tumor grade (univariate P = 0.032), particularly in postmenopausal women (univariate P = 0.018). This association did not reach statistical significance after...

  8. SLUG/SNAI2 and Tumor Necrosis Factor Generate Breast Cells With CD44+/CD24- Phenotype

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    Bhat-Nakshatri Poornima

    2010-08-01

    Full Text Available Abstract Background Breast cancer cells with CD44+/CD24- cell surface marker expression profile are proposed as cancer stem cells (CSCs. Normal breast epithelial cells that are CD44+/CD24- express higher levels of stem/progenitor cell associated genes. We, amongst others, have shown that cancer cells that have undergone epithelial to mesenchymal transition (EMT display the CD44+/CD24- phenotype. However, whether all genes that induce EMT confer the CD44+/CD24- phenotype is unknown. We hypothesized that only a subset of genes associated with EMT generates CD44+/CD24- cells. Methods MCF-10A breast epithelial cells, a subpopulation of which spontaneously acquire the CD44+/CD24- phenotype, were used to identify genes that are differentially expressed in CD44+/CD24- and CD44-/CD24+ cells. Ingenuity pathway analysis was performed to identify signaling networks that linked differentially expressed genes. Two EMT-associated genes elevated in CD44+/CD24- cells, SLUG and Gli-2, were overexpressed in the CD44-/CD24+ subpopulation of MCF-10A cells and MCF-7 cells, which are CD44-/CD24+. Flow cytometry and mammosphere assays were used to assess cell surface markers and stem cell-like properties, respectively. Results Two thousand thirty five genes were differentially expressed (p Conclusions EMT-mediated generation of CD44+/CD24- or CD44+/CD24+ cells depends on the genes that induce or are associated with EMT. Our studies reveal a role for TNF in altering the phenotype of breast CSC. Additionally, the CD44+/CD24+ phenotype, in the context of SLUG overexpression, can be associated with breast CSC "stemness" behavior based on mammosphere forming ability.

  9. Multiparametric classification links tumor microenvironments with tumor cell phenotype.

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    Bojana Gligorijevic

    2014-11-01

    occurred in spatially distinct microenvironments of primary tumors. We show how machine-learning analysis can classify heterogeneous microenvironments in vivo to enable prediction of motility phenotypes and tumor cell fate. The ability to predict the locations of tumor cell behavior leading to metastasis in breast cancer models may lead towards understanding the heterogeneity of response to treatment.

  10. A mouse model for triple-negative breast cancer tumor-initiating cells (TNBC-TICs) exhibits similar aggressive phenotype to the human disease

    International Nuclear Information System (INIS)

    Triple-negative breast cancer (TNBC) exhibit characteristics quite distinct from other kinds of breast cancer, presenting as an aggressive disease--recurring and metastasizing more often than other kinds of breast cancer, without tumor-specific treatment options and accounts for 15% of all types of breast cancer with higher percentages in premenopausal African-American and Hispanic women. The reason for this aggressive phenotype is currently the focus of intensive research. However, progress is hampered by the lack of suitable TNBC cell model systems. To understand the mechanistic basis for the aggressiveness of TNBC, we produced a stable TNBC cell line by sorting for 4T1 cells that do not express the estrogen receptor (ER), progesterone receptor (PgR) or the gene for human epidermal growth factor receptor 2 (HER2). As a control, we produced a stable triple-positive breast cancer (TPBC) cell line by transfecting 4T1 cells with rat HER2, ER and PgR genes and sorted for cells with high expression of ER and PgR by flow cytometry and high expression of the HER2 gene by Western blot analysis. We isolated tumor-initiating cells (TICs) by sorting for CD24+/CD44high/ALDH1+ cells from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) stable cell lines. Limiting dilution transplantation experiments revealed that CD24+/CD44high/ALDH1+ cells derived from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) were significantly more effective at repopulating the mammary glands of naïve female BALB/c mice than CD24-/CD44-/ALDH1- cells. Implantation of the TNBC-TICs resulted in significantly larger tumors, which metastasized to the lungs to a significantly greater extent than TNBC, TPBC-TICs, TPBC or parental 4T1 cells. We further demonstrated that the increased aggressiveness of TNBC-TICs correlates with the presence of high levels of mouse twenty-five kDa heat shock protein (Hsp25/mouse HspB1) and seventy-two kDa heat shock protein (Hsp72/HspA1A). Taken together, we have developed a TNBC-TICs model system

  11. Sleep Duration and Breast Cancer Phenotype

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    Ali Khawaja

    2013-01-01

    Full Text Available Emerging evidence suggests that short sleep is associated with an increased risk of cancer; however, little has been done to study the role of sleep on tumor characteristics. In this study, we evaluated the relationship between sleep duration and tumor phenotype in 972 breast cancer patients. Sleep duration was inversely associated with tumor grade (univariate P=0.032, particularly in postmenopausal women (univariate P=0.018. This association did not reach statistical significance after adjustments for age, race, body mass index, hormone replacement therapy use, alcohol consumption, smoking, and physical activity in the entire study sample (P=0.052, but it remained statistically significant (P=0.049 among post-menopausal patients. We did not observe a statistically significant association between sleep duration and stage at diagnosis, ER, or HER2 receptor status. These results present a modest association between short duration of sleep and higher grade breast cancer in post-menopausal women. Further work needs to be done to validate these findings.

  12. Hypoxic conditions induce a cancer-like phenotype in human breast epithelial cells

    DEFF Research Database (Denmark)

    Vaapil, Marica; Helczynska, Karolina; Villadsen, René;

    2012-01-01

    Solid tumors are less oxygenated than their tissue of origin. Low intra-tumor oxygen levels are associated with worse outcome, increased metastatic potential and immature phenotype in breast cancer. We have reported that tumor hypoxia correlates to low differentiation status in breast cancer. Les...... is known about effects of hypoxia on non-malignant cells. Here we address whether hypoxia influences the differentiation stage of non-malignant breast epithelial cells and potentially have bearing on early stages of tumorigenesis....

  13. Epigenetic reversion of breast carcinoma phenotype is accompaniedby DNA sequestration

    Energy Technology Data Exchange (ETDEWEB)

    Sandal, Tone; Valyi-Nagy, Klara; Spencer, Virginia A.; Folberg,Robert; Bissell, Mina J.; Maniotis, Andrew J.

    2006-07-19

    The importance of microenvironment and context in regulation of tissue-specific genes is finally well established. DNA exposure to, or sequestration from, nucleases can be used to detect differences in higher order chromatin structure in intact cells without disturbing cellular or tissue architecture. To investigate the relationship between chromatin organization and tumor phenotype, we utilized an established 3-D assay where normal and malignant human breast cells can be easily distinguished by the morphology of the structures they make (acinus-like vs tumor-like, respectively). We show that these phenotypes can be distinguished also by sensitivity to AluI digestion where the malignant cells are resistant to digestion relative to non-malignant cells. Reversion of the T4-2 breast cancer cells by either cAMP analogs, or a phospatidylinositol 3-kinase (P13K) inhibitor not only reverted the phenotype, but also the chromatin sensitivity to AluI. By using different cAMP-analogs, we show that the cAMP-induced phenotypic reversion, polarization, and shift in DNA organization act through a cAMP-dependent-protein-kinase A-coupled signaling pathway. Importantly, inhibitory antibody to fibronectin also reverted the malignant phenotype, polarized the acini, and changed chromatin sequestration. These experiments show not only that modifying the tumor microenvironment can alter the organization of tumor cells but also that architecture of the tissues and the global chromatin organization are coupled and yet highly plastic.

  14. Novel Stromal Biomarkers in Human Breast Cancer Tissues Provide Evidence for the More Malignant Phenotype of Estrogen Receptor-Negative Tumors

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    Zahraa I. Khamis

    2011-01-01

    Full Text Available Research efforts were focused on genetic alterations in epithelial cancer cells. Epithelial-stromal interactions play a crucial role in cancer initiation, progression, invasion, angiogenesis, and metastasis; however, the active role of stroma in human breast tumorigenesis in relation to estrogen receptor (ER status of epithelial cells has not been explored. Using proteomics and biochemical approaches, we identified two stromal proteins in ER-positive and ER-negative human breast cancer tissues that may affect malignant transformation in breast cancer. Two putative biomarkers, T-cell receptor alpha (TCR-α and zinc finger and BRCA1-interacting protein with a KRAB domain (ZBRK1, were detected in leukocytes of ER-positive and endothelial cells of ER-negative tissues, respectively. Our data suggest an immunosuppressive role of leukocytes in invasive breast tumors, propose a multifunctional nature of ZBRK1 in estrogen receptor regulation and angiogenesis, and demonstrate the aggressiveness of ER-negative human breast carcinomas. This research project may identify new stromal drug targets for the treatment of breast cancer patients.

  15. S100 protein in breast tumor

    OpenAIRE

    Li, F; X Men; Zhang, W

    2014-01-01

    S100 protein is the largest subtribe in calcium binding protein family. According to recent researches, abnormal expression of S100 protein is often related to tumor, including breast tumor. Breast tumor is the most common malignant disease in female with high mortality mainly due to metastasis. Estimating early diagnostic and prognostic markers are helpful to conduct treatment for patients with breast cancer. Accumulating investigations focused on the role of S100 proteins in breast tumor de...

  16. Cancer-associated adipocytes promotes breast tumor radioresistance

    Energy Technology Data Exchange (ETDEWEB)

    Bochet, Ludivine; Meulle, Aline [Universite de Toulouse, UPS, F-31077 Toulouse Cedex (France); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP 64182, F-31077 Toulouse Cedex (France); Institut National de la Sante et de la Recherche Medicale, INSERM U1048, 1 Avenue du Pr Jean Poulhes, BP 84225, F-31432 Toulouse Cedex (France); Imbert, Sandrine [CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP 64182, F-31077 Toulouse Cedex (France); Salles, Bernard [Universite de Toulouse, UPS, F-31077 Toulouse Cedex (France); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP 64182, F-31077 Toulouse Cedex (France); Valet, Philippe [Universite de Toulouse, UPS, F-31077 Toulouse Cedex (France); Institut National de la Sante et de la Recherche Medicale, INSERM U1048, 1 Avenue du Pr Jean Poulhes, BP 84225, F-31432 Toulouse Cedex (France); Muller, Catherine, E-mail: muller@ipbs.fr [Universite de Toulouse, UPS, F-31077 Toulouse Cedex (France); CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP 64182, F-31077 Toulouse Cedex (France)

    2011-07-22

    Highlights: {yields} Tumor-surrounding adipocytes contribute to breast cancer progression. {yields} Breast tumor cells previously co-cultivated with mature adipocytes exhibit radioresistance. {yields} Increased in Chk1 phosphorylation is observed in irradiated co-cultivated tumor cells. {yields} IL-6 is over-expressed in tumor cells co-cultivated with adipocytes. {yields} IL-6 exposure confers increased Chk1 phosphorylation and radioresistance in tumor cells. -- Abstract: Mature adipocytes are excellent candidates to influence tumor behavior through heterotypic signaling processes since these cells produce hormones, growth factors, cytokines and other molecules, a heterogeneous group of molecules named adipokines. Using a 2D coculture system, we demonstrate that breast tumor cells previously co-cultivated with mature adipocytes exhibit radioresistance and an earlier and higher increase in the effector kinase Chk1, a phenotype that was associated with decreased cell death as compared to tumor cells grown alone. Interestingly, the adipocytes-induced tumor changes taking place during the coculture time preceding the exposure to IR were sufficient to confer the radioresistant effect. Notorious among the changes brought by adipocytes was the significant increase of IL-6 expression in tumor cells, whose activity may well account for the observed tumor cell protection from IR toxicity. Indeed, our data confirmed the protective role of this cytokine as tumor cells incubated after irradiation with recombinant IL-6 exhibit an increased in Chk1 phosphorylation and a radioresistant phenotype, thus far recapitulating the effects observed in the presence of adipocytes. Our current study sheds light on a new role of tumor-surrounding adipocytes in fostering a radioresistant phenotype in breast tumors, a finding that might have important clinical implications in obese patients that frequently exhibit aggressive diseases.

  17. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy

    OpenAIRE

    Fillmore, Christine M.; Kuperwasser, Charlotte

    2008-01-01

    Introduction The phenotypic and functional differences between cells that initiate human breast tumors (cancer stem cells) and those that comprise the tumor bulk are difficult to study using only primary tumor tissue. We embarked on this study hypothesizing that breast cancer cell lines would contain analogous hierarchical differentiation programs to those found in primary breast tumors. Methods Eight human breast cell lines (human mammary epithelial cells, and MCF10A, MCF7, SUM149, SUM159, S...

  18. Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer.

    Directory of Open Access Journals (Sweden)

    Julie A Wallace

    Full Text Available Tumor fibroblasts are active partners in tumor progression, but the genes and pathways that mediate this collaboration are ill-defined. Previous work demonstrates that Ets2 function in stromal cells significantly contributes to breast tumor progression. Conditional mouse models were used to study the function of Ets2 in both mammary stromal fibroblasts and epithelial cells. Conditional inactivation of Ets2 in stromal fibroblasts in PyMT and ErbB2 driven tumors significantly reduced tumor growth, however deletion of Ets2 in epithelial cells in the PyMT model had no significant effect. Analysis of gene expression in fibroblasts revealed a tumor- and Ets2-dependent gene signature that was enriched in genes important for ECM remodeling, cell migration, and angiogenesis in both PyMT and ErbB2 driven-tumors. Consistent with these results, PyMT and ErbB2 tumors lacking Ets2 in fibroblasts had fewer functional blood vessels, and Ets2 in fibroblasts elicited changes in gene expression in tumor endothelial cells consistent with this phenotype. An in vivo angiogenesis assay revealed the ability of Ets2 in fibroblasts to promote blood vessel formation in the absence of tumor cells. Importantly, the Ets2-dependent gene expression signatures from both mouse models were able to distinguish human breast tumor stroma from normal stroma, and correlated with patient outcomes in two whole tumor breast cancer data sets. The data reveals a key function for Ets2 in tumor fibroblasts in signaling to endothelial cells to promote tumor angiogenesis. The results highlight the collaborative networks that orchestrate communication between stromal cells and tumor cells, and suggest that targeting tumor fibroblasts may be an effective strategy for developing novel anti-angiogenic therapies.

  19. Tumor and serum ferritin in breast cancer

    International Nuclear Information System (INIS)

    In order to assess whether serum ferritin may be considered as a tumoral marker in breast cancer, we have measured in 38 patients the contents of ferritin in the tumor and the pre- and postoperative ferritin concentrations in serum. The study of isoferritins by iso-electric focusing was also performed in tumor extracts and in the corresponding sera

  20. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity

    NARCIS (Netherlands)

    Almendro, Vanessa; Cheng, Yu-Kang; Randles, Amanda; Itzkovitz, Shalev; Marusyk, Andriy; Ametller, Elisabet; Gonzalez-Farre, Xavier; Muñoz, Montse; Russnes, Hege G; Helland, Aslaug; Rye, Inga H; Borresen-Dale, Anne-Lise; Maruyama, Reo; van Oudenaarden, Alexander; Dowsett, Mitchell; Jones, Robin L; Reis-Filho, Jorge; Gascon, Pere; Gönen, Mithat; Michor, Franziska; Polyak, Kornelia

    2014-01-01

    Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-

  1. The Human Cell Surfaceome of Breast Tumors

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    Júlia Pinheiro Chagas da Cunha

    2013-01-01

    Full Text Available 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.

  2. Laminin isoform expression in breast tumors

    OpenAIRE

    Holler, Eggehard

    2005-01-01

    Certain laminins of vascular basement membranes have been identified in human breast tumors and brain gliomas that share the same β1 chain. These laminins are new carcinoma angiogenic markers and might represent potential targets for antiangiogenic therapy.

  3. Genomic tumor evolution of breast cancer.

    Science.gov (United States)

    Sato, Fumiaki; Saji, Shigehira; Toi, Masakazu

    2016-01-01

    Owing to recent technical development of comprehensive genome-wide analysis such as next generation sequencing, deep biological insights of breast cancer have been revealed. Information of genomic mutations and rearrangements in patients' tumors is indispensable to understand the mechanism in carcinogenesis, progression, metastasis, and resistance to systemic treatment of breast cancer. To date, comprehensive genomic analyses illustrate not only base substitution patterns and lists of driver mutations and key rearrangements, but also a manner of tumor evolution. Breast cancer genome is dynamically changing and evolving during cancer development course from non-invasive disease via invasive primary tumor to metastatic tumor, and during treatment exposure. The accumulation pattern of base substitution and genomic rearrangement looks gradual and punctuated, respectively, in analogy with contrasting theories for evolution manner of species, Darwin's phyletic gradualism, and Eldredge and Gould's "punctuated equilibrium". Liquid biopsy is a non-invasive method to detect the genomic evolution of breast cancer. Genomic mutation patterns in circulating tumor cells and circulating cell-free tumor DNA represent those of tumors existing in patient body. Liquid biopsy methods are now under development for future application to clinical practice of cancer treatment. In this article, latest knowledge regarding breast cancer genome, especially in terms of 'tumor evolution', is summarized. PMID:25998191

  4. Cancer-Associated Adipocytes Exhibit an ActivatedPhenotype and Contribute to Breast Cancer Invasion

    OpenAIRE

    2011-01-01

    Early local tumor invasion in breast cancer results in a likely encounter between cancer cells and matureadipocytes, but the role of these fat cells in tumor progression remains unclear. We show that murine and humantumor cells cocultivated with mature adipocytes exhibit increased invasive capacities in vitro and in vivo, usingan original two-dimensional coculture system. Likewise, adipocytes cultivated with cancer cells also exhibit analtered phenotype in terms of delipidation and decreased ...

  5. Differential expression of immune-related markers in breast cancer by molecular phenotypes.

    Science.gov (United States)

    Choi, Junjeong; Kim, Do Hee; Jung, Woo Hee; Koo, Ja Seung

    2013-01-01

    The purpose of this study is to investigate the relationship between expression of immune-related molecules such as STAT1, CD20, IL-8, IFN-γ, tumor genetic phenotype, and the clinical course of invasive breast cancer. We constructed tissue microarrays from the breast cancers of 727 patients and classified the cases as either luminal A, luminal B, HER-2, or triple negative breast cancer (TNBC) based on standard pathological and clinical classifications using genetic phenotype. Surrogate immunohistochemical stains (STAT1, CD20, IL-8, IFN-γ) and HER-2 FISH were performed on each microarray. Of the 727 patients cases, 303 (41.7 %) were luminal A, 169 (23.2 %) were luminal B, 71 (9.8 %) were HER2+, and 184 (25.3 %) were TNBC. The expression of STAT1 in tumor cells was higher in luminal-type cancers than in HER2+ and TNBC (P IL-8 expression (P = 0.005), and CD20 index (P IL-8 positivity was associated with shorter DFS and OS in ER positive group, HER-2 negative group, and luminal A group (P IL-8, and CD20 are differentially expressed and define particular molecular subtypes which correlate with genetically defined types of tumors. High expression of STAT1 in tumor cells is observed in luminal-type tumors, whereas stromal expression of STAT1, stromal IL-8, and IL-8 in tumor cells is the highest in TNBC-type tumors.

  6. DNMT3b overexpression contributes to a hypermethylator phenotype in human breast cancer cell lines

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    Rivenbark Ashley G

    2008-01-01

    Full Text Available Abstract Background DNA hypermethylation events and other epimutations occur in many neoplasms, producing gene expression changes that contribute to neoplastic transformation, tumorigenesis, and tumor behavior. Some human cancers exhibit a hypermethylator phenotype, characterized by concurrent DNA methylation-dependent silencing of multiple genes. To determine if a hypermethylation defect occurs in breast cancer, the expression profile and promoter methylation status of methylation-sensitive genes were evaluated among breast cancer cell lines. Results The relationship between gene expression (assessed by RT-PCR and quantitative real-time PCR, promoter methylation (assessed by methylation-specific PCR, bisulfite sequencing, and 5-aza-2'deoxycytidine treatment, and the DNA methyltransferase machinery (total DNMT activity and expression of DNMT1, DNMT3a, and DNMT3b proteins were examined in 12 breast cancer cell lines. Unsupervised cluster analysis of the expression of 64 methylation-sensitive genes revealed two groups of cell lines that possess distinct methylation signatures: (i hypermethylator cell lines, and (ii low-frequency methylator cell lines. The hypermethylator cell lines are characterized by high rates of concurrent methylation of six genes (CDH1, CEACAM6, CST6, ESR1, LCN2, SCNN1A, whereas the low-frequency methylator cell lines do not methylate these genes. Hypermethylator cell lines coordinately overexpress total DNMT activity and DNMT3b protein levels compared to normal breast epithelial cells. In contrast, most low-frequency methylator cell lines possess DNMT activity and protein levels that are indistinguishable from normal. Microarray data mining identified a strong cluster of primary breast tumors that express the hypermethylation signature defined by CDH1, CEACAM6, CST6, ESR1, LCN2, and SCNN1A. This subset of breast cancers represents 18/88 (20% tumors in the dataset analyzed, and 100% of these tumors were classified as basal

  7. SU-E-J-248: Contributions of Tumor and Stroma Phenotyping in Computer-Aided Diagnosis

    International Nuclear Information System (INIS)

    Purpose: To gain insight into the role of parenchyma stroma in the characterization of breast tumors by incorporating computerized mammographic parenchyma assessment into breast CADx in the task of distinguishing between malignant and benign lesions. Methods: This study was performed on 182 biopsy-proven breast mass lesions, including 76 benign and 106 malignant lesions. For each full-field digital mammogram (FFDM) case, our quantitative imaging analysis was performed on both the tumor and a region-of-interest (ROI) from the normal contralateral breast. The lesion characterization includes automatic lesion segmentation and feature extraction. Radiographic texture analysis (RTA) was applied on the normal ROIs to assess the mammographic parenchymal patterns of these contralateral normal breasts. Classification performance of both individual computer extracted features and the output from a Bayesian artificial neural network (BANN) were evaluated with a leave-one-lesion-out method using receiver operating characteristic (ROC) analysis with area under the curve (AUC) as the figure of merit. Results: Lesion characterization included computer-extracted phenotypes of spiculation, size, shape, and margin. For parenchymal pattern characterization, five texture features were selected, including power law beta, contrast, and edge gradient. Merging of these computer-selected features using BANN classifiers yielded AUC values of 0.79 (SE=0.03) and 0.67 (SE=0.04) in the task of distinguishing between malignant and benign lesions using only tumor phenotypes and texture features from the contralateral breasts, respectively. Incorporation of tumor phenotypes with parenchyma texture features into the BANN yielded improved classification performance with an AUC value of 0.83 (SE=0.03) in the task of differentiating malignant from benign lesions. Conclusion: Combining computerized tumor and parenchyma phenotyping was found to significantly improve breast cancer diagnostic accuracy

  8. SU-E-J-248: Contributions of Tumor and Stroma Phenotyping in Computer-Aided Diagnosis

    Energy Technology Data Exchange (ETDEWEB)

    Li, H; Lan, L; Sennett, C; Giger, M [Univ Chicago, Chicago, IL (United States)

    2015-06-15

    Purpose: To gain insight into the role of parenchyma stroma in the characterization of breast tumors by incorporating computerized mammographic parenchyma assessment into breast CADx in the task of distinguishing between malignant and benign lesions. Methods: This study was performed on 182 biopsy-proven breast mass lesions, including 76 benign and 106 malignant lesions. For each full-field digital mammogram (FFDM) case, our quantitative imaging analysis was performed on both the tumor and a region-of-interest (ROI) from the normal contralateral breast. The lesion characterization includes automatic lesion segmentation and feature extraction. Radiographic texture analysis (RTA) was applied on the normal ROIs to assess the mammographic parenchymal patterns of these contralateral normal breasts. Classification performance of both individual computer extracted features and the output from a Bayesian artificial neural network (BANN) were evaluated with a leave-one-lesion-out method using receiver operating characteristic (ROC) analysis with area under the curve (AUC) as the figure of merit. Results: Lesion characterization included computer-extracted phenotypes of spiculation, size, shape, and margin. For parenchymal pattern characterization, five texture features were selected, including power law beta, contrast, and edge gradient. Merging of these computer-selected features using BANN classifiers yielded AUC values of 0.79 (SE=0.03) and 0.67 (SE=0.04) in the task of distinguishing between malignant and benign lesions using only tumor phenotypes and texture features from the contralateral breasts, respectively. Incorporation of tumor phenotypes with parenchyma texture features into the BANN yielded improved classification performance with an AUC value of 0.83 (SE=0.03) in the task of differentiating malignant from benign lesions. Conclusion: Combining computerized tumor and parenchyma phenotyping was found to significantly improve breast cancer diagnostic accuracy

  9. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity

    International Nuclear Information System (INIS)

    Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and post-treatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution

  10. Genotyping and Phenotyping of Male Breast Cancer

    NARCIS (Netherlands)

    Kornegoor, R.

    2012-01-01

    Male breast cancer is a rare disease and most of the knowledge has been extrapolated from females, although these entities are likely different. A better understanding of male breast carcinogenesis is crucial for developing novel targets suitable for personalized treatment. A major problem in studyi

  11. The lipid phenotype of breast cancer cells characterized by Raman microspectroscopy: towards a stratification of malignancy.

    Directory of Open Access Journals (Sweden)

    Claudia Nieva

    Full Text Available Although molecular classification brings interesting insights into breast cancer taxonomy, its implementation in daily clinical care is questionable because of its expense and the information supplied in a single sample allocation is not sufficiently reliable. New approaches, based on a panel of small molecules derived from the global or targeted analysis of metabolic profiles of cells, have found a correlation between activation of de novo lipogenesis and poorer prognosis and shorter disease-free survival for many tumors. We hypothesized that the lipid content of breast cancer cells might be a useful indirect measure of a variety of functions coupled to breast cancer progression. Raman microspectroscopy was used to characterize metabolism of breast cancer cells with different degrees of malignancy. Raman spectra from MDA-MB-435, MDA-MB-468, MDA-MB-231, SKBR3, MCF7 and MCF10A cells were acquired with an InVia Raman microscope (Renishaw with a backscattered configuration. We used Principal Component Analysis and Partial Least Squares Discriminant Analyses to assess the different profiling of the lipid composition of breast cancer cells. Characteristic bands related to lipid content were found at 3014, 2935, 2890 and 2845 cm(-1, and related to lipid and protein content at 2940 cm(-1. A classificatory model was generated which segregated metastatic cells and non-metastatic cells without basal-like phenotype with a sensitivity of 90% and a specificity of 82.1%. Moreover, expression of SREBP-1c and ABCA1 genes validated the assignation of the lipid phenotype of breast cancer cells. Indeed, changes in fatty acid unsaturation were related with the epithelial-to-mesenchymal transition phenotype. Raman microspectroscopy is a promising technique for characterizing and classifying the malignant phenotype of breast cancer cells on the basis of their lipid profiling. The algorithm for the discrimination of metastatic ability is a first step towards

  12. Three-dimensional in vitro co-culture model of breast tumor using magnetic levitation.

    Science.gov (United States)

    Jaganathan, Hamsa; Gage, Jacob; Leonard, Fransisca; Srinivasan, Srimeenakshi; Souza, Glauco R; Dave, Bhuvanesh; Godin, Biana

    2014-01-01

    In this study, we investigate a novel in vitro model to mimic heterogeneous breast tumors without the use of a scaffold while allowing for cell-cell and tumor-fibroblast interactions. Previous studies have shown that magnetic levitation system under conventional culturing conditions results in the formation of three-dimensional (3D) structures, closely resembling in vivo tissues (fat tissue, vasculature, etc.). Three-dimensional heterogeneous tumor models for breast cancer were designed to effectively model the influences of the tumor microenvironment on drug efficiency. Various breast cancer cells were co-cultured with fibroblasts and then magnetically levitated. Size and cell density of the resulting tumors were measured. The model was phenotypically compared to in vivo tumors and examined for the presence of ECM proteins. Lastly, the effects of tumor stroma in the 3D in vitro model on drug transport and efficiency were assessed. Our data suggest that the proposed 3D in vitro breast tumor is advantageous due to the ability to: (1) form large-sized (millimeter in diameter) breast tumor models within 24 h; (2) control tumor cell composition and density; (3) accurately mimic the in vivo tumor microenvironment; and (4) test drug efficiency in an in vitro model that is comparable to in vivo tumors. PMID:25270048

  13. 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.

  14. Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes

    DEFF Research Database (Denmark)

    Broeks, Annegien; Schmidt, Marjanka K; Sherman, Mark E;

    2011-01-01

    Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtype...

  15. Primary Neuroendocrine Tumor of the Breast: Imaging Features

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Eun Deok [Department of Clinical Pathology, Uijeongbu St. Mary' s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 480-717 (Korea, Republic of); Kim, Min Kyun [Department of Radiology, Uijeongbu St. Mary' s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 480-717 (Korea, Republic of); Kim, Jeong Soo [Department of Surgery, Uijeongbu St. Mary' s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 480-717 (Korea, Republic of); Whang, In Yong [Department of Radiology, Uijeongbu St. Mary' s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 480-717 (Korea, Republic of)

    2013-07-01

    Focal neuroendocrine differentiation can be found in diverse histological types of breast tumors. However, the term, neuroendocrine breast tumor, indicates the diffuse expression of neuroendocrine markers in more than 50% of the tumor cell population. The imaging features of neuroendocrine breast tumor have not been accurately described due to extreme rarity of this tumor type. We present a case of a pathologically confirmed, primary neuroendocrine breast tumor in a 42-year-old woman, with imaging findings difficult to be differentiated from that of invasive ductal carcinoma.

  16. Prevalence of Papillomaviruses, Polyomaviruses, and Herpesviruses in Triple-Negative and Inflammatory Breast Tumors from Algeria Compared with Other Types of Breast Cancer Tumors

    Science.gov (United States)

    Corbex, Marilys; Bouzbid, Sabiha; Traverse-Glehen, Alexandra; Aouras, Hayette; McKay-Chopin, Sandrine; Carreira, Christine; Lankar, Abdelaziz; Tommasino, Massimo; Gheit, Tarik

    2014-01-01

    Background The possible role of viruses in breast cancer etiology remains an unresolved question. We hypothesized that if some viruses are involved, it may be in a subgroup of breast cancers only. Epidemiological arguments drove our interest in breast cancer subgroups that are more frequent in Africa, namely inflammatory breast cancer (IBC) and triple-negative breast cancer. We tested whether viral prevalence was significantly higher in these subgroups. Materials and Methods One hundred fifty-five paraffin-embedded malignant breast tumors were randomly selected at the pathology laboratory of the University Hospital of Annaba (Algeria) to include one third of IBC and two thirds of non-IBC. They were tested for the presence of DNA from 61 viral agents (46 human papillomaviruses, 10 polyomaviruses, and 5 herpesviruses) using type-specific multiplex genotyping assays, which combine multiplex PCR and bead-based Luminex technology. Results Viral DNA was found in 22 (17.9%) of 123 tumors. The most prevalent viruses were EBV1 and HPV16. IBC tumors carried significantly more viruses (any type) than non-IBC tumors (30% vs. 13%, p<0.04). Similarly, triple-negative tumors displayed higher virus-positivity than non-triple-negative tumors (44% vs. 14%, p<0.009). Conclusions Our results suggest an association between the presence of viral DNA and aggressive breast cancer phenotypes (IBC, triple-negative). While preliminary, they underline the importance of focusing on subgroups when studying viral etiology in breast cancer. Further studies on viruses in breast cancer should be conducted in much larger samples to confirm these initial findings. PMID:25478862

  17. Prevalence of papillomaviruses, polyomaviruses, and herpesviruses in triple-negative and inflammatory breast tumors from algeria compared with other types of breast cancer tumors.

    Directory of Open Access Journals (Sweden)

    Marilys Corbex

    Full Text Available The possible role of viruses in breast cancer etiology remains an unresolved question. We hypothesized that if some viruses are involved, it may be in a subgroup of breast cancers only. Epidemiological arguments drove our interest in breast cancer subgroups that are more frequent in Africa, namely inflammatory breast cancer (IBC and triple-negative breast cancer. We tested whether viral prevalence was significantly higher in these subgroups.One hundred fifty-five paraffin-embedded malignant breast tumors were randomly selected at the pathology laboratory of the University Hospital of Annaba (Algeria to include one third of IBC and two thirds of non-IBC. They were tested for the presence of DNA from 61 viral agents (46 human papillomaviruses, 10 polyomaviruses, and 5 herpesviruses using type-specific multiplex genotyping assays, which combine multiplex PCR and bead-based Luminex technology.Viral DNA was found in 22 (17.9% of 123 tumors. The most prevalent viruses were EBV1 and HPV16. IBC tumors carried significantly more viruses (any type than non-IBC tumors (30% vs. 13%, p<0.04. Similarly, triple-negative tumors displayed higher virus-positivity than non-triple-negative tumors (44% vs. 14%, p<0.009.Our results suggest an association between the presence of viral DNA and aggressive breast cancer phenotypes (IBC, triple-negative. While preliminary, they underline the importance of focusing on subgroups when studying viral etiology in breast cancer. Further studies on viruses in breast cancer should be conducted in much larger samples to confirm these initial findings.

  18. Choice of treatment and diagnostic tactics at nonpalpable breast tumors

    Directory of Open Access Journals (Sweden)

    Ye. P. Kulikov

    2013-01-01

    Full Text Available Results of inspection, treatment and dynamic supervision of 166 patients with nonpalpable breast tumors are presented. Distribution of tumors on BI-RADS system is given. Possibilities of a mammography and ultrasonography in diagnostics of a preclinical breast cancer are shown. Practical recommendations about a choice of an optimum way of presurgical verification of nonpalpable tumors are offered. Indications for surgical treat- ment and dynamic supervision are specified at nonpalpable breast tumors.

  19. The Role and Clinical Relevance of Disseminated Tumor Cells in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Malgorzata Banys

    2014-01-01

    Full Text Available Tumor cell dissemination is a common phenomenon observed in most cancers of epithelial origin. One-third of breast cancer patients present with disseminated tumor cells (DTCs in bone marrow at time of diagnosis; these patients, as well as patients with persistent DTCs, have significantly worse clinical outcome than DTC-negative patients. Since DTC phenotype may differ from the primary tumor with regard to ER and HER2 status, reevaluation of predictive markers on DTCs may optimize treatment choices. In the present review, we report on the clinical relevance of DTC detection in breast cancer.

  20. The Role and Clinical Relevance of Disseminated Tumor Cells in Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Banys, Malgorzata, E-mail: maggybanys@yahoo.de [Department of Obstetrics and Gynecology, University of Duesseldorf, Duesseldorf D-40225 (Germany); Department of Obstetrics and Gynecology, Marienkrankenhaus Hamburg, Hamburg D-22087 (Germany); Krawczyk, Natalia; Fehm, Tanja [Department of Obstetrics and Gynecology, University of Duesseldorf, Duesseldorf D-40225 (Germany)

    2014-01-15

    Tumor cell dissemination is a common phenomenon observed in most cancers of epithelial origin. One-third of breast cancer patients present with disseminated tumor cells (DTCs) in bone marrow at time of diagnosis; these patients, as well as patients with persistent DTCs, have significantly worse clinical outcome than DTC-negative patients. Since DTC phenotype may differ from the primary tumor with regard to ER and HER2 status, reevaluation of predictive markers on DTCs may optimize treatment choices. In the present review, we report on the clinical relevance of DTC detection in breast cancer.

  1. Ewing’s sarcoma: an uncommon breast tumor

    Directory of Open Access Journals (Sweden)

    Sawsen Meddeb

    2014-10-01

    Full Text Available Ewing’s sarcoma/primitive neuroectodermal tumors (EWS/PNET are rare malignant and aggressive tumors, usually seen in the trunk and lower limbs of children and young adults. They are uncommon in the breast. We report a case of a 43-year-old woman who developed a painless breast mass. An initial core needle biopsy concluded to a fibrocystic dystrophy contrasting with a rapidly growing mass; thus a large lumpectomy was done. Diagnosis of primary PNET of the breast was established, based on both histopathological examination and immunohistochemical findings. Surgical margins were positive, therefore, left modified radical mastectomy with axillary lymph nodes dissection was performed. The patient was given 6 cycles of adjuvant chemotherapy containing cyclophosphamide, adriamycin and vincristine. Twenty months later, she is in life without recurrence or metastasis. EWS/PNET may impose a diagnostic challenge. Indeed, mammography and ultrasonography features are non specific. The histopathological pattern is variable depending on the degree of neuroectodermal differentiation. Immuno-phenotyping is necessary and genetic study is the only confirmatory tool of diagnosis showing a characteristic cytogenetic anomaly; t (11; 22 translocation.

  2. Mitochondrial DNA content in breast cancer: Impact on in vitro and in vivo phenotype and patient prognosis

    Science.gov (United States)

    Weerts, Marjolein J.A.; Sieuwerts, Anieta M.; Smid, Marcel; Look, Maxime P.; Foekens, John A.; Sleijfer, Stefan; Martens, John W.M.

    2016-01-01

    Reduced mitochondrial DNA (mtDNA) content in breast cancer cell lines has been associated with transition towards a mesenchymal phenotype, but its clinical consequences concerning breast cancer dissemination remain unidentified. Here, we aimed to clarify the link between mtDNA content and a mesenchymal phenotype and its relation to prognosis of breast cancer patients. We analyzed mtDNA content in 42 breast cancer cell lines and 207 primary breast tumor specimens using a combination of quantitative PCR and array-based copy number analysis. By associating mtDNA content with expression levels of genes involved in epithelial-to-mesenchymal transition (EMT) and with the intrinsic breast cancer subtypes, we could not identify a relation between low mtDNA content and mesenchymal properties in the breast cancer cell lines or in the primary breast tumors. In addition, we explored the relation between mtDNA content and prognosis in our cohort of primary breast tumor specimens that originated from patients with lymph node-negative disease who did not receive any (neo)adjuvant systemic therapy. When patients were divided based on the tumor quartile levels of mtDNA content, those in the lowest quarter (≤ 350 mtDNA molecules per cell) showed a poorer 10-year distant metastasis-free survival than patients with > 350 mtDNA molecules per cell (HR 0.50 [95% CI 0.29–0.87], P = 0.015). The poor prognosis was independent of established clinicopathological markers (HR 0.54 [95% CI 0.30–0.97], P = 0.038). We conclude that, despite a lack of evidence between mtDNA content and EMT, low mtDNA content might provide meaningful prognostic value for distant metastasis in breast cancer. PMID:27081694

  3. HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients

    OpenAIRE

    Pannu, Vaishali; Rida, Padmashree C. G.; Ogden, Angela; Turaga, Ravi Chakra; Donthamsetty, Shashikiran; Bowen, Nathan J.; Rudd, Katie; Gupta, Meenakshi V.; Reid, Michelle D.; Cantuaria, Guilherme; Walczak, Claire E.; Aneja, Ritu

    2015-01-01

    Human breast tumors harbor supernumerary centrosomes in almost 80% of tumor cells. Although amplified centrosomes compromise cell viability via multipolar spindles resulting in death-inducing aneuploidy, cancer cells tend to cluster extra centrosomes during mitosis. As a result cancer cells display bipolar spindle phenotypes to maintain a tolerable level of aneuploidy, an edge to their survival. HSET/KifC1, a kinesin-like minus-end directed microtubule motor has recently found fame as a cruci...

  4. Impact of tumor chronology and tumor biology on lymph node metastasis in breast cancer

    OpenAIRE

    Smeets, Ann; Ryckx, Andries; Belmans, Ann; Wildiers, Hans; Neven, Patrick; Floris, Giuseppe; Schöffski, Patrick; Christiaens, Marie-Rose

    2013-01-01

    Synopsis The significance of nodal metastasis in breast cancer is under discussion. We investigated the impact of variables of tumor chronology and tumor biology on the presence of lymph node metastases. Purpose Lymph node involvement is the main prognostic factor in breast cancer. However, it is under discussion whether nodal metastasis in breast cancer only reflects the chronological age of the tumor or whether it is also a marker of tumor biology. The goal of our study was to investigate t...

  5. GRANULAR CELL TUMOR OF BREAST (CYTOLOGICAL DIAGNOSIS CONFIRMED BY HISTOPATHOLOGY

    Directory of Open Access Journals (Sweden)

    Divvya

    2014-10-01

    Full Text Available Granular cell tumor is a tumor derived from Schwann cells of peripheral nerves and it can occur throughout the body. About 5% of granular cell tumors occur in breast and are mostly benign in nature. We report a case of 30 year old female who presented with a swelling in right breast which on histo pathological examination revealed features consistent with granular cell tumor. This case is highlighted to reveal the importance of histopathology in differentiating granular cell tumor from carcinoma breast which is difficult based on clinical, radiological and cytological examination alone.

  6. Magnetic Resonance Spectroscopic Imaging of Tumor Metabolic Markers for Cancer Diagnosis, Metabolic Phenotyping, and Characterization of Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Qiuhong He

    2004-01-01

    Full Text Available Cancer cells display heterogeneous genetic characteristics, depending on the tumor dynamic microenvironment. Abnormal tumor vasculature and poor tissue oxygenation generate a fraction of hypoxic tumor cells that have selective advantages in metastasis and invasion and often resist chemo- and radiation therapies. The genetic alterations acquired by tumors modify their biochemical pathways, which results in abnormal tumor metabolism. An elevation in glycolysis known as the “Warburg effect” and changes in lipid synthesis and oxidation occur. Magnetic resonance spectroscopy (MRS has been used to study tumor metabolism in preclinical animal models and in clinical research on human breast, brain, and prostate cancers. This technique can identify specific genetic and metabolic changes that occur in malignant tumors. Therefore, the metabolic markers, detectable by MRS, not only provide information on biochemical changes but also define different metabolic tumor phenotypes. When combined with the contrast-enhanced Magnetic Resonance Imaging (MRI, which has a high sensitivity for cancer diagnosis, in vivo magnetic resonance spectroscopic imaging (MRSI improves the diagnostic specificity of malignant human cancers and is becoming an important clinical tool for cancer management and care. This article reviews the MRSI techniques as molecular imaging methods to detect and quantify metabolic changes in various tumor tissue types, especially in extracranial tumor tissues that contain high concentrations of fat. MRI/MRSI methods have been used to characterize tumor microenvironments in terms of blood volume and vessel permeability. Measurements of tissue oxygenation and glycolytic rates by MRS also are described to illustrate the capability of the MR technology in probing molecular information non-invasively in tumor tissues and its important potential for studying molecular mechanisms of human cancers in physiological conditions.

  7. ADP ribosylation factor like 2 (Arl2 regulates breast tumor aggressivity in immunodeficient mice.

    Directory of Open Access Journals (Sweden)

    Anne Beghin

    Full Text Available We have previously reported that ADP ribosylation factor like 2 (Arl2, a small GTPase, content influences microtubule dynamics and cell cycle distribution in breast tumor cells, as well as the degree and distribution of phosphorylated P53. Here we show, in two different human breast adenocarcinoma models, that Arl2 content has a major impact on breast tumor cell aggressivity both in vitro and in vivo. Cells with reduced content of Arl2 displayed reduced contact inhibition, increased clonogenic or cluster formation as well as a proliferative advantage over control cells in an in vitro competition assay. These cells also caused larger tumors in SCID mice, a phenotype which was mimicked by the in vivo administration of siRNA directed against Arl2. Cells with increased Arl2 content displayed reduced aggressivity, both in vitro and in vivo, with enhanced necrosis and were also found to contain increased PP2A phosphatase activity. A rt-PCR analysis of fresh human tumor breast samples suggested that low Arl2 expression was associated with larger tumor size and greater risk of lymph node involvement at diagnosis. These data underline the role of Arl2, a small GTPase, as an important regulator of breast tumor cell aggressivity, both in vitro and in vivo.

  8. Simulation of avascular tumor growth by agent-based game model involving phenotype-phenotype interactions.

    Science.gov (United States)

    Chen, Yong; Wang, Hengtong; Zhang, Jiangang; Chen, Ke; Li, Yumin

    2015-01-01

    All tumors, both benign and metastatic, undergo an avascular growth stage with nutrients supplied by the surrounding tissue. This avascular growth process is much easier to carry out in more qualitative and quantitative experiments starting from tumor spheroids in vitro with reliable reproducibility. Essentially, this tumor progression would be described as a sequence of phenotypes. Using agent-based simulation in a two-dimensional spatial lattice, we constructed a composite growth model in which the phenotypic behavior of tumor cells depends on not only the local nutrient concentration and cell count but also the game among cells. Our simulation results demonstrated that in silico tumors are qualitatively similar to those observed in tumor spheroid experiments. We also found that the payoffs in the game between two living cell phenotypes can influence the growth velocity and surface roughness of tumors at the same time. Finally, this current model is flexible and can be easily extended to discuss other situations, such as environmental heterogeneity and mutation. PMID:26648395

  9. Primary extraskeletal Ewing's sarcoma/primitive neuroectodermal tumor of breast

    Science.gov (United States)

    Srivastava, Smita; Arora, Jyoti; Parakh, Anushri; Goel, Ruchika Kumar

    2016-01-01

    Extraskeletal Ewing's sarcoma (EES) is a rare soft tissue tumor that is morphologically indistinguishable from skeletal ES. We report a case of a 25-year-old female with recurrent EES/primitive neuroectodermal tumor of right breast with imaging findings on mammogram, ultrasound, magnetic resonance imaging breast, and positron emission tomography–computed tomography.

  10. Dose determination in breast tumor in brachytherapy using Iridium-192

    International Nuclear Information System (INIS)

    Thermoluminescent dosimetry studies in vivo and in vitro aiming to determing radiation dose in the breast tumor, in brachytherapy using Iridium-192 was done. The correlation between radiation doses in tumor and external surface of the breast was investigated for correcting the time interval of radiation source implantation. (author)

  11. Molecular Markers for Breast Cancer: Prediction on Tumor Behavior

    OpenAIRE

    Bruna Karina Banin Hirata; Julie Massayo Maeda Oda; Roberta Losi Guembarovski; Carolina Batista Ariza; Carlos Eduardo Coral de Oliveira; Maria Angelica Ehara Watanabe

    2014-01-01

    Breast cancer is one of the most common cancers with greater than 1,300,000 cases and 450,000 deaths each year worldwide. The development of breast cancer involves a progression through intermediate stages until the invasive carcinoma and finally into metastatic disease. Given the variability in clinical progression, the identification of markers that could predict the tumor behavior is particularly important in breast cancer. The determination of tumor markers is a useful tool for clinical m...

  12. Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer.

    Science.gov (United States)

    Singhal, Hari; Greene, Marianne E; Tarulli, Gerard; Zarnke, Allison L; Bourgo, Ryan J; Laine, Muriel; Chang, Ya-Fang; Ma, Shihong; Dembo, Anna G; Raj, Ganesh V; Hickey, Theresa E; Tilley, Wayne D; Greene, Geoffrey L

    2016-06-01

    The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER(+) (estrogen receptor-positive)/PR(+) human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER(+)/PR(+) breast cancers should be explored. PMID:27386569

  13. Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes

    DEFF Research Database (Denmark)

    Broeks, Annegien; Schmidt, Marjanka K; Sherman, Mark E;

    2011-01-01

    Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtype...... stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment.......Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes...... were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations...

  14. The Motile Breast Cancer Phenotype Roles of Proteoglycans/Glycosaminoglycans

    Directory of Open Access Journals (Sweden)

    Dragana Nikitovic

    2014-01-01

    Full Text Available The consecutive stages of cancer growth and dissemination are obligatorily perpetrated through specific interactions of the tumor cells with their microenvironment. Importantly, cell-associated and tumor microenvironment glycosaminoglycans (GAGs/proteoglycan (PG content and distribution are markedly altered during tumor pathogenesis and progression. GAGs and PGs perform multiple functions in specific stages of the metastatic cascade due to their defined structure and ability to interact with both ligands and receptors regulating cancer pathogenesis. Thus, GAGs/PGs may modulate downstream signaling of key cellular mediators including insulin growth factor receptor (IGFR, epidermal growth factor receptor (EGFR, estrogen receptors (ERs, or Wnt members. In the present review we will focus on breast cancer motility in correlation with their GAG/PG content and critically discuss mechanisms involved. Furthermore, new approaches involving GAGs/PGs as potential prognostic/diagnostic markers or as therapeutic agents for cancer-related pathologies are being proposed.

  15. 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.

  16. 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)

    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

  17. The Potential Role of Hedgehog Signaling in the Luminal/Basal Phenotype of Breast Epithelia and in Breast Cancer Invasion and Metastasis

    Directory of Open Access Journals (Sweden)

    Arwa Flemban

    2015-09-01

    Full Text Available 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.

  18. The Potential Role of Hedgehog Signaling in the Luminal/Basal Phenotype of Breast Epithelia and in Breast Cancer Invasion and Metastasis.

    Science.gov (United States)

    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. PMID:26389956

  19. Endothelial cell pseudopods and angiogenesis of breast cancer tumors

    OpenAIRE

    Sun LuZhe; Short Nicholas; Cameron Ivan L; Hardman W Elaine

    2005-01-01

    Abstract Background A neoplastic tumor cannot grow beyond a millimeter or so in diameter without recruitment of endothelial cells and new blood vessels to supply nutrition and oxygen for tumor cell survival. This study was designed to investigate formation of new blood vessels within a human growing breast cancer tumor model (MDA MB231 in mammary fat pad of nude female mouse). Once the tumor grew to 35 mm3, it developed a well-vascularized capsule. Histological sections of tumors greater than...

  20. Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue

    Directory of Open Access Journals (Sweden)

    Ana M. Santander

    2015-01-01

    Full Text Available The relationship between obesity and breast cancer (BC has focused on serum factors. However, the mammary gland contains adipose tissue (AT which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations. In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity.

  1. Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue

    International Nuclear Information System (INIS)

    The relationship between obesity and breast cancer (BC) has focused on serum factors. However, the mammary gland contains adipose tissue (AT) which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT) is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations). In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity

  2. Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue

    Energy Technology Data Exchange (ETDEWEB)

    Santander, Ana M.; Lopez-Ocejo, Omar; Casas, Olivia; Agostini, Thais; Sanchez, Lidia; Lamas-Basulto, Eduardo; Carrio, Roberto [Department of Microbiology and Immunology, University of Miami Miller School of Medicine, 1600 NW 10th Ave, Miami, FL 33136 (United States); Cleary, Margot P. [Hormel Institute, University of Minnesota, Austin, MN 55912 (United States); Gonzalez-Perez, Ruben R. [Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30314 (United States); Torroella-Kouri, Marta, E-mail: mtorroella@med.miami.edu [Department of Microbiology and Immunology, University of Miami Miller School of Medicine, 1600 NW 10th Ave, Miami, FL 33136 (United States); Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1475 NW 12th Ave, Miami, FL 33136 (United States)

    2015-01-15

    The relationship between obesity and breast cancer (BC) has focused on serum factors. However, the mammary gland contains adipose tissue (AT) which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT) is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations). In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity.

  3. Influences of tumor stroma on the malignant phenotype

    DEFF Research Database (Denmark)

    Nielsen, Jørgen Dau; Moeslund, Mette; Wandall, Hans H;

    2008-01-01

    , fibronectin and laminin 5 are all characteristics of the tumor stroma. Less is, however, known of the significance of the biophysical properties of the tumor stroma. The purpose of the present study was to investigate how cellular and mechanical properties of the three-dimensional collagen matrix may...... and laminin 5 was investigated. RESULTS: We found that expression of glycosylated oncofetal fibronectin was increased in the invasive phenotype of oral carcinoma cell lines. Furthermore we demonstrated that certain concentrations of collagen in the connective tissue equivalent, appears to stimulate...

  4. Breast cancer cells mechanosensing in engineered matrices: Correlation with aggressive phenotype.

    Science.gov (United States)

    Li, Ji; Wu, Yang; Schimmel, Nicholas; Al-Ameen, Mohammad Ali; Ghosh, Gargi

    2016-08-01

    The pathogenesis of cancer is often driven by the modulation of the tumor microenvironment. Recent reports have highlighted that the progressive stiffening of tumor matrix is crucial for malignant transformation. Though extensive work has been done analyzing the mechanotransductive signals involved in tumor progression, it is still not clear whether the stiffness induced changes in cancer cell behavior is conserved across the invasive/aggressive phenotype of cells. Here, we used synthetic hydrogel based cell culture platform to correlate the aggressive potential of the breast cancer cells to the responses to matrix stiffness. The cellular functions such as proliferation, migration, and angiogenic capability were characterized. We report that the proliferation and motility of the highly aggressive cell line MDA-MB-231 increased with increase in matrix rigidity. We also demonstrated for the first time that the change in matrix stiffness stimulated the angiogenic activity of these cells as manifested from enhanced expression of vascular endothelial growth factor (VEGF). Inhibition of actomyosin contractility attenuated proliferation of MDA-MB-231 cells on stiff matrices while promoted the growth on soft gels. In addition, the release of VEGF was reduced upon inhibition of contractility. The less and non-aggressive breast cancer cells, SKBr3 and MCF-7 respectively displayed less dependency on matrix stiffness. PMID:26874251

  5. Radiologic findings of metastatic tumors to the breast

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sang Heum; Cha, Eun Suk; Park, Jeong Mi; Kim, Hak Hee; Kim, Ji Young; Park, Young Ha; Shinn, Kyung Sub [The Catholic Univ. of Korea College of Medicine, Suwon (Korea, Republic of)

    1999-09-01

    To analyze the radiologic findings of metastatic tumors of the breast. We retrospectively analyzed the findings of mammography (n = 12), ultrasonography (n = 9) and CT (n = 4) of 13 patients with metastatic tumors of the breast. Methods for confirmation were biopsy (n = 8) and clinical follow-up (n = 5). The patient' s ages ranged from 24 to 63 (mean 43)years. Primary malignancies were contralateral breast cancer (n = 3), non-Hodgkin' s lymphoma (n = 3), stomach cancer (n = 2), uterine cervix cancer (n = 1), laryngeal cancer (n = 1), esophageal melanoma (n = 1), malignant thymoma (n 1), and lung cancer (n = 1). Patterns of metastasis from contralateral breast cancer and the stomach cancer were diffuse and infiltrative, while metastasis from other cancers was of the focal mass-forming type. The radiologic findings of metastasis from contralateral breast cancer (n = 3) were diffuse skin thickening and increased density or echogenicity in the medial aspect of the breast, while in cases involving metastasis from stomach cancer (n = 2) radiographs revealed extensive skin thickening, increased density or echogenicity, lymphedema and ipsilateral lymphadenopathy in the left breast. In cases of metastatic tumors to the breast in which focal masses were seen on mammography (n = 7), marginal spiculation or microcalcification of the tumors was not present. In six such cases, ultrasonography revealed well-defined margin, posterior acoustic shadowing or an irregular thick echogenic boundary was not seen. It two patients who underwent CT scanning, well-defined masses with moderate contrast enhancement were present. Radiographs of metastatic tumors to the breast from contralateral breast cancer and stomach cancer showed diffuse infiltration. The metastatic tumors with focal masses showed oval to round, smooth-mar-ginated, well-defined masses without spiculation or microcalcification on mammography, and a well-defined mass without posterior acoustic shadowing or irregular

  6. Radiologic findings of metastatic tumors to the breast

    International Nuclear Information System (INIS)

    To analyze the radiologic findings of metastatic tumors of the breast. We retrospectively analyzed the findings of mammography (n = 12), ultrasonography (n = 9) and CT (n = 4) of 13 patients with metastatic tumors of the breast. Methods for confirmation were biopsy (n = 8) and clinical follow-up (n = 5). The patient' s ages ranged from 24 to 63 (mean 43)years. Primary malignancies were contralateral breast cancer (n = 3), non-Hodgkin' s lymphoma (n = 3), stomach cancer (n = 2), uterine cervix cancer (n = 1), laryngeal cancer (n = 1), esophageal melanoma (n = 1), malignant thymoma (n 1), and lung cancer (n = 1). Patterns of metastasis from contralateral breast cancer and the stomach cancer were diffuse and infiltrative, while metastasis from other cancers was of the focal mass-forming type. The radiologic findings of metastasis from contralateral breast cancer (n = 3) were diffuse skin thickening and increased density or echogenicity in the medial aspect of the breast, while in cases involving metastasis from stomach cancer (n = 2) radiographs revealed extensive skin thickening, increased density or echogenicity, lymphedema and ipsilateral lymphadenopathy in the left breast. In cases of metastatic tumors to the breast in which focal masses were seen on mammography (n = 7), marginal spiculation or microcalcification of the tumors was not present. In six such cases, ultrasonography revealed well-defined margin, posterior acoustic shadowing or an irregular thick echogenic boundary was not seen. It two patients who underwent CT scanning, well-defined masses with moderate contrast enhancement were present. Radiographs of metastatic tumors to the breast from contralateral breast cancer and stomach cancer showed diffuse infiltration. The metastatic tumors with focal masses showed oval to round, smooth-mar-ginated, well-defined masses without spiculation or microcalcification on mammography, and a well-defined mass without posterior acoustic shadowing or irregular thick

  7. Circulating tumor cells in newly diagnosed inflammatory breast cancer

    OpenAIRE

    Mego, Michal; Giordano, Antonio; De Giorgi, Ugo; Masuda, Hiroko; Hsu, Limin; Giuliano, Mario; Fouad, Tamer M.; Dawood, Shaheenah; Ueno, Naoto T.; Valero, Vicente; Andreopoulou, Eleni; Alvarez, Ricardo H.; Wendy A Woodward; Hortobagyi, Gabriel N; Cristofanilli, Massimo

    2015-01-01

    Introduction Circulating tumor cells (CTCs) are an independent prognostic factor for progression-free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer. Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. The prognostic value of a CTC count in newly diagnosed IBC has not been established. The aim of this study was to assess the prognostic value of a baseline CTC count in patients with newly diagnosed IBC. Methods This retrosp...

  8. Bilateral desmoid tumor of the breast: case seriesand literature review

    Science.gov (United States)

    Wongmaneerung, Phanchaporn; Somwangprasert, Areewan; Watcharachan, Kirati; Ditsatham, Chagkrit

    2016-01-01

    Background Desmoid tumor of the breast is very rare and locally aggressive but has no distant metastasis. Bilateral lesions are extremely rare, found in only 4% of patients. Two cases of bilateral desmoid tumor of the breast are reported. The clinical presentation, diagnosis, imaging, treatment, and follow-up outcomes of recurrence as well as a brief literature review are provided. Case reports Case 1 is a 31-year-old woman who presented with nipple retraction. An ultrasound revealed BIRAD V in both breasts. She underwent a bilateral excisional biopsy under ultrasound mark with the pathology result of extra-abdominal desmoid tumor in both breasts. The patient had a bilateral mastectomy with silicone implantation due to the involved margins by excision. She remained tumor free after 7-year follow-up. Case 2 is a 28-year-old woman who presented with a lump on her right breast that she had discovered ~2 months earlier. An ultrasound showed a spiculated mass in the right breast and some circumscribed hypoechoic masses in both breasts. A bilateral breast excision was done. The pathology result was an extra-abdominal desmoid tumor. She had recurrence on both sides and underwent a mastectomy and silicone implantation. The tumor has not recurred after 1-year follow-up. Conclusion Imaging cannot distinguish between benign breast lesions and malignancy. Pathology results are helpful in making a definitive diagnosis. Given that the desmoid tumor is locally aggressive, a local excision with clear margins is recommended. Chemotherapy and hormonal treatment are controversial. PMID:27578999

  9. Human breast tumor cells are more resistant to cardiac glycoside toxicity than non-tumorigenic breast cells.

    Directory of Open Access Journals (Sweden)

    Rebecca J Clifford

    Full Text Available Cardiotonic steroids (CTS, specific inhibitors of Na,K-ATPase activity, have been widely used for treating cardiac insufficiency. Recent studies suggest that low levels of endogenous CTS do not inhibit Na,K-ATPase activity but play a role in regulating blood pressure, inducing cellular kinase activity, and promoting cell viability. Higher CTS concentrations inhibit Na,K-ATPase activity and can induce reactive oxygen species, growth arrest, and cell death. CTS are being considered as potential novel therapies in cancer treatment, as they have been shown to limit tumor cell growth. However, there is a lack of information on the relative toxicity of tumor cells and comparable non-tumor cells. We have investigated the effects of CTS compounds, ouabain, digitoxin, and bufalin, on cell growth and survival in cell lines exhibiting the full spectrum of non-cancerous to malignant phenotypes. We show that CTS inhibit membrane Na,K-ATPase activity equally well in all cell lines tested regardless of metastatic potential. In contrast, the cellular responses to the drugs are different in non-tumor and tumor cells. Ouabain causes greater inhibition of proliferation and more extensive apoptosis in non-tumor breast cells compared to malignant or oncogene-transfected cells. In tumor cells, the effects of ouabain are accompanied by activation of anti-apoptotic ERK1/2. However, ERK1/2 or Src inhibition does not sensitize tumor cells to CTS cytotoxicity, suggesting that other mechanisms provide protection to the tumor cells. Reduced CTS-sensitivity in breast tumor cells compared to non-tumor cells indicates that CTS are not good candidates as cancer therapies.

  10. An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype.

    Directory of Open Access Journals (Sweden)

    Irina M Shapiro

    2011-08-01

    Full Text Available Epithelial-mesenchymal transition (EMT, a mechanism important for embryonic development, plays a critical role during malignant transformation. While much is known about transcriptional regulation of EMT, alternative splicing of several genes has also been correlated with EMT progression, but the extent of splicing changes and their contributions to the morphological conversion accompanying EMT have not been investigated comprehensively. Using an established cell culture model and RNA-Seq analyses, we determined an alternative splicing signature for EMT. Genes encoding key drivers of EMT-dependent changes in cell phenotype, such as actin cytoskeleton remodeling, regulation of cell-cell junction formation, and regulation of cell migration, were enriched among EMT-associated alternatively splicing events. Our analysis suggested that most EMT-associated alternative splicing events are regulated by one or more members of the RBFOX, MBNL, CELF, hnRNP, or ESRP classes of splicing factors. The EMT alternative splicing signature was confirmed in human breast cancer cell lines, which could be classified into basal and luminal subtypes based exclusively on their EMT-associated splicing pattern. Expression of EMT-associated alternative mRNA transcripts was also observed in primary breast cancer samples, indicating that EMT-dependent splicing changes occur commonly in human tumors. The functional significance of EMT-associated alternative splicing was tested by expression of the epithelial-specific splicing factor ESRP1 or by depletion of RBFOX2 in mesenchymal cells, both of which elicited significant changes in cell morphology and motility towards an epithelial phenotype, suggesting that splicing regulation alone can drive critical aspects of EMT-associated phenotypic changes. The molecular description obtained here may aid in the development of new diagnostic and prognostic markers for analysis of breast cancer progression.

  11. Medial tumor localization in breast cancer. An unappreciated risk factor?

    International Nuclear Information System (INIS)

    Purpose: to demonstrate the unfavorable results in survival rates in patients with medial breast cancer compared to patients with laterally located tumors of the mammary gland. Patients and Methods: Between 1984 and 1995, 1,089 patients presenting with a total of 1,100 pT1-2 invasive carcinomas of the breast were treated at the authors' institution. 707 presented with tumors in the lateral quadrants, 294 with tumors in the medial quadrants, and 99 with tumors in the central quadrant. Treatment protocols involved breast-conserving surgery and whole-breast radiotherapy in all women, followed by a tumor bed boost dose according to risk factors for local recurrence. All axillary node-positive patients underwent systemic therapy (six cycles of classic CMF and/or 2-5 years of tamoxifen 20 mg/day). Rates of actuarial survival and local control were calculated by the Kaplan-Meier method and differences in survival curves were compared by use of the log-rank test. Results: the mean follow-up of survivors was 97 months (range 36-192 months). Comparing patients with medial and lateral tumors, the actuarial survival data were significantly better for patients with lateral tumors. At 10 years, overall survival for patients with medial tumors was 71%, for patients with lateral tumors 81.8% (p < 0.025), disease-specific survival for patients with medial tumors 79.9%, for patients with lateral tumors 89.1% (p < 0.025). There was no significant difference in local tumor control according to tumor location. Conclusion: medial tumor location is associated with a lower survival rate, but not with inferior local tumor control. Failure to identify nodal metastases confined to the internal mammary chain may lead to undertreatment with systemic/local agents and compromised survival. (orig.)

  12. Medial tumor localization in breast cancer. An unappreciated risk factor?

    Energy Technology Data Exchange (ETDEWEB)

    Braeeutigam, Elisabeth; Feichtinger, Johann; Spiegl, Kurt; Hammer, Josef [Dept. of Radiation Oncology, Barmherzige Schwestern Hospital, Linz (Austria); Track, Christine [Dept. of Radiation Oncology, Barmherzige Schwestern Hospital, Linz (Austria); Comprehensive Breast Health Center, Barmherzige Schwestern Hospital, Linz (Austria); Seewald, Dietmar H. [Dept. of Radiation Oncology, General Hospital Voecklabruck (Austria)

    2009-10-15

    Purpose: to demonstrate the unfavorable results in survival rates in patients with medial breast cancer compared to patients with laterally located tumors of the mammary gland. Patients and Methods: Between 1984 and 1995, 1,089 patients presenting with a total of 1,100 pT1-2 invasive carcinomas of the breast were treated at the authors' institution. 707 presented with tumors in the lateral quadrants, 294 with tumors in the medial quadrants, and 99 with tumors in the central quadrant. Treatment protocols involved breast-conserving surgery and whole-breast radiotherapy in all women, followed by a tumor bed boost dose according to risk factors for local recurrence. All axillary node-positive patients underwent systemic therapy (six cycles of classic CMF and/or 2-5 years of tamoxifen 20 mg/day). Rates of actuarial survival and local control were calculated by the Kaplan-Meier method and differences in survival curves were compared by use of the log-rank test. Results: the mean follow-up of survivors was 97 months (range 36-192 months). Comparing patients with medial and lateral tumors, the actuarial survival data were significantly better for patients with lateral tumors. At 10 years, overall survival for patients with medial tumors was 71%, for patients with lateral tumors 81.8% (p < 0.025), disease-specific survival for patients with medial tumors 79.9%, for patients with lateral tumors 89.1% (p < 0.025). There was no significant difference in local tumor control according to tumor location. Conclusion: medial tumor location is associated with a lower survival rate, but not with inferior local tumor control. Failure to identify nodal metastases confined to the internal mammary chain may lead to undertreatment with systemic/local agents and compromised survival. (orig.)

  13. Value of ultrasound elastography in detecting small breast tumors

    Institute of Scientific and Technical Information of China (English)

    FU Li-na; WANG Yi; WANG Yong; HUANG Yong-hong

    2011-01-01

    Background Detecting small breast tumors is difficult for conventional ultrasound. The goal of this study was to assess the value of ultrasound elastography in characterizing small breast tumors and to compare its sensitivity, specificity and accuracy with conventional ultrasound. Methods A total of 308 breast tumors less than 2 cm in size from 283 in-hospital patients examined with both conventional ultrasound and ultrasound elastography were retrospectively analyzed. The results were compared to surgical pathology. Results There were 104 malignant and 204 benign lesions. The sensitivities of sonography and sonoelastography were similar (P <0.05), and the sensitivity of the two modalities combined improved remarkably to 97.1%. The mean elastic score of malignant and benign tumors less than 2 cm were 3.76±1.01 and 1.73±0.99, respectively (P<0.05), and the mean elastic score of the false-negative lesions on conventional ultrasound was 3.61 ±1.14. Conclusions Ultrasound elastography in combination with conventional ultrasound can improve the sensitivity for detecting small breast tumors. It is also valuable in detecting small malignant tumors which are difficult to diagnose with conventional ultrasound. Ultrasound elastography can be a useful adjunct to conventional ultrasound in diagnosing small breast tumors.

  14. In vitro analysis of the invasive phenotype of SUM 149, an inflammatory breast cancer cell line

    Directory of Open Access Journals (Sweden)

    Dharmawardhane Suranganie F

    2005-04-01

    Full Text Available Abstract Background Inflammatory breast cancer (IBC is the most lethal form of locally invasive breast cancer known. However, very little information is available on the cellular mechanisms responsible for manifestation of the IBC phenotype. To understand the unique phenotype of IBC, we compared the motile and adhesive interactions of an IBC cell line, SUM 149, to the non-IBC cell line SUM 102. Results Our results demonstrate that both IBC and non-IBC cell lines exhibit similar adhesive properties to basal lamina, but SUM 149 showed a marked increase in adhesion to collagen I. In vitro haptotaxis assays demonstrate that SUM 149 was less invasive, while wound healing assays show a less in vitro migratory phenotype for SUM 149 cells relative to SUM 102 cells. We also demonstrate a role for Rho and E-cadherin in the unique invasive phenotype of IBC. Immunoblotting reveals higher E-cadherin and RhoA expression in the IBC cell line but similar RhoC expression. Rhodamine phalloidin staining demonstrates increased formation of actin stress fibers and larger focal adhesions in SUM 149 relative to the SUM 102 cell line. Conclusion The observed unique actin and cellular architecture as well as the invasive and adhesive responses to the extracellular matrix of SUM 149 IBC cells suggest that the preference of IBC cells for connective tissue, possibly a mediator important for the vasculogenic mimicry via tubulogenesis seen in IBC pathological specimens. Overexpression of E-cadherin and RhoA may contribute to passive dissemination of IBC by promoting cell-cell adhesion and actin cytoskeletal structures that maintain tissue integrity. Therefore, we believe that these findings indicate a passive metastatic mechanism by which IBC cells invade the circulatory system as tumor emboli rather than by active migratory mechanisms.

  15. ADAM12 produced by tumor cells rather than stromal cells accelerates breast tumor progression

    DEFF Research Database (Denmark)

    Frohlich, Camilla; Nehammer, Camilla; Albrechtsen, Reidar;

    2011-01-01

    hypothesized, however, that the tumor-associated stroma may stimulate ADAM12 expression in tumor cells, based on the fact that TGF-ß1 stimulates ADAM12 expression and is a well-known growth factor released from tumor-associated stroma. TGF-ß1 stimulation of ADAM12-negative Lewis lung tumor cells induced ADAM12...... synthesis, and growth of these cells in vivo induced a >200-fold increase in ADAM12 expression. Our observation that ADAM12 expression is significantly higher in the terminal duct lobular units (TDLUs) adjacent to human breast carcinoma compared with TDLUs found in normal breast tissue supports our......Expression of ADAM12 is low in most normal tissues, but is markedly increased in numerous human cancers, including breast carcinomas. We have previously shown that overexpression of ADAM12 accelerates tumor progression in a mouse model of breast cancer (PyMT). In the present study, we found...

  16. Modeling Breast Tumor Development with a Humanized Mouse Model.

    Science.gov (United States)

    Arendt, Lisa M

    2016-01-01

    The tumor microenvironment plays a critical role in breast cancer growth and progression to metastasis. Here, we describe a method to examine stromal-epithelial interactions during tumor formation and progression utilizing human-derived mammary epithelial cells and breast stromal cells. This method outlines the isolation of each cell type from reduction mammoplasty tissue, the culture and genetic modification of both epithelial and stromal cells using lentiviral technology, and the method of humanizing and implantation of transformed epithelial cells into the cleared mammary fat pads of immunocompromised mice. This model system may be a useful tool to dissect signaling interactions that contribute to invasive tumor behavior and therapeutic resistance. PMID:27581027

  17. Active Roles of Tumor Stroma in Breast Cancer Metastasis

    Directory of Open Access Journals (Sweden)

    Zahraa I. Khamis

    2012-01-01

    Full Text Available Metastasis is the major cause of death for breast cancer patients. Tumors are heterogenous cellular entities composed of cancer cells and cells of the microenvironment in which they reside. A reciprocal dynamic interaction occurs between the tumor cells and their surrounding stroma under physiological and pathological conditions. This tumor-host communication interface mediates the escape of tumor cells at the primary site, survival of circulating cancer cells in the vasculature, and growth of metastatic cancer at secondary site. Each step of the metastatic process is accompanied by recruitment of stromal cells from the microenvironment and production of unique array of growth factors and chemokines. Stromal microenvironment may play active roles in breast cancer metastasis. Elucidating the types of cells recruited and signal pathways involved in the crosstalk between tumor cells and stromal cells will help identify novel strategies for cotargeting cancer cells and tumor stromal cells to suppress metastasis and improve patient outcome.

  18. Transcription factors link mouse WAP-T mammary tumors with human breast cancer.

    Science.gov (United States)

    Otto, Benjamin; Streichert, Thomas; Wegwitz, Florian; Gevensleben, Heidrun; Klätschke, Kristin; Wagener, Christoph; Deppert, Wolfgang; Tolstonog, Genrich V

    2013-03-15

    Mouse models are important tools to decipher the molecular mechanisms of mammary carcinogenesis and to mimic the respective human disease. Despite sharing common phenotypic and genetic features, the proper translation of murine models to human breast cancer remains a challenging task. In a previous study we showed that in the SV40 transgenic WAP-T mice an active Met-pathway and epithelial-mesenchymal characteristics distinguish low- and high-grade mammary carcinoma. To assign these murine tumors to corresponding human tumors we here incorporated the analysis of expression of transcription factor (TF) coding genes and show that thereby a more accurate interspecies translation can be achieved. We describe a novel cross-species translation procedure and demonstrate that expression of unsupervised selected TFs, such as ELF5, HOXA5 and TFCP2L1, can clearly distinguish between the human molecular breast cancer subtypes--or as, for example, expression of TFAP2B between yet unclassified subgroups. By integrating different levels of information like histology, gene set enrichment, expression of differentiation markers and TFs we conclude that tumors in WAP-T mice exhibit similarities to both, human basal-like and non-basal-like subtypes. We furthermore suggest that the low- and high-grade WAP-T tumor phenotypes might arise from distinct cells of tumor origin. Our results underscore the importance of TFs as common cross-species denominators in the regulatory networks underlying mammary carcinogenesis.

  19. Tubulin binding cofactor C (TBCC suppresses tumor growth and enhances chemosensitivity in human breast cancer cells

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    Laurier Jean-Fabien

    2010-04-01

    Full Text Available Abstract Background Microtubules are considered major therapeutic targets in patients with breast cancer. In spite of their essential role in biological functions including cell motility, cell division and intracellular transport, microtubules have not yet been considered as critical actors influencing tumor cell aggressivity. To evaluate the impact of microtubule mass and dynamics on the phenotype and sensitivity of breast cancer cells, we have targeted tubulin binding cofactor C (TBCC, a crucial protein for the proper folding of α and β tubulins into polymerization-competent tubulin heterodimers. Methods We developed variants of human breast cancer cells with increased content of TBCC. Analysis of proliferation, cell cycle distribution and mitotic durations were assayed to investigate the influence of TBCC on the cell phenotype. In vivo growth of tumors was monitored in mice xenografted with breast cancer cells. The microtubule dynamics and the different fractions of tubulins were studied by time-lapse microscopy and lysate fractionation, respectively. In vitro sensitivity to antimicrotubule agents was studied by flow cytometry. In vivo chemosensitivity was assayed by treatment of mice implanted with tumor cells. Results TBCC overexpression influenced tubulin fraction distribution, with higher content of nonpolymerizable tubulins and lower content of polymerizable dimers and microtubules. Microtubule dynamicity was reduced in cells overexpressing TBCC. Cell cycle distribution was altered in cells containing larger amounts of TBCC with higher percentage of cells in G2-M phase and lower percentage in S-phase, along with slower passage into mitosis. While increased content of TBCC had little effect on cell proliferation in vitro, we observed a significant delay in tumor growth with respect to controls when TBCC overexpressing cells were implanted as xenografts in vivo. TBCC overexpressing variants displayed enhanced sensitivity to

  20. Clinical implications of circulating tumor cells of breast cancer patients: role of epithelial mesenchymal plasticity

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    Linda Maria McInnes

    2015-02-01

    Full Text Available There is increasing interest in circulating tumor cells (CTCs due to their purported role in breast cancer metastasis, and their potential as a ‘liquid biopsy’ tool in breast cancer diagnosis and management. There are, however, questions with regards to the reliability and consistency of CTC detection and to the relationship between CTCs and prognosis, which is limiting their clinical utility. There is increasing acceptance that the ability of CTCs to alter from an epithelial to mesenchymal phenotype plays an important role in determining the metastatic potential of these cells. This review examines the phenotypic and genetic variation, which has been reported within CTC populations. Importantly, we discuss how the detection and characterization of CTCs provides additional and often differing information from that obtained from the primary tumor, and how this may be utilized in determining prognosis and treatment options. It has been shown for example that hormone receptor status often differs between the primary tumor and CTCs, which may help to explain failure of endocrine treatment. We examine how CTC status may introduce alternative treatment options and also how they may be used to monitor treatment. Finally, we discuss the most interesting current clinical trials involving CTC analysis and note further research that is required before the breast cancer liquid biopsy can be realised.

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

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    Soto Ana M

    2010-06-01

    induce near-complete tumor phenotype reversion. These human breast 3D tissue morphogenesis models promise to become reliable tools for studying tissue interactions, therapeutic screening and drug target validation.

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

    International Nuclear Information System (INIS)

    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

  3. A CLDN1-negative phenotype predicts poor prognosis in triple-negative breast cancer.

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    Fei Ma

    Full Text Available INTRODUCTION: Triple-negative breast cancer (TNBC is a heterogeneous disease with no definitive prognostic markers. As a major component of tight junctions, claudins (CLDNs presumably play an important role in carcinogenesis and progression of breast cancer. This study was aimed at determining the relationship between the expression of CLDNs and the clinical outcomes of TNBCs. MATERIALS AND METHODS: The surgical specimens of primary breast tumors from a consecutive cohort of 173 TNBC patients were retrospectively collected. The membranous expression of CLDN1, CLDN2, CLDN4, and CLDN7 was measured by immunohistochemistry. Then, the associations between CLDN expression, clinicopathological features, and clinical outcomes were assessed. RESULTS: Positive CLDN1, CLDN2, CLDN4, and CLDN7 membrane expression was detected in 44.5%, 54.9%, 76.9%, and 73.4% of the cohort specimens, respectively. A lack of CLDN1 expression was related to only lymph node metastasis (P = 0.014. The rate of CLDN4-positive tumors was significantly increased in tumors of a higher grade (P = 0.003. Importantly, negative CLDN1 expression was associated with worse relapse-free survival (RFS in both lymph node positive (LN+ and negative (LN- cases (both P<0.001. Similarly it was also associated with shorter overall survival (OS(P = 0.003 in LN+ cases; P = 0.018 in LN- cases. In the LN+ subgroup, CLDN2-negative cases had a significantly higher risk of recurrence (P = 0.008. Multivariate analysis revealed that negative CLDN1 expression was an independent prognostic factor for high risk of both recurrence and death (HR 5.529, 95% CI 2.664-11.475, P<0.001; HR 3.459, 95% CI 1.555-7.696, P = 0.002. However, neither CLDN4 nor CLDN7 expression was associated with survival. CONCLUSION: In TNBC, the CLDN1-negative phenotype predicts a high risk of recurrence and death. The absence of CLDN1 expression is strongly suggested to be an independent adverse prognostic factor

  4. Emodin Inhibits Breast Cancer Growth by Blocking the Tumor-Promoting Feedforward Loop between Cancer Cells and Macrophages.

    Science.gov (United States)

    Iwanowycz, Stephen; Wang, Junfeng; Hodge, Johnie; Wang, Yuzhen; Yu, Fang; Fan, Daping

    2016-08-01

    Macrophage infiltration correlates with severity in many types of cancer. Tumor cells recruit macrophages and educate them to adopt an M2-like phenotype through the secretion of chemokines and growth factors, such as MCP1 and CSF1. Macrophages in turn promote tumor growth through supporting angiogenesis, suppressing antitumor immunity, modulating extracellular matrix remodeling, and promoting tumor cell migration. Thus, tumor cells and macrophages interact to create a feedforward loop supporting tumor growth and metastasis. In this study, we tested the ability of emodin, a Chinese herb-derived compound, to inhibit breast cancer growth in mice and examined the underlying mechanisms. Emodin was used to treat mice bearing EO771 or 4T1 breast tumors. It was shown that emodin attenuated tumor growth by inhibiting macrophage infiltration and M2-like polarization, accompanied by increased T-cell activation and reduced angiogenesis in tumors. The tumor inhibitory effects of emodin were lost in tumor-bearing mice with macrophage depletion. Emodin inhibited IRF4, STAT6, and C/EBPβ signaling and increased inhibitory histone H3 lysine 27 tri-methylation (H3K27m3) on the promoters of M2-related genes in tumor-associated macrophages. In addition, emodin inhibited tumor cell secretion of MCP1 and CSF1, as well as expression of surface anchoring molecule Thy-1, thus suppressing macrophage migration toward and adhesion to tumor cells. These results suggest that emodin acts on both breast cancer cells and macrophages and effectively blocks the tumor-promoting feedforward loop between the two cell types, thereby inhibiting breast cancer growth and metastasis. Mol Cancer Ther; 15(8); 1931-42. ©2016 AACR. PMID:27196773

  5. Background parenchymal enhancement in breast MRIs of breast cancer patients: Impact on tumor size estimation

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    Baek, Ji Eun [Department of Radiology, Seoul St. Mary' s Hospital, College of Medicine, The Catholic University of Korea (Korea, Republic of); Kim, Sung Hun, E-mail: rad-ksh@catholic.ac.kr [Department of Radiology, Seoul St. Mary' s Hospital, College of Medicine, The Catholic University of Korea (Korea, Republic of); Lee, Ah Won [Department of Hospital Pathology, Seoul St. Mary' s Hospital, College of Medicine, The Catholic University of Korea (Korea, Republic of)

    2014-08-15

    Objective: To evaluate whether the degree of background parenchymal enhancement affects the accuracy of tumor size estimation based on breast MRI. Methods: Three hundred and twenty-two patients who had known breast cancer and underwent breast MRIs were recruited in our study. The total number of breast cancer cases was 339. All images were assessed retrospectively for the level of background parenchymal enhancement based on the BI-RADS criteria. Maximal lesion diameters were measured on the MRIs, and tumor types (mass vs. non-mass) were assessed. Tumor size differences between the MRI-based estimates and estimates based on pathological examinations were analyzed. The relationship between accuracy and tumor types and clinicopathologic features were also evaluated. Results: The cases included minimal (47.5%), mild (28.9%), moderate (12.4%) and marked background parenchymal enhancement (11.2%). The tumors of patients with minimal or mild background parenchymal enhancement were more accurately estimated than those of patients with moderate or marked enhancement (72.1% vs. 56.8%; p = 0.003). The tumors of women with mass type lesions were significantly more accurately estimated than those of the women with non-mass type lesions (81.6% vs. 28.6%; p < 0.001). The tumor of women negative for HER2 was more accurately estimated than those of women positive for HER2 (72.2% vs. 51.6%; p = 0.047). Conclusion: Moderate and marked background parenchymal enhancement is related to the inaccurate estimation of tumor size based on MRI. Non-mass type breast cancer and HER2-positive breast cancer are other factors that may cause inaccurate assessment of tumor size.

  6. Disseminated breast cancer cells acquire a highly malignant and aggressive metastatic phenotype during metastatic latency in the bone.

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    Carolyn G Marsden

    Full Text Available BACKGROUND: Disseminated tumor cells (DTCs in the bone marrow may exist in a dormant state for extended periods of time, maintaining the ability to proliferate upon activation, engraft at new sites, and form detectable metastases. However, understanding of the behavior and biology of dormant breast cancer cells in the bone marrow niche remains limited, as well as their potential involvement in tumor recurrence and metastasis. Therefore, the purpose of this study was to investigate the tumorigenicity and metastatic potential of dormant disseminated breast cancer cells (prior to activation in the bone marrow. METHODOLOGY/PRINCIPAL FINDINGS: Total bone marrow, isolated from mice previously injected with tumorspheres into the mammary fat pad, was injected into the mammary fat pad of NUDE mice. As a negative control, bone marrow isolated from non-injected mice was injected into the mammary fat pad of NUDE mice. The resultant tumors were analyzed by immunohistochemistry for expression of epithelial and mesenchymal markers. Mouse lungs, livers, and kidneys were analyzed by H+E staining to detect metastases. The injection of bone marrow isolated from mice previously injected with tumorspheres into the mammary fat pad, resulted in large tumor formation in the mammary fat pad 2 months post-injection. However, the injection of bone marrow isolated from non-injected mice did not result in tumor formation in the mammary fat pad. The DTC-derived tumors exhibited accelerated development of metastatic lesions within the lung, liver and kidney. The resultant tumors and the majority of metastatic lesions within the lung and liver exhibited a mesenchymal-like phenotype. CONCLUSIONS/SIGNIFICANCE: Dormant DTCs within the bone marrow are highly malignant upon injection into the mammary fat pad, with the accelerated development of metastatic lesions within the lung, liver and kidney. These results suggest the acquisition of a more aggressive phenotype of DTCs during

  7. Glutathione Transferase GSTπ In Breast Tumors Evaluated By Three Techniques

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    Rafael Molina

    1993-01-01

    Full Text Available The glutathione transferases are involved in intracellular detoxification reactions. One of these, GSTπ, is elevated in some breast cancer cells, particularly cells selected for resistance to anticancer agents. We evaluated GSTπ expression in 60 human breast tumors by three techniques, immunohistochemistry, Northern hybridization, and Western blot analysis. There was a significant positive correlation between the three methods, with complete concordance seen in 64% of the tumors. There was strong, inverse relationship between GSTπ expression and steroid receptor status with all of the techniques utili zed. [n addition, there was a trend toward higher GSTπ expression in poorly differentiated tumors, but no correlation was found between tumor GSTπ content and DNA ploidy or %S-phase. GSTπ expression was also detected in adjacent benign breast tissue as well as infiltrating lymphocytes; this expression may contribute to GSTπ measurements using either Northern hybridization or Western blot analysis. These re sults suggest that immunohistochemistry is the method of choice for measuring GSTπ in breast tumors.

  8. Investigating the KLF4 Gene Expression as a New Molecular Marker in Breast Tumors

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    MA Hosseinpour Feizi

    2013-12-01

    Results: The results showed that: 1 KLF4 is over expressed in Breast tumors rather than adjacent normal tissues. 2 KLF4 is an oncogene in breast tumors (at least in IDC type. 3 The KLF4 expression levels are related significantly with nature of malignant breast tumors. Conclusion: Findings do not confirm KLF4 as a diagnostic marker in classification and identification of tumoral tissues from non-tumoral ones in breast, but we can use this marker to identify at least 50% of invasive Ductal Carcinoma in breast and utilize it as a potential predictive factor to demonstrate severity degree in various tumors.

  9. Multiple breast cancer cell-lines derived from a single tumor differ in their molecular characteristics and tumorigenic potential.

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    Goar Mosoyan

    Full Text Available BACKGROUND: Breast cancer cell lines are widely used tools to investigate breast cancer biology and to develop new therapies. Breast cancer tissue contains molecularly heterogeneous cell populations. Thus, it is important to understand which cell lines best represent the primary tumor and have similarly diverse phenotype. Here, we describe the development of five breast cancer cell lines from a single patient's breast cancer tissue. We characterize the molecular profiles, tumorigenicity and metastatic ability in vivo of all five cell lines and compare their responsiveness to 4-hydroxytamoxifen (4-OHT treatment. METHODS: Five breast cancer cell lines were derived from a single patient's primary breast cancer tissue. Expression of different antigens including HER2, estrogen receptor (ER, CK8/18, CD44 and CD24 was determined by flow cytometry, western blotting and immunohistochemistry (IHC. In addition, a Fluorescent In Situ Hybridization (FISH assay for HER2 gene amplification and p53 genotyping was performed on all cell lines. A xenograft model in nude mice was utilized to assess the tumorigenic and metastatic abilities of the breast cancer cells. RESULTS: We have isolated, cloned and established five new breast cancer cell lines with different tumorigenicity and metastatic abilities from a single primary breast cancer. Although all the cell lines expressed low levels of ER, their growth was estrogen-independent and all had high-levels of expression of mutated non-functional p53. The HER2 gene was rearranged in all cell lines. Low doses of 4-OHT induced proliferation of these breast cancer cell lines. CONCLUSIONS: All five breast cancer cell lines have different antigenic expression profiles, tumorigenicity and organ specific metastatic abilities although they derive from a single tumor. None of the studied markers correlated with tumorigenic potential. These new cell lines could serve as a model for detailed genomic and proteomic analyses to

  10. Race-associated biological differences among Luminal A breast tumors.

    Science.gov (United States)

    D'Arcy, Monica; Fleming, Jodie; Robinson, Whitney R; Kirk, Erin L; Perou, Charles M; Troester, Melissa A

    2015-07-01

    African-American (AA) women have higher breast cancer-specific mortality rates. A higher prevalence of the worse outcome Basal-like breast cancer subtype contributes to this, but AA women also have higher mortality even within the more favorable outcome Luminal A breast cancers. These differences may reflect treatment or health care access issues, inherent biological differences, or both. To identify potential biological differences by race among Luminal A breast cancers, gene expression data from 108 CAU and 57 AA breast tumors were analyzed. Race-associated genes were evaluated for associations with survival. Finally, expression of race- and survival-associated genes was evaluated in normal tissue of AA and CAU women. Six genes (ACOX2, MUC1, CRYBB2, PSPH, SQLE, TYMS) were differentially expressed by race among Luminal A breast cancers and were associated with survival (HR 1.25). For all six genes, tumors in AA had higher expression of poor prognosis genes (CRYBB2, PSPH, SQLE, TYMS) and lower expression of good prognosis genes (ACOX2, MUC1). A score based on all six genes predicted survival in a large independent dataset (HR = 1.9 top vs. bottom quartile, 95% CI: 1.4-2.5). For four genes, normal tissue of AA and CAU women showed similar expression (ACOX2, MUC1, SQLE, TYMS); however, the poor outcome-associated genes CRYBB2 and PSPH were more highly expressed in AA versus CAU women's normal tissue. This analysis identified gene expression differences that may contribute to mortality disparities and suggests that among Luminal A breast tumors there are biological differences between AA and CAU patients. Some of these differences (CRYBB2 and PSPH) may exist from the earliest stages of tumor development, or may even precede malignancy. PMID:26109344

  11. Expression of Toll-Like Receptors on Breast Tumors: Taking a Toll on Tumor Microenvironment

    International Nuclear Information System (INIS)

    Breast cancer remains a major cause of death in women in the developed world. As Toll-like receptors (TLRs) are widely expressed on tumor cells and play important roles in the initiation and progression of cancer, they may thus serve as important targets and have an effective perspective on breast cancer treatment. Expression of TLRs on breast cancer cells and mononuclear inflammatory cells can promote inflammation and cell survival in the tumor microenvironment. Inflammation and cancer are related. It is well known that persistent inflammatory conditions can induce cancer formation, due to production of cytokines and chemokines, which play a crucial role in promoting angiogenesis, metastasis, and subversion of adaptive immunity. TLR signaling in tumor cells can mediate tumor cell immune escape and tumor progression, and it is regarded as one of the mechanisms for chronic inflammation in tumorigenesis and progression. This paper delineates the expression of various TLRs in promotion of inflammation and development of mammary tumors. Understanding the mechanisms through which TLRs on breast cancer cells and inflammatory cells regulate growth, survival, and metastatic progression can make them potential targets for breast cancer therapy

  12. Phenotypic switch in blood: effects of pro-inflammatory cytokines on breast cancer cell aggregation and adhesion.

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    Yue Geng

    Full Text Available Hematogeneous metastasis can occur via a cascade of circulating tumor cell adhesion events to the endothelial lining of the vasculature, i.e. the metastatic cascade. Interestingly, the pro-inflammatory cytokines IL-6 and TNF-α, which play an important role in potentiating the inflammatory cascade, are significantly elevated in metastatic breast cancer (BCa patients. Despite their high metastatic potential, human breast carcinoma cells MDA-MB-231 lack interactions with E-selectin functionalized surfaces under physiological shear stresses. We hypothesized that human plasma, 3-D tumor spheroid culture, and cytokine-supplemented culture media could induce a phenotypic switch that allows BCa cells to interact with E-selectin coated surfaces under physiological flow. Flow cytometry, immunofluorescence imaging, and flow-based cell adhesion assay were utilized to investigate the phenotypic changes of MDA-MB-231 cells with various treatments. Our results indicate that plasma, IL-6, and TNF-α promote breast cancer cell growth as aggregates and induce adhesive recruitment of BCa cells on E-selectin coated surfaces under flow. 3-D tumor spheroid culture exhibits the most significant increases in the interactions between BCa and E-selectin coated surfaces by upregulating CD44V4 and sLe(x expression. Furthermore, we show that IL-6 and TNF-α concentrations in blood may regulate the recruitment of BCa cells to the inflamed endothelium. Finally, we propose a mechanism that could explain the invasiveness of 'triple-negative' breast cancer cell line MDA-MB-231 via a positive feedback loop of IL-6 secretion and maintenance. Taken together, our results suggest that therapeutic approaches targeting cytokine receptors and adhesion molecules on cancer cells may potentially reduce metastatic load and improve current cancer treatments.

  13. Characterization of adjacent breast tumors using oligonucleotide microarrays

    International Nuclear Information System (INIS)

    Current methodology often cannot distinguish second primary breast cancers from multifocal disease, a potentially important distinction for clinical management. In the present study we evaluated the use of oligonucleotide-based microarray analysis in determining the clonality of tumors by comparing gene expression profiles. Total RNA was extracted from two tumors with no apparent physical connection that were located in the right breast of an 87-year-old woman diagnosed with invasive ductal carcinoma (IDC). The RNA was hybridized to the Affymetrix Human Genome U95A Gene Chip® (12,500 known human genes) and analyzed using the Gene Chip Analysis Suite® 3.3 (Affymetrix, Inc, Santa Clara, CA, USA) and JMPIN® 3.2.6 (SAS Institute, Inc, Cary, NC, USA). Gene expression profiles of tumors from five additional patients were compared in order to evaluate the heterogeneity in gene expression between tumors with similar clinical characteristics. The adjacent breast tumors had a pairwise correlation coefficient of 0.987, and were essentially indistinguishable by microarray analysis. Analysis of gene expression profiles from different individuals, however, generated a pairwise correlation coefficient of 0.710. Transcriptional profiling may be a useful diagnostic tool for determining tumor clonality and heterogeneity, and may ultimately impact on therapeutic decision making

  14. A RETROSPECTIVE ANALYSIS OF SURGICAL TREATMENT FOR BREAST MALIGNANT TUMORS

    Institute of Scientific and Technical Information of China (English)

    范志民; 刘国津; 盖学良; 王晓军; 辛志泳

    2002-01-01

    Objective: To review the evolution of the current surgical treatment for breast malignant tumors over the past twenty years in the First Hospital of Jilin University (the former Bethune University of Medical Sciences). Methods: 1195 eligible patients with primary breast malignant tumor diagnosed and surgically treated at the First Teaching Hospital from January 1980 and December 2000 were retrospectively analyzed. Results: The peak frequency was in 40-49 years of age (40.00%), the age of the patients with breast malignant tumors trends to become young. The most common pTNM classification was Stage Ⅱ. The most common histological type was infiltrating ductal carcinoma (398 patients, 33.31%), and simple carcinoma (279 patients, 23.53%). Modified radical mastectomy was the most common operation procedure performed (779 patients, 65.19%), and was increasingly used while radical mastectomy was adopted decreasingly in recent decade. Conclusion: The variation of operation procedures performed on patients with breast malignant tumors reflected the advance of our understanding of the biology of cancer and the progression of new treatment principles.

  15. Molecular profiles of progesterone receptor loss in human breast tumors

    NARCIS (Netherlands)

    C.J. Creighton; C. Kent Osborne; M.J. van de Vijver; J.A. Foekens; J.G. Klijn; H.M. Horlings; D. Nuyten; Y. Wang; Y. Zhang; G.C. Chamness; S.G. Hilsenbeck; A.V. Lee; R. Schiff

    2009-01-01

    Background Patient prognosis and response to endocrine therapy in breast cancer correlate with protein expression of both estrogen receptor (ER) and progesterone receptor (PR), with poorer outcome in patients with ER+/PR- compared to ER+/PR+ tumors. Methods To better understand the underlying biolog

  16. Assessment of breast tumor size in electrical impedance scanning

    Science.gov (United States)

    Kim, Sungwhan

    2012-02-01

    Electrical impedance scanning (EIS) is a newly introduced imaging technique for early breast cancer detection. In EIS, we apply a sinusoidal voltage between a hand-held electrode and a scanning probe placed on the breast skin to make current travel through the breast. We measure induced currents (Neumann data) through the scanning probe. In this paper, we investigate the frequency-dependent behavior of the induced complex potential and show how the frequency differential of the current measurement on the scanning probe reflects the contrast in complex conductivity values between surrounding and cancerous tissues. Furthermore, we develop the formula for breast tumor size using the frequency differential of the current measurement and provide its feasibility.

  17. Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity

    DEFF Research Database (Denmark)

    Kim, Jiyoung; Villadsen, René; Sørlie, Therese;

    2012-01-01

    The majority of human breast cancers exhibit luminal epithelial differentiation. However, most aggressive behavior, including invasion and purported cancer stem cell activity, are considered characteristics of basal-like cells. We asked the following questions: Must luminal-like breast cancer cells...... become basal-like to initiate tumors or to invade? Could luminally differentiated cells within a basally initiated hierarchy also be tumorigenic? To answer these questions, we used rare and mutually exclusive lineage markers to isolate subsets of luminal-like and basal-like cells from human breast tumors....... We enriched for populations with or without prominent basal-like traits from individual tumors or single cell cloning from cell lines and recovered cells with a luminal-like phenotype. Tumor cells with basal-like traits mimicked phenotypic and functional behavior associated with stem cells assessed...

  18. Boswellia sacra essential oil induces tumor cell-specific apoptosis and suppresses tumor aggressiveness in cultured human breast cancer cells

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    Suhail Mahmoud M

    2011-12-01

    Full Text Available Abstract Background Gum resins obtained from trees of the Burseraceae family (Boswellia sp. are important ingredients in incense and perfumes. Extracts prepared from Boswellia sp. gum resins have been shown to possess anti-inflammatory and anti-neoplastic effects. Essential oil prepared by distillation of the gum resin traditionally used for aromatic therapy has also been shown to have tumor cell-specific anti-proliferative and pro-apoptotic activities. The objective of this study was to optimize conditions for preparing Boswellea sacra essential oil with the highest biological activity in inducing tumor cell-specific cytotoxicity and suppressing aggressive tumor phenotypes in human breast cancer cells. Methods Boswellia sacra essential oil was prepared from Omani Hougari grade resins through hydrodistillation at 78 or 100 oC for 12 hours. Chemical compositions were identified by gas chromatography-mass spectrometry; and total boswellic acids contents were quantified by high-performance liquid chromatography. Boswellia sacra essential oil-mediated cell viability and death were studied in established human breast cancer cell lines (T47D, MCF7, MDA-MB-231 and an immortalized normal human breast cell line (MCF10-2A. Apoptosis was assayed by genomic DNA fragmentation. Anti-invasive and anti-multicellular tumor properties were evaluated by cellular network and spheroid formation models, respectively. Western blot analysis was performed to study Boswellia sacra essential oil-regulated proteins involved in apoptosis, signaling pathways, and cell cycle regulation. Results More abundant high molecular weight compounds, including boswellic acids, were present in Boswellia sacra essential oil prepared at 100 oC hydrodistillation. All three human breast cancer cell lines were sensitive to essential oil treatment with reduced cell viability and elevated cell death, whereas the immortalized normal human breast cell line was more resistant to essential oil

  19. The Malignant Phenotype of Breast Cancer Cells Is Reduced by COX-2 Silencing

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    Ioannis Stasinopoulos

    2008-11-01

    Full Text Available The cyclooxygenase (COX pathway is currently targeted for therapeutic intervention in different cancers. We have previously shown that silencing of COX-2 in the poorly differentiated metastatic breast cell line MDA-MB-231 by RNA interference markedly delayed tumor onset and inhibited metastasis. To understand the functional effects of COX-2 silencing underlying the inhibition of tumor growth and metastasis previously reported, we investigated changes in these cells for a number of cancer-associated phenotypes. Cyclooxygenase-2-silenced cells were less able to acidify tissue culture medium, a response that could partly be attributed to decreased lactate production or export detected by reduced lactate in the medium. Consistent with the significantly reduced transcript levels of hyaluronan synthase 2, an enzyme responsible for the total level of hyaluronan secreted by these cells, COX-2 silencing resulted in lower hyaluronan levels secreted in culture medium. Inhibition of human umbilical vein endothelial cell network association in a coculture assay was also observed in COX-2-silenced cells. These data highlight the functional role of COX-2 in pathways that mediate increased malignancy.

  20. Didymin reverses phthalate ester-associated breast cancer aggravation in the breast cancer tumor microenvironment

    OpenAIRE

    Hsu, Ya-Ling; Hsieh, Chia-Jung; Tsai, Eing-Mei; HUNG, JEN-YU; CHANG, WEI-AN; Hou, Ming-Feng; Kuo, Po-Lin

    2015-01-01

    The present study demonstrated two novel findings. To the best of our knowledge, it is the first study to demonstrate that regulated upon activation, normal T-cell expressed and secreted (RANTES), produced by breast tumor-associated monocyte-derived dendritic cells (TADCs) following breast cancer cell exposure to phthalate esters, may contribute to the progression of cancer via enhancement of cancer cell proliferation, migration and invasion. Furthermore, the present study revealed that didym...

  1. Expression of p53 and CD44 in Canine Breast Tumor

    Institute of Scientific and Technical Information of China (English)

    LIU Yun; CUI Wen; CHENG Xi; FENG Xinchang

    2008-01-01

    The p53 and CD44 expression of 10 cases in canine breast tumor were examined utilizing immunohistochemical assay with rabbit anti-mouse polyclonal antibodies against p53 or CD44,respectively.The p53 expression was significantly higher in malignant than in benign breast tumor.The expression of CD44 was not significantly different in malignant breast cancer and benign breast tumor.This suggests that p53 can be used as an indicator for animal prognosis.

  2. Tumor marker CA 15-3 in breast cancer patients

    OpenAIRE

    Hanifa Fejzić; Svjetlana Mujagić; Sanida Azabagić; Mensura Burina

    2015-01-01

    Objective. The aim of this study was to determine whether there is a correlation between the serum concentration of the tumor marker CA 15-3 and breast cancer, which has not been proven by the existence of regional and distant metastases, and breast cancer with the presence of regional and distant metastases. Patients and methods. The study was a retrospective-prospective study, and was conducted on 100 women aged 40-70 years of age in the period of January 2007 until June 2011, in whom, afte...

  3. Uncommon breast tumor attenuation artifact on radionuclide ventriculography.

    Science.gov (United States)

    Metrard, Gilles; Girault, Sylvie; Capitain, Olivier; Jeanguillaume, Christian; Rakotonirina, Hervé; Berthelot, Cécile; Le Jeune, Jean-Jacques; Morel, Olivier

    2008-04-01

    A 39-year-old woman with locally advanced left breast cancer (T4 N0 M0) underwent equilibrium radionuclide ventriculography for baseline assessment of left ventricular function before neoadjuvant chemotherapy. The left ventricular ejection fraction was 76% at 75 beats per minute, without localized wall motion abnormality. In the best septal left anterior oblique projection, a large photopenic "halo" surrounded the cardiac chambers, mimicking a pericardial effusion. In fact, this aspect resulted from an attenuation artifact by a large left breast tumor, as demonstrated by FDG-PET/CT imaging. PMID:18356673

  4. Infrared Spectra of Human Breast Tumor Tissue and Experimental Animal Tumors

    Science.gov (United States)

    Tolstorozhev, G. B.; Belkov, M. V.; Skornyakov, I. V.; Pekhnyo, V. I.; Kozachkova, A. N.; Tsarik, H. V.; Kutsenko, I. P.; Sharykina, N. I.; Butra, V. A.

    2015-01-01

    We have used Fourier transform IR spectroscopy methods to conduct comparative studies of human breast tumors and sarcoma 180 tumor grafted into mice. The IR spectral parameters used to identify tumor tissue in mice with the sarcoma 180 strain proved to be identical to the parameters for human breast tissue in cancer. In the presence of a malignant tumor in humans, the most intense C=O vibrational bands in the protein molecules are observed in the interval 1710-1680 cm-1. For a benign tumor, in the IR spectra of breast tissue the intense bands are located in the interval 1670-1650 cm-1. We spectroscopically monitored the diagnosis and the chemotherapy process using the model of sarcoma 180 in mice. As the therapeutic drugs, we used synthesized coordination compounds based on palladium complexes with diphosphonic acid derivatives. We demonstrate the promising potential of palladium complexes with zoledronic acid as an effective cytostatic. In therapy using a palladium complex with zoledronic acid, the effect of tumor growth inhibition is accompanied by a change in its spectral characteristics. The parameters of the IR spectra for tumor tissue after treatment are close to those of the IR spectra for healthy tissue.

  5. Tumor microenvironment and metabolic synergy in breast cancers: critical importance of mitochondrial fuels and function.

    Science.gov (United States)

    Martinez-Outschoorn, Ubaldo; Sotgia, Federica; Lisanti, Michael P

    2014-04-01

    Metabolic synergy or metabolic coupling between glycolytic stromal cells (Warburg effect) and oxidative cancer cells occurs in human breast cancers and promotes tumor growth. The Warburg effect or aerobic glycolysis is the catabolism of glucose to lactate to obtain adenosine triphosphate (ATP). This review summarizes the main findings on this stromal metabolic phenotype, and the associated signaling pathways, as well as the critical role of oxidative stress and autophagy, all of which promote carcinoma cell mitochondrial metabolism and tumor growth. Loss of Caveolin 1 (Cav-1) and the upregulation of monocarboxylate transporter 4 (MCT4) in stromal cells are novel markers of the Warburg effect and metabolic synergy between stromal and carcinoma cells. MCT4 and Cav-1 are also breast cancer prognostic biomarkers. Reactive oxygen species (ROS) are key mediators of the stromal Warburg effect. High ROS also favors cancer cell mitochondrial metabolism and tumorigenesis, and anti-oxidants can reverse this altered stromal and carcinoma metabolism. A pseudo-hypoxic state with glycolysis and low mitochondrial metabolism in the absence of hypoxia is a common feature in breast cancer. High ROS induces loss of Cav-1 in stromal cells and is sufficient to generate a pseudo-hypoxic state. Loss of Cav-1 in the stroma drives glycolysis and lactate extrusion via HIF-1α stabilization and the upregulation of MCT4. Stromal cells with loss of Cav-1 and/or high expression of MCT4 also show a catabolic phenotype, with enhanced macroautophagy. This catabolic state in stromal cells is driven by hypoxia-inducible factor (HIF)-1α, nuclear factor κB (NFκB), and JNK activation and high ROS generation. A feed-forward loop in stromal cells regulates pseudo-hypoxia and metabolic synergy, with Cav-1, MCT4, HIF-1α, NFκB, and ROS as its key elements. Metabolic synergy also may occur between cancer cells and cells in distant organs from the tumor. Cancer cachexia, which is due to severe organismal

  6. HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients

    Science.gov (United States)

    Pannu, Vaishali; Rida, Padmashree C.G.; Ogden, Angela; Turaga, Ravi Chakra; Donthamsetty, Shashikiran; Bowen, Nathan J.; Rudd, Katie; Gupta, Meenakshi V.; Reid, Michelle D.; Cantuaria, Guilherme; Walczak, Claire E.; Aneja, Ritu

    2015-01-01

    Human breast tumors harbor supernumerary centrosomes in almost 80% of tumor cells. Although amplified centrosomes compromise cell viability via multipolar spindles resulting in death-inducing aneuploidy, cancer cells tend to cluster extra centrosomes during mitosis. As a result cancer cells display bipolar spindle phenotypes to maintain a tolerable level of aneuploidy, an edge to their survival. HSET/KifC1, a kinesin-like minus-end directed microtubule motor has recently found fame as a crucial centrosome clustering molecule. Here we show that HSET promotes tumor progression via mechanisms independent of centrosome clustering. We found that HSET is overexpressed in breast carcinomas wherein nuclear HSET accumulation correlated with histological grade and predicted poor progression-free and overall survival. In addition, deregulated HSET protein expression was associated with gene amplification and/or translocation. Our data provide compelling evidence that HSET overexpression is pro-proliferative, promotes clonogenic-survival and enhances cell-cycle kinetics through G2 and M-phases. Importantly, HSET co-immunoprecipitates with survivin, and its overexpression protects survivin from proteasome-mediated degradation, resulting in its increased steady-state levels. We provide the first evidence of centrosome clustering-independent activities of HSET that fuel tumor progression and firmly establish that HSET can serve both as a potential prognostic biomarker and as a valuable cancer-selective therapeutic target. PMID:25788277

  7. Giant breast tumors: Surgical management of phyllodes tumors, potential for reconstructive surgery and a review of literature

    Directory of Open Access Journals (Sweden)

    McKelvey Michael T

    2008-11-01

    Full Text Available Abstract Background Phyllodes tumors are biphasic fibroepithelial neoplasms of the breast. While the surgical management of these relatively uncommon tumors has been addressed in the literature, few reports have commented on the surgical approach to tumors greater than ten centimeters in diameter – the giant phyllodes tumor. Case presentation We report two cases of giant breast tumors and discuss the techniques utilized for pre-operative diagnosis, tumor removal, and breast reconstruction. A review of the literature on the surgical management of phyllodes tumors was performed. Conclusion Management of the giant phyllodes tumor presents the surgeon with unique challenges. The majority of these tumors can be managed by simple mastectomy. Axillary lymph node metastasis is rare, and dissection should be limited to patients with pathologic evidence of tumor in the lymph nodes.

  8. Accuracy of lesion boundary tracking in navigated breast tumor excision

    Science.gov (United States)

    Heffernan, Emily; Ungi, Tamas; Vaughan, Thomas; Pezeshki, Padina; Lasso, Andras; Gauvin, Gabrielle; Rudan, John; Engel, C. Jay; Morin, Evelyn; Fichtinger, Gabor

    2016-03-01

    PURPOSE: An electromagnetic navigation system for tumor excision in breast conserving surgery has recently been developed. Preoperatively, a hooked needle is positioned in the tumor and the tumor boundaries are defined in the needle coordinate system. The needle is tracked electromagnetically throughout the procedure to localize the tumor. However, the needle may move and the tissue may deform, leading to errors in maintaining a correct excision boundary. It is imperative to quantify these errors so the surgeon can choose an appropriate resection margin. METHODS: A commercial breast biopsy phantom with several inclusions was used. Location and shape of a lesion before and after mechanical deformation were determined using 3D ultrasound volumes. Tumor location and shape were estimated from initial contours and tracking data. The difference in estimated and actual location and shape of the lesion after deformation was quantified using the Hausdorff distance. Data collection and analysis were done using our 3D Slicer software application and PLUS toolkit. RESULTS: The deformation of the breast resulted in 3.72 mm (STD 0.67 mm) average boundary displacement for an isoelastic lesion and 3.88 mm (STD 0.43 mm) for a hyperelastic lesion. The difference between the actual and estimated tracked tumor boundary was 0.88 mm (STD 0.20 mm) for the isoelastic and 1.78 mm (STD 0.18 mm) for the hyperelastic lesion. CONCLUSION: The average lesion boundary tracking error was below 2mm, which is clinically acceptable. We suspect that stiffness of the phantom tissue affected the error measurements. Results will be validated in patient studies.

  9. Tumor progression: analysis of the instability of the metastatic phenotype, sensitivity to radiation and chemotherapy

    International Nuclear Information System (INIS)

    The major complications for tumor therapy are 1) tumor spread (metastasis); 2) the mixed nature of tumors (heterogeneity); and 3) the capacity of tumors to evolve (progress). To study these tumor characteristics, the rat 13762NF mammary adenocarcinoma was cloned and studied for metastatic properties and sensitivities to therapy (chemotherapy, radiation and hyperthermia). The cell clones were heterogeneous and no correlation between metastatic potential and therapeutic sensitivities was observed. Further, these phenotypes were unstable during pasage in vitro; yet, the changes were clone dependent and reproducible using different cryoprotected cell stocks. To understand the phenotypic instability, subclones were isolated from low and high passage cell clones. The results demonstrated that 1) tumor cells are heterogeneous for multiple phenotypes; 2) tumor cells are unstable for multiple phenotypes; 3) the magnitude, direction and time of occurrence of phenotypic drift is clone dependent; 4) the sensitivity of cell clones to ionizing radiation (γ or heat) and chemotherapy agents is independent of their metastatic potential; 5) shifts in metastatic potential and sensitivity to therapy may occur simultaneously but are not linked; and 6) tumor cells independently diverge to form several subpopulations with unique phenotypic profiles

  10. Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies

    DEFF Research Database (Denmark)

    Yang, Xiaohong R; Chang-Claude, Jenny; Goode, Ellen L;

    2011-01-01

    Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.......Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors....

  11. Associations of Breast Cancer Risk Factors With Tumor Subtypes : A Pooled Analysis From the Breast Cancer Association Consortium Studies

    NARCIS (Netherlands)

    Yang, Xiaohong R.; Chang-Claude, Jenny; Goode, Ellen L.; Couch, Fergus J.; Nevanlinna, Heli; Milne, Roger L.; Gaudet, Mia; Schmidt, Marjanka K.; Broeks, Annegien; Cox, Angela; Fasching, Peter A.; Hein, Rebecca; Spurdle, Amanda B.; Blows, Fiona; Driver, Kristy; Flesch-Janys, Dieter; Heinz, Judith; Sinn, Peter; Vrieling, Alina; Heikkinen, Tuomas; Aittomaeki, Kristiina; Heikkilae, Paeivi; Blomqvist, Carl; Lissowska, Jolanta; Peplonska, Beata; Chanock, Stephen; Figueroa, Jonine; Brinton, Louise; Hall, Per; Czene, Kamila; Humphreys, Keith; Darabi, Hatef; Liu, Jianjun; Van 't Veer, Laura J.; Van Leeuwen, Flora E.; Andrulis, Irene L.; Glendon, Gord; Knight, Julia A.; Mulligan, Anna Marie; O'Malley, Frances P.; Weerasooriya, Nayana; John, Esther M.; Beckmann, Matthias W.; Hartmann, Arndt; Weihbrecht, Sebastian B.; Wachter, David L.; Jud, Sebastian M. S.; Loehberg, Christian R.; Baglietto, Laura; English, Dallas R.; Giles, Graham G.; McLean, Catriona A.; Severi, Gianluca; Lambrechts, Diether; Vandorpe, Thijs; Weltens, Caroline; Paridaens, Robert; Smeets, Ann; Neven, Patrick; Wildiers, Hans; Wang, Xianshu; Olson, Janet E.; Cafourek, Victoria; Fredericksen, Zachary; Kosel, Matthew; Vachon, Celine; Cramp, Helen E.; Connley, Daniel; Cross, Simon S.; Balasubramanian, Sabapathy P.; Reed, Malcolm W. R.; Doerk, Thilo; Bremer, Michael; Meyer, Andreas; Karstens, Johann H.; Ay, Aysun; Park-Simon, Tjoung-Won; Hillemanns, Peter; Arias Perez, Jose Ignacio; Menendez Rodriguez, Primitiva; Zamora, Pilar; Bentez, Javier; Ko, Yon-Dschun; Fischer, Hans-Peter; Hamann, Ute; Pesch, Beate; Bruening, Thomas; Justenhoven, Christina; Brauch, Hiltrud; Eccles, Diana M.; Tapper, William J.; Gerty, Sue M.; Sawyer, Elinor J.; Tomlinson, Ian P.; Jones, Angela; Kerin, Michael; Miller, Nicola; McInerney, Niall; Anton-Culver, Hoda; Ziogas, Argyrios; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Yang, Show-Lin; Yu, Jyh-Cherng; Chen, Shou-Tung; Hsu, Giu-Cheng; Haiman, Christopher A.; Henderson, Brian E.; Le Marchand, Loic; Kolonel, Laurence N.; Lindblom, Annika; Margolin, Sara; Jakubowska, Anna; Lubinski, Jan; Huzarski, Tomasz; Byrski, Tomasz; Gorski, Bohdan; Gronwald, Jacek; Hooning, Maartje J.; Hollestelle, Antoinette; van den Ouweland, Ans M. W.; Jager, Agnes; Kriege, Mieke; Tilanus-Linthorst, Madeleine M. A.; Collee, Margriet; Wang-Gohrke, Shan; Pylkaes, Katri; Jukkola-Vuorinen, Arja; Mononen, Kari; Grip, Mervi; Hirvikoski, Pasi; Winqvist, Robert; Mannermaa, Arto; Kosma, Veli-Matti; Kauppinen, Jaana; Kataja, Vesa; Auvinen, Paeivi; Soini, Ylermi; Sironen, Reijo; Bojesen, Stig E.; Orsted, David Dynnes; Kaur-Knudsen, Diljit; Flyger, Henrik; Nordestgaard, Borge G.; Holland, Helene; Chenevix-Trench, Georgia; Manoukian, Siranoush; Barile, Monica; Radice, Paolo; Hankinson, Susan E.; Hunter, David J.; Tamimi, Rulla; Sangrajrang, Suleeporn; Brennan, Paul; Mckay, James; Odefrey, Fabrice; Gaborieau, Valerie; Devilee, Peter; Huijts, P. E. A.; Tollenaar, R. A. E. M.; Seynaeve, C.; Dite, Gillian S.; Apicella, Carmel; Hopper, John L.; Hammet, Fleur; Tsimiklis, Helen; Smith, Letitia D.; Southey, Melissa C.; Humphreys, Manjeet K.; Easton, Douglas; Pharoah, Paul; Sherman, Mark E.; Garcia-Closas, Montserrat

    2011-01-01

    Background Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. Methods We pooled tumor marker and epidemiological risk factor data from 35 568 invasive breast cancer case patients f

  12. Ultrasound imaging of breast tumor perfusion and neovascular morphology.

    Science.gov (United States)

    Hoyt, Kenneth; Umphrey, Heidi; Lockhart, Mark; Robbin, Michelle; Forero-Torres, Andres

    2015-09-01

    A novel image processing strategy is detailed for simultaneous measurement of tumor perfusion and neovascular morphology parameters from a sequence of dynamic contrast-enhanced ultrasound (DCE-US) images. After normalization and tumor segmentation, a global time-intensity curve describing contrast agent flow was analyzed to derive surrogate measures of tumor perfusion (i.e., peak intensity, time-to-peak intensity, area under the curve, wash-in rate, wash-out rate). A maximum intensity image was generated from these same segmented image sequences, and each vascular component was skeletonized via a thinning algorithm. This skeletonized data set and collection of vessel segments were then investigated to extract parameters related to the neovascular network and physical architecture (i.e., vessel-to-tissue ratio, number of bifurcations, vessel count, average vessel length and tortuosity). An efficient computation of local perfusion parameters was also introduced and operated by averaging time-intensity curve data over each individual neovascular segment. Each skeletonized neovascular segment was then color-coded by these local measures to produce a parametric map detailing spatial properties of tumor perfusion. Longitudinal DCE-US image data sets were collected in six patients diagnosed with invasive breast cancer using a Philips iU22 ultrasound system equipped with a L9-3 transducer and Definity contrast agent. Patients were imaged using US before and after contrast agent dosing at baseline and again at weeks 6, 12, 18 and 24 after treatment started. Preliminary clinical results suggested that breast tumor response to neoadjuvant chemotherapy may be associated with temporal and spatial changes in DCE-US-derived parametric measures of tumor perfusion. Moreover, changes in neovascular morphology parametric measures may also help identify any breast tumor response (or lack thereof) to systemic treatment. Breast cancer management from early detection to therapeutic

  13. Comprehensive Quantitative Analysis of Ovarian and Breast Cancer Tumor Peptidomes

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Zhe; Wu, Chaochao; Xie, Fang; Slysz, Gordon W.; Tolic, Nikola; Monroe, Matthew E.; Petyuk, Vladislav A.; Payne, Samuel H.; Fujimoto, Grant M.; Moore, Ronald J.; Fillmore, Thomas L.; Schepmoes, Athena A.; Levine, Douglas; Townsend, Reid; Davies, Sherri; Li, Shunqiang; Ellis, Matthew; Boja, Emily; Rivers, Robert; Rodriguez, Henry; Rodland, Karin D.; Liu, Tao; Smith, Richard D.

    2015-01-01

    Aberrant degradation of proteins is associated with many pathological states, including cancers. Mass spectrometric analysis of tumor peptidomes, the intracellular and intercellular products of protein degradation, has the potential to provide biological insights on proteolytic processing in cancer. However, attempts to use the information on these smaller protein degradation products from tumors for biomarker discovery and cancer biology studies have been fairly limited to date, largely due to the lack of effective approaches for robust peptidomics identification and quantification, and the prevalence of confounding factors and biases associated with sample handling and processing. Herein, we have developed an effective and robust analytical platform for comprehensive analyses of tissue peptidomes, and which is suitable for high throughput quantitative studies. The reproducibility and coverage of the platform, as well as the suitability of clinical ovarian tumor and patient-derived breast tumor xenograft samples with post-excision delay of up to 60 min before freezing for peptidomics analysis, have been demonstrated. Moreover, our data also show that the peptidomics profiles can effectively separate breast cancer subtypes, reflecting tumor-associated protease activities. Peptidomics complements results obtainable from conventional bottom-up proteomics, and provides insights not readily obtainable from such approaches.

  14. Comprehensive Quantitative Analysis of Ovarian and Breast Cancer Tumor Peptidomes

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Zhe; Wu, Chaochao; Xie, Fang; Slysz, Gordon W.; Tolic, Nikola; Monroe, Matthew E.; Petyuk, Vladislav A.; Payne, Samuel H.; Fujimoto, Grant M.; Moore, Ronald J.; Fillmore, Thomas L.; Schepmoes, Athena A.; Levine, Douglas; Townsend, Reid; Davies, Sherri; Li, Shunqiang; Ellis, Matthew; Boja, Emily; Rivers, Robert; Rodriguez, Henry; Rodland, Karin D.; Liu, Tao; Smith, Richard D.

    2015-01-02

    Aberrant degradation of proteins is associated with many pathological states, including cancers. Mass spectrometric analysis of tumor peptidomes, the intracellular and intercellular products of protein degradation, has the potential to provide biological insights on proteolytic processing in cancer. However, attempts to use the information on these smaller protein degradation products from tumors for biomarker discovery and cancer biology studies have been fairly limited to date, largely due to the lack of effective approaches for robust peptidomics identification and quantification, and the prevalence of confounding factors and biases associated with sample handling and processing. Herein, we have developed an effective and robust analytical platform for comprehensive analyses of tissue peptidomes, which is suitable for high throughput quantitative studies. The reproducibility and coverage of the platform, as well as the suitability of clinical ovarian tumor and patient-derived breast tumor xenograft samples with post-excision delay of up to 60 min before freezing for peptidomics analysis, have been demonstrated. Moreover, our data also show that the peptidomics profiles can effectively separate breast cancer subtypes, reflecting tumor-associated protease activities. Peptidomics complements results obtainable from conventional bottom-up proteomics, and provides insights not readily obtainable from such approaches.

  15. Intrinsic Near-Infrared Spectroscopic Markers of Breast Tumors

    OpenAIRE

    Shwayta Kukreti; Albert Cerussi; Bruce Tromberg; Enrico Gratton

    2009-01-01

    We have discovered quantitative optical biomarkers unique to cancer by developing a double-differential spectroscopic analysis method for near-infrared (NIR, 650–1000 nm) spectra acquired non-invasively from breast tumors. These biomarkers are characterized by specific NIR absorption bands. The double-differential method removes patient specific variations in molecular composition which are not related to cancer, and reveals these specific cancer biomarkers. Based on the spectral regions of a...

  16. Glioma Cells in the Tumor Periphery Have a Stem Cell Phenotype

    DEFF Research Database (Denmark)

    Munthe, Sune; Petterson, Stine Asferg; Dahlrot, Rikke Hedegaard;

    2016-01-01

    in the periphery of patient gliomas have a stem cell phenotype, although it is less pronounced than in the tumor core. Novel therapies aiming at preventing recurrence should therefore take tumor stemness into account. Migrating cells in orthotopic glioblastoma xenografts preserve expression and stem cell markers......Gliomas are highly infiltrative tumors incurable with surgery. Although surgery removes the bulk tumor, tumor cells in the periphery are left behind resulting in tumor relapses. The aim of the present study was to characterize the phenotype of tumor cells in the periphery focusing on tumor stemness...... and a panel of markers was used. The panel comprised of six stem cell-related markers (CD133, Musashi-1, Bmi-1, Sox-2, Nestin and Glut-3), a proliferation marker (Ki-67) as well as a chemo-resistance marker (MGMT). Computer-based automated classifiers were designed to measure the mIDH1 positive nucleus area...

  17. Epigenetic regulation of ID4 in the determination of the BRCAness phenotype in breast cancer.

    Science.gov (United States)

    Branham, M T; Campoy, E; Laurito, S; Branham, R; Urrutia, G; Orozco, J; Gago, F; Urrutia, R; Roqué, M

    2016-01-01

    BRCAness breast tumors represent a group of sporadic tumors characterized by a reduction in BRCA1 gene expression. As BRCA1 is involved in double-strand breaks (DSBs) repair, dysfunctional BRCA pathway could make a tumor sensitive to DNA damaging drugs (e.g., platinum agents). Thus, accurately identifying BRCAness could contribute to therapeutic decision making in patients harboring these tumors. The purpose of this study was to identify if BRCAness tumors present a characteristic methylation profile and/or were related to specific clinico-pathological features. BRCAness was measured by MLPA in 63 breast tumors; methylation status of 98 CpG sites within 84 cancer-related genes was analyzed by MS-MLPA. Protein and mRNA expressions of the selected genes were measured by quantitative real-time PCR and Western Blot. BRCAness was associated with younger age, higher nuclear pleomorphism, and triple-negative (TN) status. Epigenetically, we found that the strongest predictors for BRCAness tumors were the methylations of MLH1 and PAX5 plus the unmethylations of CCND2 and ID4. We determined that ID4 unmethylation correlated with the expression levels of both its mRNA and protein. We observed an inverse relation between the expressions of ID4 and BRCA1. To the best of our knowledge, this is the first report suggesting an epigenetic regulation of ID4 in BRCAness tumors. Our findings give new information of BRCAness etiology and encourage future studies on potential drug targets for BRCAness breast tumors.

  18. Tumor-to-tumor metastasis: an unusual case of breast cancer metastatic to a solitary fibrous tumor

    OpenAIRE

    Velez-Cubian, Frank O.; Gabordi, Robert C.; Smith, Prudence V.; Toloza, Eric M.

    2016-01-01

    Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that most commonly involves the visceral or parietal pleura, but that has also been described arising from virtually all organs. This neoplasm exhibits rich vascularity, a characteristic it shares with renal cell carcinoma, making these tumors especially suitable for harboring metastases. We present a case of a 64-year-old woman with history of right breast cancer treated six years previously and who presents with a left pulmonary SF...

  19. Establishment of VX2 breast carcinoma model in rabbit by injecting tumor mass suspension

    Institute of Scientific and Technical Information of China (English)

    CHEN Jiang-hao; YAO Qing; WANG Ling; LING Rui; ZHANG Ju-liang; WANG Ting; WANG Hui; YANG Hua

    2004-01-01

    Objective: To establish a stable model of VX2 breast carcinoma in rabbit and select the optimal way.Methods: Thirty female New Zealand rabbits were randomly divided into 3 groups with 10 in each. Tumor cell suspensions or tumor mass suspensions were injected into breast tissues of rabbits of group A and B, respectively. Tumor blocks were surgically implanted in rabbit breasts of group C. Tumor formation rate, tumor growth rate, and tumor-bearing survival time was compared, and the histological feature of tumor was observed. Results: Models were established conveniently and successfully in rabbits received injection of tumor mass suspensions. Tumor proliferated rapidly with the biological feature of squamous cell carcinoma. Conclusion: VX2 breast carcinoma model in rabbit was established successfully. Intramammary injection of tumor mass suspension is the best method.

  20. Human breast microvascular endothelial cells retain phenotypic traits in long-term finite life span culture

    DEFF Research Database (Denmark)

    Sigurdsson, Valgardur; Fridriksdottir, Agla J R; Kjartansson, Jens;

    2007-01-01

    Attempts to study endothelial-epithelial interactions in the human breast have been hampered by lack of protocols for long-term cultivation of breast endothelial cells (BRENCs). The aim of this study was to establish long-term cultures of BRENCs and to compare their phenotypic traits with the tis......Attempts to study endothelial-epithelial interactions in the human breast have been hampered by lack of protocols for long-term cultivation of breast endothelial cells (BRENCs). The aim of this study was to establish long-term cultures of BRENCs and to compare their phenotypic traits...... with the tissue of origin. Microvasculature was localized in situ by immunohistochemistry in breast samples. From this tissue, collagen-rich stroma and adipose tissue were dissected mechanically and further disaggregated to release microvessel organoids. BRENCs were cultured from these organoids in endothelial......-galactosidase staining. We demonstrate here that breast microvasculature may serve as a large-scale source for expansion of BRENCs with molecular and functional traits preserved. These cells will form the basis for studies on the role of endothelial cells in breast morphogenesis....

  1. BRCA1 Protein Expression Level and CD44+ Phenotype in Breast Cancer Patients

    Directory of Open Access Journals (Sweden)

    Saadat Molanae

    2011-01-01

    Full Text Available Objective: CD44+/CD24-/low breast cancer cells have tumour-initiating properties with stemcell-like features. Breast cancer gene 1 (BRCA1 is a tumour suppressor gene that playsa crucial role in DNA repair and maintenance of chromosome stability. The clinicopathologicalfeatures of breast cancer in BRCA1 mutation carriers suggest that BRCA1 mayfunction as a stem-cell regulator.Materials and Methods: In the present experimental study we examined the expressionand localization of the BRCA1 protein and investigated the prognostic value aswell as its relationship with the putative cancer stem cell (CSC marker (CD44 in 156tumour samples from a well-characterized series of unselected breast carcinomas usingimmunohistochemistry. Statistical analysis of the data was performed using SPSSsoftware version 16 (Chicago, IL, USA.Results: In breast tumours, the loss of nuclear expression was detected in 23 cases(15%, whereas cytoplasmic expression of BRCA1 was observed in 133 breast carcinomas(85%. Altered BRCA1 expression was significantly associated with high grade and poorprognosis breast tumours (p=0.006. We further established an inverse significant correlationbetween BRCA1 expression levels and CD44+ cancer cell phenotype (p=0.02Conclusion: Loss of BRCA1 expression is a marker of tumour aggressiveness andcorrelates with CD44+ tumour cell phenotype. Taken together, the present study supportsthe idea that the loss of BRCA1 results in persistent errors in DNA replication inbreast stem cells and provides targets for additional carcinogenic events.

  2. Risk factors for ipsilateral breast tumor recurrence and uncontrolled local disease

    OpenAIRE

    Dalberg, Kristina

    1998-01-01

    The aims of the study were to assess intrinsic and treatment related risk factors for ipsilateral breast tumor recurrence (IBTR) and uncontrolled local disease (ULD) following breast-conserving surgery of early-stage invasive breast cancer. In a cohort of 759 women with T1-T2 tumors risk factors were evaluated. The majority of the patients (88%) had received postoperative irradiation to the breast. A continuous 1-1.5% yearly increase in IBTR was seen. Three independent r...

  3. Nonrigid registration algorithm for longitudinal breast MR images and the preliminary analysis of breast tumor response

    Science.gov (United States)

    Li, Xia; Dawant, Benoit M.; Welch, E. Brian; Chakravarthy, A. Bapsi; Freehardt, Darla; Mayer, Ingrid; Kelley, Mark; Meszoely, Ingrid; Gore, John C.; Yankeelov, Thomas E.

    2009-02-01

    Although useful for the detection of breast cancers, conventional imaging methods, including mammography and ultrasonography, do not provide adequate information regarding response to therapy. Dynamic contrast enhanced MRI (DCE-MRI) has emerged as a promising technique to provide relevant information on tumor status. Consequently, accurate longitudinal registration of breast MR images is critical for the comparison of changes induced by treatment at the voxel level. In this study, a nonrigid registration algorithm is proposed to allow for longitudinal registration of breast MR images obtained throughout the course of treatment. We accomplish this by modifying the adaptive bases algorithm (ABA) through adding a tumor volume preserving constraint in the cost function. The registration results demonstrate the proposed algorithm can successfully register the longitudinal breast MR images and permit analysis of the parameter maps. We also propose a novel validation method to evaluate the proposed registration algorithm quantitatively. These validations also demonstrate that the proposed algorithm constrains tumor deformation well and performs better than the unconstrained ABA algorithm.

  4. Circulating tumor cells in breast cancer: A tool whose time has come of age

    Directory of Open Access Journals (Sweden)

    Cristofanilli Massimo

    2011-04-01

    Full Text Available Abstract Circulating tumor cells (CTCs are isolated tumor cells disseminated from the site of disease in metastatic and/or primary cancers, including breast cancer, that can be identified and measured in the peripheral blood of patients. As recent technical advances have rendered it easier to reproducibly and repeatedly sample this population of cells with a high degree of accuracy, these cells represent an attractive surrogate marker of the site of disease. Currently, CTCs are being integrated into clinical trial design as a surrogate for phenotypic and genotypic markers in correlation with development of molecularly targeted therapies. As CTCs play a crucial role in tumor dissemination, translational research is implicating CTCs in several biological processes, including epithelial to mesenchymal transition. In this mini-review, we review CTCs in metastatic breast cancer, and discuss their clinical utility for assessing prognosis and monitoring response to therapy. We will also introduce their utility in pharmacodynamic monitoring for rational selection of molecularly targeted therapies and briefly address how they can help elucidate the biology of cancer metastasis.

  5. RANKL/RANK/MMP-1 molecular triad contributes to the metastatic phenotype of breast and prostate cancer cells in vitro.

    Directory of Open Access Journals (Sweden)

    Sandra Casimiro

    Full Text Available The osteolytic nature of bone metastasis results from a tumor-driven increased bone resorption. Bone remodeling is orchestrated by the molecular triad RANK-RANKL-OPG. This process is dysregulated in bone metastases, mostly via induction of RANKL by tumor-derived factors. These factors increase expression of RANKL, which induce osteoclast formation, function, and survival, thereby increasing bone resorption. RANK is unexpectedly expressed by cancer cells, and the activation of RANKL-RANK pathway correlates with an increased invasive phenotype. To investigate the interaction between RANK expression in human breast and prostate cancer cells and their pro-metastatic phenotype we analyzed the activation of RANKL-RANK pathway and its effects on cell migration, invasion, gene expression in vitro, and osteolysis-inducing ability in vivo. RANKL activates kinase signaling pathways, stimulates cell migration, increases cell invasion, and up-regulates MMP-1 expression. In vivo, MMP-1 knockdown resulted in smaller x-ray osteolytic lesions and osteoclastogenesis, and decreased tumor burden. Therefore, RANKL inhibition in bone metastatic disease may decrease the levels of the osteoclastogenesis inducer MMP-1, contributing to a better clinical outcome.

  6. Endothelial cell pseudopods and angiogenesis of breast cancer tumors

    Directory of Open Access Journals (Sweden)

    Sun LuZhe

    2005-05-01

    Full Text Available Abstract Background A neoplastic tumor cannot grow beyond a millimeter or so in diameter without recruitment of endothelial cells and new blood vessels to supply nutrition and oxygen for tumor cell survival. This study was designed to investigate formation of new blood vessels within a human growing breast cancer tumor model (MDA MB231 in mammary fat pad of nude female mouse. Once the tumor grew to 35 mm3, it developed a well-vascularized capsule. Histological sections of tumors greater than 35 mm3 were stained with PAS, with CD-31 antibody (an endothelial cell maker, or with hypoxia inducible factor 1α antibody (HIF. The extent of blood vessel and endothelial cell pseudopod volume density was measured by ocular grid intercept counting in the PAS stained slides. Results The tumor area within 100–150 μm of the well-vascularized capsule had few blood vessels and only occasional endothelial cell pseudopods, whereas the area greater than 150 μm from the capsule had more blood vessels, capillaries, and a three-fold increase in volume density of pseudopods sprouting from the capillary endothelial cells. This subcortical region, rich in pseudopods, some of which were observed to have vacuoles/lumens, was strongly positive for presence of HIF. In some larger tumors, pseudopods were observed to insinuate for mm distances through hypoxic regions of the tumor. Conclusion The positive correlation between presence of HIF and the increased extent of pseudopods suggests volume density measure of the latter as a quantifiable marker of tumor hypoxia. Apparently, hypoxic regions of the tumor produce HIF leading to production of vascular endothelial growth factors that stimulate sprouting of capillary endothelial cells and formation of endothelial cell pseudopods.

  7. Combination therapy targeting both cancer stem-like cells and bulk tumor cells for improved efficacy of breast cancer treatment.

    Science.gov (United States)

    Wang, Tao; Narayanaswamy, Radhika; Ren, Huilan; Torchilin, Vladimir P

    2016-06-01

    Many types of tumors are organized in a hierarchy of heterogeneous cell populations. The cancer stem-like cells (CSCs) hypothesis suggests that tumor development and metastasis are driven by a minority population of cells, which are responsible for tumor initiation, growth and recurrences. The inability to efficiently eliminate CSCs during chemotherapy, together with CSCs being highly tumorigenic and invasive, may result in treatment failure due to cancer relapse and metastases. CSCs are emerging as a promising target for the development of translational cancer therapies. Ideal panacea for cancer would kill all malignant cells, including CSCs and bulk tumor cells. Since both chemotherapy and CSCs-specific therapy are insufficient to cure cancer, we propose combination therapy with CSCs-targeted agents and chemotherapeutics for improved breast cancer treatment. We generated in vitro mammosphere of 2 breast cancer cell lines, and demonstrated ability of mammospheres to grow and enrich cancer cells with stem-like properties, including self-renewal, multilineage differentiation and enrichment of cells expressing breast cancer stem-like cell biomarkers CD44(+)/CD24(-/low). The formation of mammospheres was significantly inhibited by salinomycin, validating its pharmacological role against the cancer stem-like cells. In contrast, paclitaxel showed a minimal effect on the proliferation and growth of breast cancer stem-like cells. While combination therapies of salinomycin with conventional chemotherapy (paclitaxel or lipodox) showed a potential to improve tumor cell killing, different subtypes of breast cancer cells showed different patterns in response to the combination therapies. While optimization of combination therapy is warranted, the design of combination therapy should consider phenotypic attributes of breast cancer types. PMID:27259361

  8. Combination therapy targeting both cancer stem-like cells and bulk tumor cells for improved efficacy of breast cancer treatment.

    Science.gov (United States)

    Wang, Tao; Narayanaswamy, Radhika; Ren, Huilan; Torchilin, Vladimir P

    2016-06-01

    Many types of tumors are organized in a hierarchy of heterogeneous cell populations. The cancer stem-like cells (CSCs) hypothesis suggests that tumor development and metastasis are driven by a minority population of cells, which are responsible for tumor initiation, growth and recurrences. The inability to efficiently eliminate CSCs during chemotherapy, together with CSCs being highly tumorigenic and invasive, may result in treatment failure due to cancer relapse and metastases. CSCs are emerging as a promising target for the development of translational cancer therapies. Ideal panacea for cancer would kill all malignant cells, including CSCs and bulk tumor cells. Since both chemotherapy and CSCs-specific therapy are insufficient to cure cancer, we propose combination therapy with CSCs-targeted agents and chemotherapeutics for improved breast cancer treatment. We generated in vitro mammosphere of 2 breast cancer cell lines, and demonstrated ability of mammospheres to grow and enrich cancer cells with stem-like properties, including self-renewal, multilineage differentiation and enrichment of cells expressing breast cancer stem-like cell biomarkers CD44(+)/CD24(-/low). The formation of mammospheres was significantly inhibited by salinomycin, validating its pharmacological role against the cancer stem-like cells. In contrast, paclitaxel showed a minimal effect on the proliferation and growth of breast cancer stem-like cells. While combination therapies of salinomycin with conventional chemotherapy (paclitaxel or lipodox) showed a potential to improve tumor cell killing, different subtypes of breast cancer cells showed different patterns in response to the combination therapies. While optimization of combination therapy is warranted, the design of combination therapy should consider phenotypic attributes of breast cancer types.

  9. Aberrant methylation of the Adenomatous Polyposis Coli (APC) gene promoter is associated with the inflammatory breast cancer phenotype

    OpenAIRE

    Van der Auwera, I; Laere, S.J.; Van den Bosch, S M; Van den Eynden, G. G.; Trinh, B X; van Dam, P A; Colpaert, C G; van Engeland, M; Van Marck, E A; Vermeulen, P B; Dirix, L Y

    2008-01-01

    Aberrant methylation of the adenomatous polyposis coli (APC) gene promoter occurs in about 40% of breast tumours and has been correlated with reduced APC protein levels. To what extent epigenetic alterations of the APC gene may differ according to specific breast cancer phenotypes, remains to be elucidated. Our aim was to explore the role of APC methylation in the inflammatory breast cancer (IBC) phenotype. The status of APC gene promoter hypermethylation was investigated in DNA from normal b...

  10. Phyllodes tumor of the breast with lung metastasis

    International Nuclear Information System (INIS)

    The case report of a 63-year-old patient is described, who was admitted to 'Dr. Juan Bruno Zayas Alfonso' Teaching General Hospital of Santiago de Cuba due to persistent dry cough, little expectoration (sometimes yellowish), asthenia and loss of weight. On physical examination a tumor was palpated in the right breast, which was confirmed through sonography and mammogram. The results of the fine-needle biopsy were positive for neoplastic cells, consistent with carcinoma. Chest radiography and computerized axial tomography revealed the presence of lung metastatic images, reason why tumor excision with a safety margin of 2 cm was performed. The presence of phyllodes tumor was confirmed by means of the histopathologic study, so that it was necessary to indicate 3 cycles of chemotherapy (CISCYVADACT scheme), of which only two were administered as the old woman had an unfavorable course and she died 3 months later

  11. Radiation-associated breast tumors display a distinct gene expression profile

    DEFF Research Database (Denmark)

    Broeks, Annegien; Braaf, Linde M; Wessels, Lodewyk F A;

    2010-01-01

    radiation-associated cause underlies the carcinogenic process. METHODS AND MATERIALS: In this study we used gene expression profiling technology to assess gene expression changes in radiation-associated breast tumors compared with a set of control breast tumors of women unexposed to radiation, diagnosed...... at the same age. RNA was obtained from fresh frozen tissue samples from 22 patients who developed breast cancer after Hodgkin's lymphoma (BfHL) and from 20 control breast tumors. RESULTS: Unsupervised hierarchical clustering of the profile data resulted in a clustering of the radiation-associated tumors...... separate from the control tumors (p tumors were often of the intrinsic basal breast tumor subtype, and they showed a chromosomal instability profile and a higher expression...

  12. Attenuation of malignant phenotypes of breast cancer cells through eIF2α-mediated downregulation of Rac1 signaling.

    Science.gov (United States)

    Hamamura, Kazunori; Minami, Kazumasa; Tanjung, Nancy; Wan, Qiaoqiao; Koizumi, Masahiko; Matsuura, Nariaki; Na, Sungsoo; Yokota, Hiroki

    2014-06-01

    Blocking dephosphorylation of eukaryotic translation initiation factor 2α (eIF2α) is reported to alter proliferation and differentiation of various cells. Using salubrinal and guanabenz as an inhibitory agent of dephosphorylation of eIF2α, we addressed a question whether an elevated level of phosphorylated eIF2α attenuates malignant phenotypes of triple negative breast cancer cells (TNBCs) that lack estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2. We determined effects of salubrinal and guanabenz on in vitro phenotype of 4T1 mammary tumor cells and MDA-MB-231 human breast cancer cells and evaluated their effects on in vivo tumor growth using BALB/c mice injected with 4T1 cells. The results revealed that these agents block the proliferation and survival of 4T1 and MDA-MB-231 cells, as well as their invasion and motility. Silencing eIF2α revealed that eIF2α is involved in the reduction in invasion and motility. Furthermore, salubrinal-driven inactivation of Rac1 was suppressed in the cells treated with eIF2α siRNA, and treatment with Rac1 siRNA reduced cell invasion and motility. In vivo assay revealed that subcutaneous administration of salubrinal reduced the volume and weight of tumors induced by 4T1 cells. Collectively, the results indicate that these agents can attenuate malignant phenotype and tumor growth of breast cancer cells through the eIF2α-mediated Rac1 pathway. Since salubrinal and guanabenz are known to inhibit bone resorption, this study provides a potential use of eIF2α-mediated Rac1 regulation in suppressing the growth and metastasis of breast cancer. PMID:24691491

  13. "A novel in vivo model for the study of human breast cancer metastasis using primary breast tumor-initiating cells from patient biopsies"

    Directory of Open Access Journals (Sweden)

    Marsden Carolyn G

    2012-01-01

    Full Text Available Abstract Background The study of breast cancer metastasis depends on the use of established breast cancer cell lines that do not accurately represent the heterogeneity and complexity of human breast tumors. A tumor model was developed using primary breast tumor-initiating cells isolated from patient core biopsies that would more accurately reflect human breast cancer metastasis. Methods Tumorspheres were isolated under serum-free culture conditions from core biopsies collected from five patients with clinical diagnosis of invasive ductal carcinoma (IDC. Isolated tumorspheres were transplanted into the mammary fat pad of NUDE mice to establish tumorigenicity in vivo. Tumors and metastatic lesions were analyzed by hematoxylin and eosin (H+E staining and immunohistochemistry (IHC. Results Tumorspheres were successfully isolated from all patient core biopsies, independent of the estrogen receptor α (ERα/progesterone receptor (PR/Her2/neu status or tumor grade. Each tumorsphere was estimated to contain 50-100 cells. Transplantation of 50 tumorspheres (1-5 × 103 cells in combination with Matrigel into the mammary fat pad of NUDE mice resulted in small, palpable tumors that were sustained up to 12 months post-injection. Tumors were serially transplanted three times by re-isolation of tumorspheres from the tumors and injection into the mammary fat pad of NUDE mice. At 3 months post-injection, micrometastases to the lung, liver, kidneys, brain and femur were detected by measuring content of human chromosome 17. Visible macrometastases were detected in the lung, liver and kidneys by 6 months post-injection. Primary tumors variably expressed cytokeratins, Her2/neu, cytoplasmic E-cadherin, nuclear β catenin and fibronectin but were negative for ERα and vimentin. In lung and liver metastases, variable redistribution of E-cadherin and β catenin to the membrane of tumor cells was observed. ERα was re-expressed in lung metastatic cells in two of five

  14. Breast cancer phenotypes regulated by tissue factor-factor VII pathway: Possible therapeutic targets.

    Science.gov (United States)

    Koizume, Shiro; Miyagi, Yohei

    2014-12-10

    Breast cancer is a leading cause of cancer death in women, worldwide. Fortunately, breast cancer is relatively chemosensitive, with recent advances leading to the development of effective therapeutic strategies, significantly increasing disease cure rate. However, disease recurrence and treatment of cases lacking therapeutic molecular targets, such as epidermal growth factor receptor 2 and hormone receptors, referred to as triple-negative breast cancers, still pose major hurdles in the treatment of breast cancer. Thus, novel therapeutic approaches to treat aggressive breast cancers are essential. Blood coagulation factor VII (fVII) is produced in the liver and secreted into the blood stream. Tissue factor (TF), the cellular receptor for fVII, is an integral membrane protein that plays key roles in the extrinsic coagulation cascade. TF is overexpressed in breast cancer tissues. The TF-fVII complex may be formed in the absence of injury, because fVII potentially exists in the tissue fluid within cancer tissues. The active form of this complex (TF-fVIIa) may stimulate the expression of numerous malignant phenotypes in breast cancer cells. Thus, the TF-fVII pathway is a potentially attractive target for breast cancer treatment. To date, a number of studies investigating the mechanisms by which TF-fVII signaling contributes to breast cancer progression, have been conducted. In this review, we summarize the mechanisms controlling TF and fVII synthesis and regulation in breast cancer cells. Our current understanding of the TF-fVII pathway as a mediator of breast cancer progression will be also described. Finally, we will discuss how this knowledge can be applied to the design of future therapeutic strategies. PMID:25493229

  15. Circulating tumor cells (CTCs) in breast cancer: a diagnostic tool for prognosis and molecular analysis

    Institute of Scientific and Technical Information of China (English)

    Xiaoshen Dong; R.Katherine Alpaugh; Massimo Cristofanilli

    2012-01-01

    Metastatic breast cancer (MBC) is characterized by a combination of tumor growth,proliferation and metastatic progression and is typically managed with palliative intent.The benefit of standard systemic therapies is relatively limited and the disease is considered incurable suggesting the need to investigate the biological drivers of the various phases of the metastatic process in order to improve the selection of molecularly driven therapies.The detection,enumeration and molecular analysis of circulating tumor cells (CTCs) provide an intriguing opportunity to advance this knowledge.CTCs enumerated by the Food and Drugs Administration-cleared CellSearchTM system are an independent prognostic factor of progression-free survival (PFS) and overall survival (OS) in MBC patients.Several published papers demonstrated the poor prognosis for MBC patients that presented basal CTC count ≥5 in 7.5 mL of blood.Therefore,the enumeration of CTCs during treatment for MBC provides a tool with the ability to predict progression of disease earlier than standard timing of anatomical assessment using conventional radiological tests.During the metastatic process cancer cells exhibit morphological and phenotypic plasticity undergoing epithelial-mesenchymal transition (EMT).This important phenomenon is associated with down regulation of epithelial marker (e.g.,EpCAM) with potential limitations in the applicability of current CTCs enrichment methods.Such observations translated in a number of investigations aimed at improving our capabilities to enumerate and perform molecular characterization of CTCs.Theoretically,the phenotypic analysis of CTCs can represent a "liquid" biopsy of breast tumor that is able to identify a new potential target against the metastatic disease and advance the development and monitoring of personalized therapies.

  16. Mass spectrometry images acylcarnitines, phosphatidylcholines, and sphingomyelin in MDA-MB-231 breast tumor models

    NARCIS (Netherlands)

    Chughtai, K; Jiang, L.; Greenwood, T.R.; Glunde, K.; Heeren, R.M.A.

    2013-01-01

    The lipid compositions of different breast tumor microenvironments are largely unknown due to limitations in lipid imaging techniques. Imaging lipid distributions would enhance our understanding of processes occurring inside growing tumors, such as cancer cell proliferation, invasion, and metastasis

  17. Cyclooxygenase-2 in tumor-associated macrophages promotes breast cancer cell survival by triggering a positive-feedback loop between macrophages and cancer cells

    OpenAIRE

    Li, Hongzhong; Yang, Bing; Huang, Jing; Lin, Yong; Xiang, Tingxiu; Wan, Jingyuan; Li, Hongyuan; Chouaib, Salem; Ren, Guosheng

    2015-01-01

    Tumor-associated macrophages (TAMs) play an important role in cancer cell survival, however, the mechanism of which remains elusive. In this study, we found that COX-2 was abundantly expressed in breast TAMs, which was correlated to poor prognosis in breast cancer patients. Ectopic over-expression of COX-2 in TAMs enhanced breast cancer cell survival both in vitro and in vivo. COX-2 in TAMs was determined to be essential for the induction and maintenance of M2-phenotype macrophage polarity. C...

  18. Significance of ipsilateral breast tumor recurrence after breast conserving treatment: role of surgical removal

    Institute of Scientific and Technical Information of China (English)

    Romano Demicheli; Ilaria Ardoino; Federico Ambrogi; Roberto Agresti; Elia Biganzoli

    2013-01-01

    To analyze the pattern over time (dynamics) of further recurrence and death after ipsilateral breast tumor recurrence (IBTR) in breast cancer patients undergoing breast conserving treatment (BCT).Methods:A total of 338 evaluable patients experiencing IBTR were extracted from a database of 3,293 patients undergoing BCT.The hazard rates for recurrence and mortality throughout 10 years of follow-up after IBTR were assessed and were compared to the analogous estimates associated to the primary treatment.Results:In a time frame with the time origin at the surgical treatment for IBTR,the hazard rate for further recurrence displays a bimodal pattern (peaks at the second and at the sixth year).Patients receiving mastectomy for IBTR reveal recurrence and mortality dynamics similar to that of node positive (N+) patients receiving mastectomy as primary surgery,apart from the first two-three years,when IBTR patients do worse.If the patients with time to IBTR longer than 2.5 years are considered,differences disappear.Conclusions:The recurrence and mortality dynamics following IBTR surgical removal is similar to the corresponding dynamics following primary tumor removal.In particular,patients with time to IBTR in excess of 2.5 years behave like N+ patients following primary tumor removal.Findings may be suitably explained by assuming that the surgical manoeuvre required by IBTR treatment is able to activate a sudden growing phase for tumor foci most of which,as suggested by the systemic model of breast cancer,would have reached the clinical level according to their own dynamics.

  19. Mind the gap: Racial differences in breast cancer incidence and biologic phenotype, but not stage, among low-income women participating in a government-funded screening program

    Science.gov (United States)

    Cunningham, Joan E.; Walters, Christine A.; Hill, Elizabeth G.; Ford, Marvella E.; Barker-Elamin, Tiffany; Bennett, Charles L.

    2013-01-01

    Background Breast cancer mortality rates in South Carolina (SC) are 40% higher among African-American (AA) than European-American (EA) women. Proposed reasons include race-associated variations in care and/or tumor characteristics, which may be subject to income effects. We evaluated race-associated differences in tumor biologic phenotype and stage among low-income participants in a government-funded screening program. Methods Best Chance Network (BCN) data were linked with the SC Central Cancer Registry. Characteristics of breast cancers diagnosed in BCN participants aged 47–64 years during 1996–2006 were abstracted. Race-specific case proportions and incidence rates based on estrogen receptor (ER) status and histologic grade were estimated. Results Among 33,880 low-income women accessing BCN services, repeat breast cancer screening utilization was poor, especially among EAs. Proportionally, stage at diagnosis did not differ by race (607 cancers, 53% among AAs), with about 40% advanced stage. Compared to EAs, invasive tumors in AAs were 67% more likely (proportions) to be of poor-prognosis phenotype (both ER-negative and high-grade); this was more a result of the 46% lesser AA incidence (rates) of better-prognosis (ER+ lower-grade) cancer than the 32% greater incidence of poor-prognosis disease (p-values <0.01). When compared to the general SC population, racial disparities in poor prognostic features within the BCN population were attenuated; this was due to more frequent adverse tumor features in EAs rather than improvements for AAs. Conclusion Among low-income women in SC, closing the breast cancer racial and income mortality gaps will require improved early diagnosis, addressing causes of racial differences in tumor biology, and improved care for cancers of poor-prognosis biology. PMID:23239148

  20. Significance of Micrometastases: Circulating Tumor Cells and Disseminated Tumor Cells in Early Breast Cancer

    Directory of Open Access Journals (Sweden)

    Catherine Oakman

    2010-06-01

    Full Text Available Adjuvant systemic therapy targets minimal residual disease. Our current clinical approach in the adjuvant setting is to presume, rather than confirm, the presence of minimal residual disease. Based on assessment of the primary tumor, we estimate an individual’s recurrence risk. Subsequent treatment decisions are based on characteristics of the primary tumor, with the presumption of consistent biology and treatment sensitivity between micrometastases and the primary lesion. An alternative approach is to identify micrometastatic disease. Detection of disseminated tumor cells (DTC in the bone marrow and circulating tumor cells (CTC from peripheral blood collection may offer quantification and biocharacterization of residual disease. This paper will review the prognostic and predictive potential of micrometastatic disease in early breast cancer.

  1. Core Needle Biopsy of Breast Cancer Tumors Increases Distant Metastases in a Mouse Model12

    OpenAIRE

    Mathenge, Edward Gitau; Dean, Cheryl Ann; Clements, Derek; Vaghar-Kashani, Ahmad; Photopoulos, Steffany; Coyle, Krysta Mila; Giacomantonio, Michael; Malueth, Benjamin; Nunokawa, Anna; Jordan, Julie; Lewis, John D.; Gujar, Shashi Ashok; Marcato, Paola; Lee, Patrick W.K.; Giacomantonio, Carman Anthony

    2014-01-01

    INTRODUCTION: Incisional biopsies, including the diagnostic core needle biopsy (CNB), routinely performed before surgical excision of breast cancer tumors are hypothesized to increase the risk of metastatic disease. In this study, we experimentally determined whether CNB of breast cancer tumors results in increased distant metastases and examine important resultant changes in the primary tumor and tumor microenvironment associated with this outcome. METHOD: To evaluate the effect of CNB on me...

  2. Effect of breast cancer phenotype on diagnostic performance of MRI in the prediction to response to neoadjuvant treatment

    Energy Technology Data Exchange (ETDEWEB)

    Bufi, Enida, E-mail: reagandus@alice.it [Department of Bioimaging and Radiological Sciences, Catholic University, Rome (Italy); Belli, Paolo; Di Matteo, Marialuisa [Department of Bioimaging and Radiological Sciences, Catholic University, Rome (Italy); Terribile, Daniela; Franceschini, Gianluca [Department of Surgery, Breast Unit, Catholic University, Rome (Italy); Nardone, Luigia [Department of Radiotherapy, Catholic University, Rome (Italy); Petrone, Gianluigi [Department of Pathology, Catholic University, Rome (Italy); Bonomo, Lorenzo [Department of Bioimaging and Radiological Sciences, Catholic University, Rome (Italy)

    2014-09-15

    Aim: The estimation of response to neoadjuvant chemotherapy (NAC) is useful in the surgical decision in breast cancer. We addressed the diagnostic reliability of conventional MRI, of diffusion weighted imaging (DWI) and of a merged criterion coupling morphological MRI and DWI. Diagnostic performance was analysed separately in different tumor subtypes, including HER2+ (human epidermal growth factor receptor 2)/HR+ (hormone receptor) (hybrid phenotype). Materials and methods: Two-hundred and twenty-five patients underwent MRI before and after NAC. The response to treatment was defined according to the RECIST classification and the evaluation of DWI with apparent diffusion coefficient (ADC). The complete pathological response – pCR was assessed (Mandard classification). Results: Tumor phenotypes were Luminal (63.6%), Triple Negative (16.4%), HER2+ (7.6%) or Hybrid (12.4%). After NAC, pCR was observed in 17.3% of cases. Average ADC was statistically higher after NAC (p < 0.001) among patients showing pCR vs. those who had not pCR. The RECIST classification showed adequate performance in predicting the pCR in Triple Negative (area under the receiver operating characteristic curve, ROC AUC = 0.9) and in the HER2+ subgroup (AUC = 0.826). Lower performance was found in the Luminal and Hybrid subgroups (AUC 0.693 and 0.611, respectively), where the ADC criterion yielded an improved performance (AUC = 0.787 and 0.722). The coupling of morphological and DWI criteria yielded maximally improved performance in the Luminal and Hybrid subgroups (AUC = 0.797 and 0.761). Conclusion: The diagnostic reliability of MRI in predicting the pCR to NAC depends on the tumor phenotype, particularly in the Luminal and Hybrid subgroups. In these cases, the coupling of morphological MRI evaluation and DWI assessment may facilitate the diagnosis.

  3. Impact of Triple-Negative Phenotype on Prognosis of Patients With Breast Cancer Brain Metastases

    Energy Technology Data Exchange (ETDEWEB)

    Xu Zhiyuan [Department of Neurosurgery, University of Virginia, Charlottesville, Virginia (United States); Schlesinger, David [Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia (United States); Toulmin, Sushila [Department of Neurosurgery, University of Virginia, Charlottesville, Virginia (United States); Rich, Tyvin [Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia (United States); Sheehan, Jason, E-mail: jps2f@virginia.edu [Department of Neurosurgery, University of Virginia, Charlottesville, Virginia (United States)

    2012-11-01

    Purpose: To elucidate survival times and identify potential prognostic factors in patients with triple-negative (TN) phenotype who harbored brain metastases arising from breast cancer and who underwent stereotactic radiosurgery (SRS). Methods and Materials: A total of 103 breast cancer patients with brain metastases were treated with SRS and then studied retrospectively. Twenty-four patients (23.3%) were TN. Survival times were estimated using the Kaplan-Meier method, with a log-rank test computing the survival time difference between groups. Univariate and multivariate analyses to predict potential prognostic factors were performed using a Cox proportional hazard regression model. Results: The presence of TN phenotype was associated with worse survival times, including overall survival after the diagnosis of primary breast cancer (43 months vs. 82 months), neurologic survival after the diagnosis of intracranial metastases, and radiosurgical survival after SRS, with median survival times being 13 months vs. 25 months and 6 months vs. 16 months, respectively (p < 0.002 in all three comparisons). On multivariate analysis, radiosurgical survival benefit was associated with non-TN status and lower recursive partitioning analysis class at the initial SRS. Conclusion: The TN phenotype represents a significant adverse prognostic factor with respect to overall survival, neurologic survival, and radiosurgical survival in breast cancer patients with intracranial metastasis. Recursive partitioning analysis class also served as an important and independent prognostic factor.

  4. Exon-level transcriptome profiling in murine breast cancer reveals splicing changes specific to tumors with different metastatic abilities.

    Directory of Open Access Journals (Sweden)

    Amandine Bemmo

    Full Text Available BACKGROUND: Breast cancer is the second most frequent type of cancer affecting women. We are increasingly aware that changes in mRNA splicing are associated with various characteristics of cancer. The most deadly aspect of cancer is metastasis, the process by which cancer spreads from the primary tumor to distant organs. However, little is known specifically about the involvement of alternative splicing in the formation of macroscopic metastases. Our study investigates transcript isoform changes that characterize tumors of different abilities to form growing metastases. METHODS AND FINDINGS: To identify alternative splicing events (ASEs that are associated with the fully metastatic phenotype in breast cancer, we used Affymetrix Exon Microarrays to profile mRNA isoform variations genome-wide in weakly metastatic (168FARN and 4T07 and highly metastatic (4T1 mammary carcinomas. Statistical analysis identified significant expression changes in 7606 out of 155,994 (4% exons and in 1725 out of 189,460 (1% intronic regions, which affect 2623 out of 16,654 (16% genes. These changes correspond to putative alternative isoforms-several of which are novel-that are differentially expressed between tumors of varying metastatic phenotypes. Gene pathway analysis showed that 1224 of genes expressing alternative isoforms were involved in cell growth, cell interactions, cell proliferation, cell migration and cell death and have been previously linked to cancers and genetic disorders. We chose ten predicted splice variants for RT-PCR validation, eight of which were successfully confirmed (MED24, MFI2, SRRT, CD44, CLK1 and HNRNPH1. These include three novel intron retentions in CD44, a gene in which isoform variations have been previously associated with the metastasis of several cancers. CONCLUSION: Our findings reveal that various genes are differently spliced and/or expressed in association with the metastatic phenotype of tumor cells. Identification of

  5. Persistence of disseminated tumor cells after neoadjuvant treatment for locally advanced breast cancer predicts poor survival

    OpenAIRE

    Mathiesen, Randi R.; Borgen, Elin; Renolen, Anne; Løkkevik, Erik; Nesland, Jahn M; Anker, Gun; Østenstad, Bjørn; Lundgren, Steinar; Risberg, Terje; Mjaaland, Ingvil; Kvalheim, Gunnar; Lønning, Per E.; Naume, Bjørn

    2012-01-01

    Introduction Presence of disseminated tumor cells (DTCs) in bone marrow (BM) and circulating tumor cells (CTC) in peripheral blood (PB) predicts reduced survival in early breast cancer. The aim of this study was to determine the presence of and alterations in DTC- and CTC-status in locally advanced breast cancer patients undergoing neoadjuvant chemotherapy (NACT) and to evaluate their prognostic impact. Methods ...

  6. Annexin A1 expression in breast cancer: tumor subtypes and prognosis

    OpenAIRE

    Sobral-Leite, Marcelo; Wesseling, Jelle; Smit, Vincent T. H. B. M.; Nevanlinna, Heli; van Miltenburg, Martine H; Sanders, Joyce; Hofland, Ingrid; Blows, Fiona M.; Coulson, Penny; Patrycja, Gazinska; Schellens, Jan H. M.; Fagerholm, Rainer; Heikkilä, Päivi; Aittomäki, Kristiina; Blomqvist, Carl

    2015-01-01

    Abstract Background Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. ...

  7. Inorganic Nanovehicle Targets Tumor in an Orthotopic Breast Cancer Model

    Science.gov (United States)

    Choi, Goeun; Kwon, Oh-Joon; Oh, Yeonji; Yun, Chae-Ok; Choy, Jin-Ho

    2014-03-01

    The clinical efficacy of conventional chemotherapeutic agent, methotrexate (MTX), can be limited by its very short plasma half-life, the drug resistance, and the high dosage required for cancer cell suppression. In this study, a new drug delivery system is proposed to overcome such limitations. To realize such a system, MTX was intercalated into layered double hydroxides (LDHs), inorganic drug delivery vehicle, through a co-precipitation route to produce a MTX-LDH nanohybrid with an average particle size of approximately 130 nm. Biodistribution studies in mice bearing orthotopic human breast tumors revealed that the tumor-to-liver ratio of MTX in the MTX-LDH-treated-group was 6-fold higher than that of MTX-treated-one after drug treatment for 2 hr. Moreover, MTX-LDH exhibited superior targeting effect resulting in high antitumor efficacy inducing a 74.3% reduction in tumor volume compared to MTX alone, and as a consequence, significant survival benefits. Annexin-V and propidium iodine dual staining and TUNEL analysis showed that MTX-LDH induced a greater degree of apoptosis than free MTX. Taken together, our data demonstrate that a new MTX-LDH nanohybrid exhibits a superior efficacy profile and improved distribution compared to MTX alone and has the potential to enhance therapeutic efficacy via inhibition of tumor proliferation and induction of apoptosis.

  8. Breast tumor specific mutation in GATA3 affects physiological mechanisms regulating transcription factor turnover

    OpenAIRE

    Adomas, Aleksandra B; Grimm, Sara A.; Malone, Christine; Takaku, Motoki; Sims, Jennifer K.; Wade, Paul A.

    2014-01-01

    Background The transcription factor GATA3 is a favorable prognostic indicator in estrogen receptor-α (ERα)-positive breast tumors in which it participates with ERα and FOXA1 in a complex transcriptional regulatory program driving tumor growth. GATA3 mutations are frequent in breast cancer and have been classified as driver mutations. To elucidate the contribution(s) of GATA3 alterations to cancer, we studied two breast cancer cell lines, MCF7, which carries a heterozygous frameshift mutation ...

  9. Correlation of primary tumor size and axillary nodal status with tumor suppressor gene p53 in breast carcinoma

    Directory of Open Access Journals (Sweden)

    Topić Brano

    2002-01-01

    Full Text Available Correlation of standard path morphological prognostic parameters, primary tumor size and axillary nodal status with new prognostic factor in breast carcinoma: tumor suppressor gene p53 was analyzed. The studied sample included 65 women who underwent surgery for breast carcinoma at the Surgical Clinic of Clinical Center Banja Luka, from January 1st 1997 till January 1st 1999. Statistical data analysis was performed and correlation of prognostic factors was determined. The majority of authors in this field agree that the primary tumor size and axillary nodal status are the two most important prognostic factors. These factors are the best predictors of prognosis and survival of women who had the tumor and were operated on. Tumor markers were immunohistochemically determined in the last ten years and, according to the majority of authors, are still considered the additional or relative prognostic factors in breast carcinoma. Their prognostic value and significance increase almost daily. Most frequently determined tumor markers are bcl-2, pS2, Ki-67 and p53. There was a positive, directly proportional relationship between primary tumor size and tumor suppressor gene p53, but there was no positive correlation between the axillary nodal status and tumor suppressor gene p53. Significance of determination of new tumor markers as the prognostic factors was emphasized. These markers represent a powerful tool in the early detection and prevention of breast carcinoma.

  10. Gastric Composite Tumor of Alpha Fetoprotein-Producing Carcinoma/Hepatoid Adenocarcinoma and Endocrine Carcinoma with Reference to Cellular Phenotypes

    Directory of Open Access Journals (Sweden)

    Akira Suzuki

    2012-01-01

    Full Text Available Alpha-fetoprotein-producing carcinoma (AFPC/hepatoid adenocarcinoma (HAC and neuroendocrine carcinoma (NEC are uncommon in the stomach. Composite tumors consisting of these carcinomas and their histologic phenotypes are not well known. Between 2002 and 2007, to estimate the prevalence of composite tumors consisting of tubular adenocarcinoma, AFPC/HAC and NEC, we reviewed specimens obtained from 294 consecutive patients treated surgically for gastric cancer. We examined histological phenotype of tumors of AFPC or NEC containing the composite tumor by evaluating immunohistochemical expressions of MUC2, MUC5AC, MUC6, CDX2, and SOX2. Immunohistochemically, AFPC/HAC dominantly showed the intestinal or mixed phenotype, and NEC frequently showed the gastric phenotype. In the composite tumor, the tubular and hepatoid components showed the gastric phenotype, and the neuroendocrine component showed the mixed type. The unique composite tumor predominantly showed the gastric phenotype, and the hepatoid and neuroendocrine components were considered to be differentiated from the tubular component.

  11. Oncogenic driver genes and the inflammatory microenvironment dictate liver tumor phenotype

    DEFF Research Database (Denmark)

    Matter, Matthias S; Marquardt, Jens U; Andersen, Jesper B;

    2016-01-01

    by distinct oncogenes is largely unresolved. To address this issue, we generated murine liver tumors by constitutively active AKT-1 (AKT) and β-catenin (CAT) followed by induction of chronic liver inflammation by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride (CCl4 ). Also...... already existent tumor characteristics as supported by transcriptome analysis. However, it also reduced lipid droplets in AKT-NRAS(G12V) tumors. CONCLUSION: Our study suggests that liver tumor phenotype is defined by a combination of driving oncogenes but also the nature of chronic liver inflammation...

  12. Exosome derived from epigallocatechin gallate treated breast cancer cells suppresses tumor growth by inhibiting tumor-associated macrophage infiltration and M2 polarization

    International Nuclear Information System (INIS)

    Tumor-associated macrophages (TAM) play an important role in tumor microenvironment. Particularly, M2 macrophages contribute to tumor progression, depending on the expression of NF-κB. Tumor-derived exosomes can modulate tumor microenvironment by transferring miRNAs to immune cells. Epigallocatechin gallate (EGCG) has well known anti-tumor effects; however, no data are available on the influence of EGCG on communication with cancer cells and TAM. Murine breast cancer cell lines, 4T1, was used for in vivo and ex vivo studies. Exosome was extracted from EGCG-treated 4T1 cells, and the change of miRNAs was screened using microarray. Tumor cells or TAM isolated from murine tumor graft were incubated with exosomes derived from EGCG-treated and/or miR-16 inhibitor-transfected 4T1 cells. Chemokines for monocytes (CSF-1 and CCL-2), cytokines both with high (IL-6 and TGF-β) and low (TNF-α) expression in M2 macrophages, and molecules in NF-κB pathway (IKKα and Iκ-B) were evaluated by RT-qPCR or western blot. EGCG suppressed tumor growth in murine breast cancer model, which was associated with decreased TAM and M2 macrophage infiltration. Expression of chemokine for monocytes (CSF-1 and CCL-2) were low in tumor cells from EGCG-treated mice, and cytokines of TAM was skewed from M2- into M1-like phenotype by EGCG as evidenced by decreased IL-6 and TGF-β and increased TNF-α. Ex vivo incubation of isolated tumor cells with EGCG inhibited the CSF-1 and CCL-2 expression. Ex vivo incubation of TAM with exosomes from EGCG-treated 4T1 cells led to IKKα suppression and concomitant I-κB accumulation; increase of IL-6 and TGF-β; and, decrease of TNF-α. EGCG up-regulated miR-16 in 4T1 cells and in the exosomes. Treatment of tumor cells or TAM with exosomes derived from EGCG-treated and miR-16-knock-downed 4T1 cells restored the above effects on chemokines, cytokines, and NF-κB pathway elicited by EGCG-treated exosomes. Our data demonstrate that EGCG up-regulates miR-16 in

  13. Targeting highly expressed extracellular HSP90 in breast cancer stem cells inhibits tumor growth in vitro and in vivo.

    Science.gov (United States)

    Stivarou, Theodora; Stellas, Dimitris; Vartzi, Georgia; Thomaidou, Dimitra; Patsavoudi, Evangelia

    2016-08-01

    Breast cancer stem cells (BCSC) have been identified in breast carcinoma as CD44(+)/CD24(-/low) cells, which display tumorigenic activity and have the ability to self-renew, differentiate and metastasize. Previous studies showed that extracellular HSP90 (eHSP90) participates in the invasion and metastatic processes of various cancers including breast cancer. Here, we show for the first time that eHSP90 is over-expressed in mammosphere cultures that are derived from the MDA-MB-231, MDA-MB-453 and MCF-7 breast cancer cell lines. These mammospheres are highly enriched in cells of the CD44(+)/CD24(-/low) BCSC phenotype and additionally show high expression of the BCSC markers CD49f and Sox2. Thus our results indicate that eHSP90 represents a potential novel BCSC marker. Moreover, we present evidence that eHSP90 is functionally involved in BCSC activity in vitro and in vivo. Selective neutralization of eHSP90, using the monoclonal antibody mAb 4C5, has the capacity to inhibit stem cell activity in vitro because the formation of mammosphere-derived colonies is dramatically reduced in its presence. In vivo, the treatment of mice with mAb4C5 using a prophylactic protocol, significantly inhibited the primary growth of MDA-MB-231 and mammosphere-derived tumors. More importantly, administration of this antibody in a therapeutic protocol caused a statistically significant regression of established tumors derived from MDA-MB-231 originating mammospheres. Tumor regression was even greater when mAb 4C5 was administered in combination with paclitaxel. Overall, our findings implicate eHSP90 as a potential novel BCSC biomarker. Moreover they show that eHSP90 participates in BCSC-derived primary tumor growth. Finally, we provide additional support for the possible therapeutic value of mAb4C5 in the treatment of breast cancer. PMID:27259689

  14. A role for ADAM12 in breast tumor progression and stromal cell apoptosis

    DEFF Research Database (Denmark)

    Kveiborg, Marie; Frohlich, Camilla; Albrechtsen, Reidar;

    2005-01-01

    of stromal fibroblasts in tumor initiation and progression has been elucidated. Here, we show that stromal cell apoptosis occurs in human breast carcinoma but is only rarely seen in nonmalignant breast lesions. Furthermore, we show that ADAM12, a disintegrin and metalloprotease up-regulated in human breast...... cancer, accelerates tumor progression in a mouse breast cancer model. ADAM12 does not influence tumor cell proliferation but rather confers both decreased tumor cell apoptosis and increased stromal cell apoptosis. This dual role of ADAM12 in governing cell survival is underscored by the finding that ADAM......12 increases the apoptotic sensitivity of nonneoplastic cells in vitro while rendering tumor cells more resistant to apoptosis. Together, these results show that the ability of ADAM12 to influence apoptosis may contribute to tumor progression....

  15. In vitro analysis of the invasive phenotype of SUM 149, an inflammatory breast cancer cell line

    OpenAIRE

    Dharmawardhane Suranganie F; Wall Kristin M; Hoffmeyer Michaela R

    2005-01-01

    Abstract Background Inflammatory breast cancer (IBC) is the most lethal form of locally invasive breast cancer known. However, very little information is available on the cellular mechanisms responsible for manifestation of the IBC phenotype. To understand the unique phenotype of IBC, we compared the motile and adhesive interactions of an IBC cell line, SUM 149, to the non-IBC cell line SUM 102. Results Our results demonstrate that both IBC and non-IBC cell lines exhibit similar adhesive prop...

  16. Molecular subtyping of serous ovarian tumors reveals multiple connections to intrinsic breast cancer subtypes.

    Directory of Open Access Journals (Sweden)

    Jenny-Maria Jönsson

    Full Text Available OBJECTIVE: Transcriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer. METHODS: Global gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published gene profiles for the ovarian and breast cancer subtypes. Correlations to gene expression modules representing key biological breast cancer features were also sought. Validation was performed using an independent, publicly available dataset. RESULTS: 5,944 genes were significantly differentially expressed between benign and malignant serous ovarian tumors, with cell cycle processes enriched in the malignant subgroup. Borderline tumors were split between the two clusters. Significant correlations between the malignant serous tumors and the highly aggressive ovarian cancer signatures, and the basal-like breast cancer subtype were found. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer signature derived from borderline tumors. The borderline tumors in the study dataset, in addition, also correlated significantly to the luminal A breast cancer subtype. These findings remained when analyzed in an independent dataset, supporting links between the molecular subtypes of ovarian cancer and breast cancer beyond those recently acknowledged. CONCLUSIONS: These data link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and

  17. Molecular phenotype is associated with survival in breast cancer patients with spinal bone metastases.

    Science.gov (United States)

    Bollen, L; Wibmer, C; Wang, M; van der Linden, Y M; Leithner, A; Bünger, C E; Jensen, A B; Fiocco, M; Bratschitsch, G; Pondaag, W; Bovée, J V M G; Dijkstra, P D S

    2015-01-01

    To aid in therapy selection for patients with spinal bone metastases (SBM), predictive models have been developed. These models consider SBM from breast cancer a positive predictive factor, but do not take phenotypes based on estrogen (ER), progesterone (PR) and human epidermal growth factor 2 (HER2) receptors into account. The aim of this study was to ascertain whether receptors are associated with survival, when the disease has progressed up to SBM. All patients who were treated for SBM from breast cancer between 2005 and 2012 were included in this international multi-center retrospective study (n = 111). Reports were reviewed for ER, PR and HER2 status and subsequently subdivided into one of four categories; luminal A, luminal B, HER2 and triple negative. Survival time was calculated as the difference between start of treatment for SBM and date of death. Analysis was performed using the Kaplan-Meier method and log-rank tests. Median follow-up was 3.7 years. Survival times in the luminal B and HER2 categories were not significantly different to the luminal A category and were joined into a single receptor positive category. Eighty-five patients (77 %) had a receptor positive phenotype and 25 (23 %) had a triple negative phenotype. Median survival time was 22.5 months (95 %CI 18.0-26.9) for the receptor positive category and 6.7 months (95 %CI 2.4-10.9) for the triple negative category (p < 0.001). Patients with SBM from breast cancer with a triple negative phenotype have a shorter survival time than patients with a receptor positive phenotype. Models estimating survival should be adjusted accordingly. PMID:25359620

  18. Apocrine carcinoma of the male breast: a case report of an exceptional tumor

    OpenAIRE

    Sekal, Mohammed; Znati, Kaoutar; Harmouch, Taoufiq; Riffi, Afaf Amarti

    2014-01-01

    Apocrine carcinoma of the male breast is an exceptional malignant tumor. It does not have a particular clinical or radiological appearance, but it's microscopically characterized by the presence of granular cells and foamy cells representing over 90% of tumor cells. These cells express most of the time the GCDFP-15 and the androgen receptors. This tumor is a distinct molecular entity. In this observation, we report the case of a 70 year old man presenting apocrine carcinoma of the left breast...

  19. Invasive Cribriform Carcinoma Arising in Malignant Phyllodes Tumor of Breast: A Case Report

    OpenAIRE

    Choi, Yoomi; Lee, Kyoung Yul; Jang, Min Hye; Seol, Hyesil; Kim, Sung-Won; Park, So Yeon

    2012-01-01

    Phyllodes tumor is an uncommon fibroepithelial neoplasm of the breast. And it is characterized by expanded stroma with increased cellularity and elongated epithelium-lined clefts. Mammary carcinomas within phyllodes tumors have been rarely reported. To date, however, no reports have described the invasive cribriform carcinoma arising in malignant phyllodes tumor. Here, we report a 62-year-old woman who presented with a large breast mass. Microscopically, the mass was a typical malignant phyll...

  20. Glioma Cells in the Tumor Periphery Have a Stem Cell Phenotype.

    Directory of Open Access Journals (Sweden)

    Sune Munthe

    Full Text Available Gliomas are highly infiltrative tumors incurable with surgery. Although surgery removes the bulk tumor, tumor cells in the periphery are left behind resulting in tumor relapses. The aim of the present study was to characterize the phenotype of tumor cells in the periphery focusing on tumor stemness, proliferation and chemo-resistance. This was investigated in situ in patient glioma tissue as well as in orthotopic glioblastoma xenografts. We identified 26 gliomas having the R132 mutation in Isocitrate DeHydrogenase 1 (mIDH1. A double immunofluorescence approach identifying mIDH1 positive tumor cells and a panel of markers was used. The panel comprised of six stem cell-related markers (CD133, Musashi-1, Bmi-1, Sox-2, Nestin and Glut-3, a proliferation marker (Ki-67 as well as a chemo-resistance marker (MGMT. Computer-based automated classifiers were designed to measure the mIDH1 positive nucleus area-fraction of the chosen markers. Moreover, orthotopic glioblastoma xenografts from five different patient-derived spheroid cultures were obtained and the tumor cells identified by human specific immunohistochemical markers. The results showed that tumor cells in the periphery of patient gliomas expressed stem cell markers, however for most markers at a significantly lower level than in the tumor core. The Ki-67 level was slightly reduced in the periphery, whereas the MGMT level was similar. In orthotopic glioblastoma xenografts all markers showed similar levels in the core and periphery. In conclusion tumor cells in the periphery of patient gliomas have a stem cell phenotype, although it is less pronounced than in the tumor core. Novel therapies aiming at preventing recurrence should therefore take tumor stemness into account. Migrating cells in orthotopic glioblastoma xenografts preserve expression and stem cell markers. The orthotopic model therefore has a promising translational potential.

  1. miRNA expression profiling of formalin-fixed paraffin-embedded (FFPE hereditary breast tumors

    Directory of Open Access Journals (Sweden)

    Miljana Tanić

    2015-03-01

    Full Text Available Hereditary breast cancer constitutes only 5–10% of all breast cancer cases and is characterized by strong family history of breast and/or other associated cancer types. Only ~25% of hereditary breast cancer cases carry a mutation in BRCA1 or BRCA2 gene, while mutations in other rare high and moderate-risk genes and common low penetrance variants may account for additional 20% of the cases. Thus the majority of cases are still unaccounted for and designated as BRCAX tumors. MicroRNAs are small non-coding RNAs that play important roles as regulators of gene expression and are deregulated in cancer. To characterize hereditary breast tumors based on their miRNA expression profiles we performed global microarray miRNA expression profiling on a retrospective cohort of 80 FFPE breast tissues, including 66 hereditary breast tumors (13 BRCA1, 10 BRCA2 and 43 BRCAX, 10 sporadic breast carcinomas and 4 normal breast tissues, using Exiqon miRCURY LNA™ microRNA Array v.11.0. Here we describe in detail the miRNA microarray expression data and tumor samples used for the study of BRCAX tumor heterogeneity (Tanic et al., 2013 and biomarkers associated with positive BRCA1/2 mutation status (Tanic et al., 2014. Additionally, we provide the R code for data preprocessing and quality control.

  2. Modulation of circulating angiogenic factors and tumor biology by aerobic training in breast cancer patients receiving neoadjuvant chemotherapy.

    Science.gov (United States)

    Jones, Lee W; Fels, Diane R; West, Miranda; Allen, Jason D; Broadwater, Gloria; Barry, William T; Wilke, Lee G; Masko, Elisabeth; Douglas, Pamela S; Dash, Rajesh C; Povsic, Thomas J; Peppercorn, Jeffrey; Marcom, P Kelly; Blackwell, Kimberly L; Kimmick, Gretchen; Turkington, Timothy G; Dewhirst, Mark W

    2013-09-01

    Aerobic exercise training (AET) is an effective adjunct therapy to attenuate the adverse side-effects of adjuvant chemotherapy in women with early breast cancer. Whether AET interacts with the antitumor efficacy of chemotherapy has received scant attention. We carried out a pilot study to explore the effects of AET in combination with neoadjuvant doxorubicin-cyclophosphamide (AC+AET), relative to AC alone, on: (i) host physiology [exercise capacity (VO2 peak), brachial artery flow-mediated dilation (BA-FMD)], (ii) host-related circulating factors [circulating endothelial progenitor cells (CEP) cytokines and angiogenic factors (CAF)], and (iii) tumor phenotype [tumor blood flow ((15)O-water PET), tissue markers (hypoxia and proliferation), and gene expression] in 20 women with operable breast cancer. AET consisted of three supervised cycle ergometry sessions/week at 60% to 100% of VO2 peak, 30 to 45 min/session, for 12 weeks. There was significant time × group interactions for VO2 peak and BA-FMD, favoring the AC+AET group (P blood flow in the AC+AET group. There were no differences in any tumor tissue markers (P > 0.05). Whole-genome microarray tumor analysis revealed significant differential modulation of 57 pathways (P < 0.01), including many that converge on NF-κB. Data from this exploratory study provide initial evidence that AET can modulate several host- and tumor-related pathways during standard chemotherapy. The biologic and clinical implications remain to be determined. PMID:23842792

  3. HER family kinase domain mutations promote tumor progression and can predict response to treatment in human breast cancer

    KAUST Repository

    Boulbes, Delphine R.

    2014-11-11

    Resistance to HER2-targeted therapies remains a major obstacle in the treatment of HER2-overexpressing breast cancer. Understanding the molecular pathways that contribute to the development of drug resistance is needed to improve the clinical utility of novel agents, and to predict the success of targeted personalized therapy based on tumor-specific mutations. Little is known about the clinical significance of HER family mutations in breast cancer. Because mutations within HER1/EGFR are predictive of response to tyrosine kinase inhibitors (TKI) in lung cancer, we investigated whether mutations in HER family kinase domains are predictive of response to targeted therapy in HER2-overexpressing breast cancer. We sequenced the HER family kinase domains from 76 HER2-overexpressing invasive carcinomas and identified 12 missense variants. Patients whose tumors carried any of these mutations did not respond to HER2 directed therapy in the metastatic setting. We developed mutant cell lines and used structural analyses to determine whether changes in protein conformation could explain the lack of response to therapy. We also functionally studied all HER2 mutants and showed that they conferred an aggressive phenotype and altered effects of the TKI lapatinib. Our data demonstrate that mutations in the finely tuned HER kinase domains play a critical function in breast cancer progression and may serve as prognostic and predictive markers.

  4. Inhibitors of Rho kinase (ROCK) signaling revert the malignant phenotype of breast cancer cells in 3D context.

    Science.gov (United States)

    Matsubara, Masahiro; Bissell, Mina J

    2016-05-31

    Loss of polarity and quiescence along with increased cellular invasiveness are associated with breast tumor progression. ROCK plays a central role in actin-cytoskeletal rearrangement. We used physiologically relevant 3D cultures of nonmalignant and cancer cells in gels made of laminin-rich extracellular matrix, to investigate ROCK function. Whereas expression levels of ROCK1 and ROCK2 were elevated in cancer cells compared to nonmalignant cells, this was not observed in 2D cultures. Malignant cells showed increased phosphorylation of MLC, corresponding to disorganized F-actin. Inhibition of ROCK signaling restored polarity, decreased disorganization of F-actin, and led to reduction of proliferation. Inhibition of ROCK also decreased EGFR and Integrinβ1 levels, and consequently suppressed activation of Akt, MAPK and FAK as well as GLUT3 and LDHA levels. Again, ROCK inhibition did not inhibit these molecules in 2D. A triple negative breast cancer cell line, which lacks E-cadherin, had high levels of ROCK but was less sensitive to ROCK inhibitors. Exogenous overexpression of E-cadherin, however, rendered these cells strikingly sensitive to ROCK inhibition. Our results add to the growing literature that demonstrate the importance of context and tissue architecture in determining not only regulation of normal and malignant phenotypes but also drug response.

  5. High throughput functional genomics: identification of novel genes with tumor suppressor phenotypes.

    Science.gov (United States)

    Koenig-Hoffmann, Kerstin; Bonin-Debs, Angelika L; Boche, Irene; Gawin, Beate; Gnirke, Andrea; Hergersberg, Christoph; Madeo, Frank; Kazinski, Michael; Klein, Matthias; Korherr, Christian; Link, Dieter; Röhrig, Sascha; Schäfer, Rolf; Brinkmann, Ulrich

    2005-01-20

    We have used a combination of high throughput functional genomics, computerized database mining and expression analyses to discover novel human tumor suppressor genes (TSGs). A genome-wide high throughput cDNA phenotype screen was established to identify genes that induce apoptosis or reduce cell viability. TSGs are expressed in normal tissue and frequently act by reduction of growth of transformed cells or induce apoptosis. In agreement with that and thus serving as platform validation, our pro-apoptotic hits included genes for which tumor suppressing activities were known, such as kangai1 and CD81 antigen. Additional genes that so far have been claimed as putative TSGs or associated with tumor inhibitory activities (prostate differentiation factor, hRAS-like suppressor 3, DPH2L1-like and the metastasis inhibitor Kiss1) were confirmed in their proposed TSG-like phenotype by functionally defining their growth inhibitory or pro-apoptotic function towards cancer cells. Finally, novel genes were identified for which neither association with cell growth nor with apoptosis were previously described. A subset of these genes show characteristics of TSGs because they (i) reduce the growth or induce apoptosis in tumor cells; (ii) show reduced expression in tumor vs. normal tissue; and (iii) are located on chromosomal (LOH-) loci for which cancer-associated deletions are described. The pro-apoptotic phenotype and differential expression of these genes in normal and malignant tissue make them promising target candidates for the diagnosis and therapy of various tumors.

  6. Malignant phyllodes tumor of the breast presenting with hypoglycemia: a case report and literature review

    International Nuclear Information System (INIS)

    Phyllodes tumors are rare fibroepithelial neoplasms that account for less than 1% of all breast tumors and are typically found in middle-aged women. Phyllodes tumors that present with hypoglycemia are even rarer. No one morphologic finding is reliable in predicting the clinical behavior of this tumor. Surgery has been the primary mode of treatment to date. However, the extent of resection and the role of adjuvant radiotherapy or chemotherapy are still controversial. Here, we present a challenging case of malignant phyllodes tumor of the breast associated with hypoglycemia, and review the literature regarding clinical findings, pathologic risk factors for recurrence, and treatment recommendations

  7. Recent translational research: stem cells as the roots of breast cancer

    OpenAIRE

    Chang, Chia-Cheng

    2006-01-01

    Common phenotypes of cancer and stem cells suggest that breast cancers arise from stem cells. Breast epithelial cells with stem cell phenotypes have been shown to be more susceptible to immortalization and neoplastic transformation. Breast tumor stem cells with CD44+/CD24-/lowLineage- markers have been isolated. The role of these cells in tumor progression and clinical outcome is not clear. The relationship between breast stem cell and tumor stem cell may be elucidated by further studies of c...

  8. A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds.

    Science.gov (United States)

    Bruna, Alejandra; Rueda, Oscar M; Greenwood, Wendy; Batra, Ankita Sati; Callari, Maurizio; Batra, Rajbir Nath; Pogrebniak, Katherine; Sandoval, Jose; Cassidy, John W; Tufegdzic-Vidakovic, Ana; Sammut, Stephen-John; Jones, Linda; Provenzano, Elena; Baird, Richard; Eirew, Peter; Hadfield, James; Eldridge, Matthew; McLaren-Douglas, Anne; Barthorpe, Andrew; Lightfoot, Howard; O'Connor, Mark J; Gray, Joe; Cortes, Javier; Baselga, Jose; Marangoni, Elisabetta; Welm, Alana L; Aparicio, Samuel; Serra, Violeta; Garnett, Mathew J; Caldas, Carlos

    2016-09-22

    The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance.

  9. ESR1 gene promoter region methylation in free circulating DNA and its correlation with estrogen receptor protein expression in tumor tissue in breast cancer patients

    International Nuclear Information System (INIS)

    Tumor expression of estrogen receptor (ER) is an important marker of prognosis, and is predictive of response to endocrine therapy in breast cancer. Several studies have observed that epigenetic events, such methylation of cytosines and deacetylation of histones, are involved in the complex mechanisms that regulate promoter transcription. However, the exact interplay of these factors in transcription activity is not well understood. In this study, we explored the relationship between ER expression status in tumor tissue samples and the methylation of the 5′ CpG promoter region of the estrogen receptor gene (ESR1) isolated from free circulating DNA (fcDNA) in plasma samples from breast cancer patients. Patients (n = 110) with non-metastatic breast cancer had analyses performed of ER expression (luminal phenotype in tumor tissue, by immunohistochemistry method), and the ESR1-DNA methylation status (fcDNA in plasma, by quantitative methylation specific PCR technique). Our results showed a significant association between presence of methylated ESR1 in patients with breast cancer and ER negative status in the tumor tissue (p = 0.0179). There was a trend towards a higher probability of ESR1-methylation in those phenotypes with poor prognosis i.e. 80% of triple negative patients, 60% of HER2 patients, compared to 28% and 5.9% of patients with better prognosis such as luminal A and luminal B, respectively. Silencing, by methylation, of the promoter region of the ESR1 affects the expression of the estrogen receptor protein in tumors of breast cancer patients; high methylation of ESR1-DNA is associated with estrogen receptor negative status which, in turn, may be implicated in the patient’s resistance to hormonal treatment in breast cancer. As such, epigenetic markers in plasma may be of interest as new targets for anticancer therapy, especially with respect to endocrine treatment

  10. Improved characterization of molecular phenotypes in breast lesions using 18F-FDG PET image homogeneity

    Science.gov (United States)

    Cao, Kunlin; Bhagalia, Roshni; Sood, Anup; Brogi, Edi; Mellinghoff, Ingo K.; Larson, Steven M.

    2015-03-01

    Positron emission tomography (PET) using uorodeoxyglucose (18F-FDG) is commonly used in the assessment of breast lesions by computing voxel-wise standardized uptake value (SUV) maps. Simple metrics derived from ensemble properties of SUVs within each identified breast lesion are routinely used for disease diagnosis. The maximum SUV within the lesion (SUVmax) is the most popular of these metrics. However these simple metrics are known to be error-prone and are susceptible to image noise. Finding reliable SUV map-based features that correlate to established molecular phenotypes of breast cancer (viz. estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression) will enable non-invasive disease management. This study investigated 36 SUV features based on first and second order statistics, local histograms and texture of segmented lesions to predict ER and PR expression in 51 breast cancer patients. True ER and PR expression was obtained via immunohistochemistry (IHC) of tissue samples from each lesion. A supervised learning, adaptive boosting-support vector machine (AdaBoost-SVM), framework was used to select a subset of features to classify breast lesions into distinct phenotypes. Performance of the trained multi-feature classifier was compared against the baseline single-feature SUVmax classifier using receiver operating characteristic (ROC) curves. Results show that texture features encoding local lesion homogeneity extracted from gray-level co-occurrence matrices are the strongest discriminator of lesion ER expression. In particular, classifiers including these features increased prediction accuracy from 0.75 (baseline) to 0.82 and the area under the ROC curve from 0.64 (baseline) to 0.75.

  11. TFF3 is a normal breast epithelial protein and is associated with differentiated phenotype in early breast cancer but predisposes to invasion and metastasis in advanced disease.

    Science.gov (United States)

    Ahmed, Ahmed R H; Griffiths, Andrew B; Tilby, Michael T; Westley, Bruce R; May, Felicity E B

    2012-03-01

    The trefoil protein TFF3 stimulates invasion and angiogenesis in vitro. To determine whether it has a role in breast tumor metastasis and angiogenesis, its levels were measured by immunohistochemistry in breast tissue with a specific monoclonal antibody raised against human TFF3. TFF3 is expressed in normal breast lobules and ducts, at higher levels in areas of fibrocystic change and papillomas, in all benign breast disease lesions, and in 89% of in situ and in 83% of invasive carcinomas. In well-differentiated tumor cells, TFF3 is concentrated at the luminal edge, whereas in poorly differentiated cells polarity is inverted and expression is directed toward the stroma. Expression was high in well-differentiated tumors and was associated significantly with low histological grade and with estrogen and progesterone receptor expression, accordant with induction of TFF3 mRNA by estrogen in breast cancer cells. Paradoxically, TFF3 expression was associated with muscle, neural, and lymphovascular invasion and the presence and number of involved lymph nodes, and it was an independent predictive marker of lymphovascular invasion and lymph node involvement. Consistent with an angiogenic function, TFF3 expression correlated strongly with microvessel density evaluated with CD31 and CD34. In conclusion, TFF3 is expressed in both the normal and diseased breast. Although associated with features of good prognosis, its profile of expression in invasive cancer is consistent with a role in breast tumor progression and tumor cell dissemination.

  12. Time of flight estimation for breast cancer margin thickness using embedded tumors

    Science.gov (United States)

    Bowman, Tyler; El-Shenawee, Magda; Campbell, Lucas

    2016-03-01

    This work aims to enact a quick and reasonable estimation of breast cancer margin thickness using time of flight analysis of embedded breast cancer tissue. A pulsed terahertz system is used to obtain reflection imaging scans from breast cancer tumors that are formalin-fixed and embedded in paraffin blocks. Time of flight analysis is then used to compare the reflection patterns seen within the block to pathology sections and paraffin-embedded sections that are taken throughout the depth of the tumor in order to estimate the three-dimensional boundaries of the tumor.

  13. Role of COX-2 in the regulation of the metastatic potential of human breast tumor cells

    Directory of Open Access Journals (Sweden)

    M. A. Taipov

    2014-01-01

    Full Text Available The expression of СOX-2, VEGF, VEGFR-1, VEGFR-2, VEGFR-3, EGFR, endoglin (СD105, and IL-6 was analyzed in the human breast tumor cells having a varying metastatic potential. The role of these factors in the regulation of the metastatic potential of breast cancer cells, as well as that of COX-2 in the regulation of metastatic processes at the cellular level were examined. The potential capacity of human breast tumor cells to elaborate factors that stimulate tumor growth, angiogenesis, and metastasis was evaluated.

  14. Analysis of dendritic cells in tumor-free and tumor-containing sentinel lymph nodes from patients with breast cancer

    International Nuclear Information System (INIS)

    Sentinel lymph node (SLN) biopsy allows identification of the first lymph node into which a primary tumor drains. In breast cancer, identification of tumor cells in the SLNs is a predictor of the tumor's metastatic potential. In the present article, we tested the hypotheses that a positive immune response can occur in tumor-free SLNs and that the activation state of dendritic cells (DCs), the major antigen presenting cells within SLNs, predicts the immune status and metastatic potential of the tumor. Fifty paraffin-embedded SLN sections, 25 tumor-free and 25 tumor-containing, from patients with breast cancer were analyzed by immunohistochemistry to determine the immune maturation state of their DCs. In addition, 12 lymph nodes from noncancer-containing breasts were analyzed. Tissues were stained with antibodies against CD3, MHC class II, CD1a, CD83, IL-10, and IL-12. Mature DCs were defined by CD83 expression and immature DCs by CD1a expression. We found a trend toward higher numbers of mature CD83-positive DCs in tumor-free SLNs than in tumor-containing SLNs (P = 0.07). In addition, tumor-free SLNs were more likely to contain cells expressing IL-10 (P = 0.02) and, to a lesser extent, IL-12 (P = 0.12). In contrast, when all SLNs, both tumor-free and tumor-containing, were compared with uninvolved lymph nodes, the numbers of mature and immature DCs were similar. Our results suggest tumor-free SLNs are immunologically competent and potentially a site of tumor-specific T-cell activation, as evidenced by the presence of greater numbers of mature DCs and cytokine-producing cells in tumor-free SLNs

  15. Morphological predictors of nipple areola involvement in malignant breast tumors

    Directory of Open Access Journals (Sweden)

    Khan Kalyan

    2010-04-01

    Full Text Available Context: Nipple areola (NA sparing mastectomy has an acceptable complication rate, is oncologically safe and facilitates an improved cosmetic result, aiding greatly in reducing psychological trauma associated with breast loss. Questions regarding preoperative case selection for NA sparing mastectomy are pertinent. Aims: The principle objective was to develop a simple model based on correlation of malignant involvement of NA with morphological factors in breast cancer cases to accurately predict the cancerous involvement of nipple areola preoperatively. Settings and Design: The present cross-sectional study was carried out on 136 patients of breast cancer. The period of study spanned 3 years from 2004 to 2007. Materials and Methods: We evaluated 17 different morphological parameters which had proven prognostic significance in breast cancer cases for their relationship with NA involvement. Data regarding cytological parameters were available in 120 cases out of the total number of 136 cases. Simple and conventional methods appropriate for any under-resourced set-up were employed to enhance the economic viability and acceptability of the project. Statistical Analysis used: Statistical analysis in this study was mostly done using SPSS version: 14 software. P-value < 0.05 was considered significant when assessing correlation between two parameters. Results: The frequency of NA involvement detected in this study was 19.1%. In univariate analysis, 13 of the 17 morphological parameters were found to have strong statistical association (P < 0.05 with NA involvement. In multivariate analysis, only four parameters-macroscopic NA changes, tumor-NA distance ( < 1.5cm, histological lymph node grade and extra capsular extension in lymph node were found to have independent role for NA involvement prediction. This multivariate Cox and Snell Regression model with Cox and Snell Regression Square of 0.551 can predict accurately 98.5% cases of nipple involvement

  16. Pattern of Ipsilateral Breast Tumor Recurrence After Breast-Conserving Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Jobsen, Jan, E-mail: j.jobsen@mst.nl [Department of Radiation Oncology, Medisch Spectrum Twente, Enschede (Netherlands); Palen, Job van der [Department of Epidemiology, Medisch Spectrum Twente, Enschede (Netherlands); Department of Research Methodology, Measurement, and Data Analysis, Faculty of Behavioral Science, University of Twente, Enschede (Netherlands); Riemersma, Sietske [Laboratory for Pathology Oost Nederland, Hengelo (Netherlands); Heijmans, Harald [Department of Surgery, Ziekenhuis Groep Twente, Hengelo (Netherlands); Ong, Francisca [Department of Radiation Oncology, Medisch Spectrum Twente, Enschede (Netherlands); Struikmans, Henk [Department of Radiation Oncology, Leiden University Medical Centre, Leiden (Netherlands); Radiotherapy Centre West, Medical Centre Haaglanden, The Hague (Netherlands)

    2014-08-01

    Purpose: To analyze the incidence and prognostic factors of ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT) in a large, population-based, single-center study with long-term follow-up. Methods and Materials: We analyzed 3595 cases in which BCT was performed in 3824 women with stage I or II breast cancer. The incidence of IBTR was analyzed over time and was based on IBTR as first event. Results: The 15-year local relapse-free survival was 90.9%. The hazard estimates for IBTR showed a time course with 2 peaks, the first at approximately 5 years and the second, twice as high, at 12 years. Stratifying subjects by age and margin status showed that, for women ≤40 years old with negative margins, adjuvant systemic therapy led to a 5-fold reduced risk of recurrence compared to none, and the presence of lymph vascular space invasion (LVSI) had a 3-fold increased risk compared to its absence. For women >40 years old, the presence of LVSI (hazard ratio [HR] 2.5) and the presence of lobular carcinoma in situ in the lumpectomy specimen (HR 2.3) were the only 2 risk factors. Conclusions: We demonstrated a pattern in risk of IBTR over time, with 2 peaks, first at approximately 5 years and a second, much higher peak at approximately 12 years, especially for women ≤40 years old. For women ≤40 years old with tumor-free resection margins, we noted that the absence of adjuvant systemic therapy and the presence of LVSI were independent prognostic factors of IBTR. For women >40 years old, the presence of LVSI and the presence of lobular carcinoma in situ were independent risk factors.

  17. Mutation Screening in the Mitochondrial D-Loop Region of Tumoral and Non-tumoral Breast Cancer in Iranian Patients

    Directory of Open Access Journals (Sweden)

    Mansour Heidari

    2012-07-01

    Full Text Available The mitochondrial DNA (mtDNA mutations in mitochondrial coding and non coding regions seem to be important in carcinogenesis. The aim of this investigation was to evaluate coding region (mt-tRNAPhe and tRNAPro and non-coding sequence, mitochondrial displacement loop (mtDNA D-loop, in the cancerous and non-cancerous lesions of Iranian patients with breast cancer (BC. Genomic DNA was extracted from 50 breast tumors and surrounding normal tissue pairs as well as from 50 unrelated normal breast tissues from Iranian Kurdish population. Subsequently, PCR amplification was performed using specific primers, and then PCR products were subjected to direct sequencing. 41 genetic variants were identified in mtDNA D-loop among tumoral and non-tumoral tissues but not in tRNAPhe and tRNAPro sequences. Our findings indicated that C182T, 194insT, 285insA and 16342delT were just found in BC tumors whereas 302insC, C309T and C16069T found in both tumors and surrounding normal tissues. Although our findings showed that the observed genetic variations were not restricted to breast cancer tissues, some genetic changes were found only in BC tumors. Our results, in agreement with the evidence from earlier studies, confirm that the mtDNA genetic alterations might be implicated in tumor initiation, progression and development. text-align: justify;

  18. CD44 isoforms are heterogeneously expressed in breast cancer and correlate with tumor subtypes and cancer stem cell markers

    International Nuclear Information System (INIS)

    The CD44 cell adhesion molecule is aberrantly expressed in many breast tumors and has been implicated in the metastatic process as well as in the putative cancer stem cell (CSC) compartment. We aimed to investigate potential associations between alternatively spliced isoforms of CD44 and CSCs as well as to various breast cancer biomarkers and molecular subtypes. We used q-RT-PCR and exon-exon spanning assays to analyze the expression of four alternatively spliced CD44 isoforms as well as the total expression of CD44 in 187 breast tumors and 13 cell lines. ALDH1 protein expression was determined by IHC on TMA. Breast cancer cell lines showed a heterogeneous expression pattern of the CD44 isoforms, which shifted considerably when cells were grown as mammospheres. Tumors characterized as positive for the CD44+/CD24- phenotype by immunohistochemistry were associated to all isoforms except the CD44 standard (CD44S) isoform, which lacks all variant exons. Conversely, tumors with strong expression of the CSC marker ALDH1 had elevated expression of CD44S. A high expression of the CD44v2-v10 isoform, which retain all variant exons, was correlated to positive steroid receptor status, low proliferation and luminal A subtype. The CD44v3-v10 isoform showed similar correlations, while high expression of CD44v8-v10 was correlated to positive EGFR, negative/low HER2 status and basal-like subtype. High expression of CD44S was associated with strong HER2 staining and also a subgroup of basal-like tumors. Unsupervised hierarchical cluster analysis of CD44 isoform expression data divided tumors into four main clusters, which showed significant correlations to molecular subtypes and differences in 10-year overall survival. We demonstrate that individual CD44 isoforms can be associated to different breast cancer subtypes and clinical markers such as HER2, ER and PgR, which suggests involvement of CD44 splice variants in specific oncogenic signaling pathways. Efforts to link CD44 to CSCs

  19. Natural selection of tumor variants in the generation of “tumor escape” phenotypes

    OpenAIRE

    Khong, Hung T.; Restifo, Nicholas P

    2002-01-01

    The idea that tumors must “escape” from immune recognition contains the implicit assumption that tumors can be destroyed by immune responses either spontaneously or as the result of immunotherapeutic intervention. Simply put, there is no need for tumor escape without immunological pressure. Here, we review evidence supporting the immune escape hypothesis and critically explore the mechanisms that may allow such escape to occur. We discuss the idea that the central engine for generating immuno...

  20. Database-guided breast tumor detection and segmentation in 2D ultrasound images

    Science.gov (United States)

    Zhang, Jingdan; Zhou, Shaohua K.; Brunke, Shelby; Lowery, Carol; Comaniciu, Dorin

    2010-03-01

    Ultrasonography is a valuable technique for diagnosing breast cancer. Computer-aided tumor detection and segmentation in ultrasound images can reduce labor cost and streamline clinic workflows. In this paper, we propose a fully automatic system to detect and segment breast tumors in 2D ultrasound images. Our system, based on database-guided techniques, learns the knowledge of breast tumor appearance exemplified by expert annotations. For tumor detection, we train a classifier to discriminate between tumors and their background. For tumor segmentation, we propose a discriminative graph cut approach, where both the data fidelity and compatibility functions are learned discriminatively. The performance of the proposed algorithms is demonstrated on a large set of 347 images, achieving a mean contour-to-contour error of 3.75 pixels with about 4.33 seconds.

  1. How to measure breast cancer tumoral size at MR imaging?

    Energy Technology Data Exchange (ETDEWEB)

    Thomassin-Naggara, I., E-mail: isabelle.thomassin@tnn.aphp.fr [Department of Radiology, Hôpital Tenon, Assistance Publique Hôpitaux de Paris, Institut Universitaire de Cancérologie (IUC) Pierre et Marie Curie, Cancer Est, Paris (France); Siles, Pascale [Department of Radiology, Hôpital Tenon, Assistance Publique Hôpitaux de Paris, Institut Universitaire de Cancérologie (IUC) Pierre et Marie Curie, Cancer Est, Paris (France); Trop, I. [Department of Radiology, Centre de recherche et d’investigation des maladies du sein (CRID), Hôtel Dieu, Centre Hospitalo-Universitaire de Montréal (CHUM) (Canada); Chopier, J. [Department of Radiology, Hôpital Tenon, Assistance Publique Hôpitaux de Paris, Institut Universitaire de Cancérologie (IUC) Pierre et Marie Curie, Cancer Est, Paris (France); Darai, E. [Department of Gynaecology and Obstetrics, Hôpital Tenon, Assistance Publique Hôpitaux de Paris, Institut Universitaire de Cancérologie (IUC) Pierre et Marie Curie, Cancer Est, Paris (France); Bazot, M. [Department of Radiology, Hôpital Tenon, Assistance Publique Hôpitaux de Paris, Institut Universitaire de Cancérologie (IUC) Pierre et Marie Curie, Cancer Est, Paris (France); and others

    2013-12-01

    Objective: To compare the accuracy of different MR sequences to measure tumor size. Methods: Eighty-six women (mean age: 53 years (30–78)) who underwent preoperative MRI for breast cancer were included. Maximal diameters of the index tumor (IT) and of the whole extent of the tumor (WET) were measured on T2-weighted (T2W) sequences, on dynamic contrast-enhanced (DCE) T1-weighted (T1W) sequences and on Maximal Intensity Projection (MIP) reconstructions. Agreements with pathological size were evaluated using concordance correlation coefficient (k). Results: Median pathological size of IT was 20 mm (13–25 mm, interquartile range). Median pathological size of the WET was 29 mm (16–50 mm, interquartile range). Measurement of IT showed a good concordance with pathological size, with best results using T2W (k = 0.690) compared to MIP (k = 0.667), early-subtracted DCE frame (k = 0.630) and early-native DCE frame (k = 0.588). IT was visible on T2W in 83.7% and accurately measured within 5 mm in 69.9%. Measurement of WET was superior using early-subtracted DCE frame (k = 0.642) compared to late-native frame (k = 0.635), early-native frame (k = 0.631), late-subtracted frame (k = 0.620) and MIP (k = 0.565). However, even using early-subtracted frame, WET was accurately measured within 5 mm only 39.3%. Conclusion: If visible, IT size is best measured on T2W with a good accuracy (69%) whereas WET is best estimated on early-subtracted DCE frame. However, when adjacent additional sites exist around IT, suspected surrounding disease components need to be proved by pathological analysis.

  2. How to measure breast cancer tumoral size at MR imaging?

    International Nuclear Information System (INIS)

    Objective: To compare the accuracy of different MR sequences to measure tumor size. Methods: Eighty-six women (mean age: 53 years (30–78)) who underwent preoperative MRI for breast cancer were included. Maximal diameters of the index tumor (IT) and of the whole extent of the tumor (WET) were measured on T2-weighted (T2W) sequences, on dynamic contrast-enhanced (DCE) T1-weighted (T1W) sequences and on Maximal Intensity Projection (MIP) reconstructions. Agreements with pathological size were evaluated using concordance correlation coefficient (k). Results: Median pathological size of IT was 20 mm (13–25 mm, interquartile range). Median pathological size of the WET was 29 mm (16–50 mm, interquartile range). Measurement of IT showed a good concordance with pathological size, with best results using T2W (k = 0.690) compared to MIP (k = 0.667), early-subtracted DCE frame (k = 0.630) and early-native DCE frame (k = 0.588). IT was visible on T2W in 83.7% and accurately measured within 5 mm in 69.9%. Measurement of WET was superior using early-subtracted DCE frame (k = 0.642) compared to late-native frame (k = 0.635), early-native frame (k = 0.631), late-subtracted frame (k = 0.620) and MIP (k = 0.565). However, even using early-subtracted frame, WET was accurately measured within 5 mm only 39.3%. Conclusion: If visible, IT size is best measured on T2W with a good accuracy (69%) whereas WET is best estimated on early-subtracted DCE frame. However, when adjacent additional sites exist around IT, suspected surrounding disease components need to be proved by pathological analysis

  3. Different Array CGH profiles within hereditary breast cancer tumors associated to BRCA1 expression and overall survival

    OpenAIRE

    Alvarez, Carolina; Aravena, Andrés; Tapia, Teresa; Rozenblum, Ester; Solís, Luisa; Corvalán, Alejandro; Camus, Mauricio; Alvarez, Manuel; Munroe, David; Maass, Alejandro; Carvallo, Pilar

    2016-01-01

    Background Array CGH analysis of breast tumors has contributed to the identification of different genomic profiles in these tumors. Loss of DNA repair by BRCA1 functional deficiency in breast cancer has been proposed as a relevant contribution to breast cancer progression for tumors with no germline mutation. Identifying the genomic alterations taking place in BRCA1 not expressing tumors will lead us to a better understanding of the cellular functions affected in this heterogeneous disease. M...

  4. Prognostic Impact of Time to Ipsilateral Breast Tumor Recurrence after Breast Conserving Surgery

    Science.gov (United States)

    Gosset, Marie; Hamy, Anne-Sophie; Mallon, Peter; Delomenie, Myriam; Mouttet, Delphine; Pierga, Jean-Yves; Lae, Marick; Fourquet, Alain; Rouzier, Roman; Reyal, Fabien; Feron, Jean-Guillaume

    2016-01-01

    Background The poor prognosis of patients who experience ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery (BCS) is established. A short time between primary cancer and IBTR is a prognostic factor but no clinically relevant threshold was determined. Classification of IBTR may help tailor treatment strategies. Purpose We determined a specific time frame, which differentiates IBTR into early and late recurrence, and identified prognostic factors for patients with IBTR at time of the recurrence. Methods We analyzed 2209 patients with IBTR after BCS. We applied the optimal cut-points method for survival data to determine the cut-off times to IBTR. A subgroup analysis was performed by hormone receptor (HR) status. Survival analyses were performed using a Cox proportional hazard model to determine clinical features associated with distant-disease-free survival (DDFS) after IBTR. We therefor built decision trees. Results On the 828 metastatic events observed, the majority occurred within the first 3 months after IBTR: 157 in the HR positive group, 98 in the HR negative group. We found different prognostic times to IBTR: 49 months in the HR positive group, 33 in the HR negative group. After multivariate analysis, time to IBTR was the first discriminant prognostic factor in both groups (HR 0.65 CI95% [0.54–0.79] and 0.42 [0.30–0.57] respectively). The other following variables were significantly correlated with the DDFS: the initial number of positive lymph nodes for both groups, the initial tumor size and grade for HR positive tumors. Conclusion A short interval time to IBTR is the strongest factor of poor prognosis and reflects occult distant disease. It would appear that prognosis after IBTR depends more on clinical and histological parameters than on surgical treatment. A prospective trial in a low-risk group of patients to validate the safety of salvage BCS instead of mastectomy in IBTR is needed. PMID:27494111

  5. Interleukin-6 Induced "Acute" Phenotypic Microenvironment Promotes Th1 Anti-Tumor Immunity in Cryo-Thermal Therapy Revealed By Shotgun and Parallel Reaction Monitoring Proteomics.

    Science.gov (United States)

    Xue, Ting; Liu, Ping; Zhou, Yong; Liu, Kun; Yang, Li; Moritz, Robert L; Yan, Wei; Xu, Lisa X

    2016-01-01

    Cryo-thermal therapy has been emerged as a promising novel therapeutic strategy for advanced breast cancer, triggering higher incidence of tumor regression and enhanced remission of metastasis than routine treatments. To better understand its anti-tumor mechanism, we utilized a spontaneous metastatic mouse model and quantitative proteomics to compare N-glycoproteome changes in 94 serum samples with and without treatment. We quantified 231 highly confident N-glycosylated proteins using iTRAQ shotgun proteomics. Among them, 53 showed significantly discriminated regulatory patterns over the time course, in which the acute phase response emerged as the most enhanced pathway. The anti-tumor feature of the acute response was further investigated using parallel reaction monitoring target proteomics and flow cytometry on 23 of the 53 significant proteins. We found that cryo-thermal therapy reset the tumor chronic inflammation to an "acute" phenotype, with up-regulation of acute phase proteins including IL-6 as a key regulator. The IL-6 mediated "acute" phenotype transformed IL-4 and Treg-promoting ICOSL expression to Th1-promoting IFN-γ and IL-12 production, augmented complement system activation and CD86(+)MHCII(+) dendritic cells maturation and enhanced the proliferation of Th1 memory cells. In addition, we found an increased production of tumor progression and metastatic inhibitory proteins under such "acute" environment, favoring the anti-metastatic effect. Moreover, cryo-thermal on tumors induced the strongest "acute" response compared to cryo/hyperthermia alone or cryo-thermal on healthy tissues, accompanying by the most pronounced anti-tumor immunological effect. In summary, we demonstrated that cryo-thermal therapy induced, IL-6 mediated "acute" microenvironment shifted the tumor chronic microenvironment from Th2 immunosuppressive and pro-tumorigenic to Th1 immunostimulatory and tumoricidal state. Moreover, the magnitude of "acute" and "danger" signals play a key

  6. Locomotor proteins in tissues of primary tumors and metastases of ovarian and breast cancer

    Science.gov (United States)

    Kondakova, I. V.; Yunusova, N. V.; Spirina, L. V.; Shashova, E. E.; Kolegova, E. S.; Kolomiets, L. A.; Slonimskaya, E. M.; Villert, A. B.

    2016-08-01

    The paper discusses the capability for active movement in an extracellular matrix, wherein remodeling of the cytoskeleton by actin binding proteins plays a significant role in metastases formation. We studied the expression of actin binding proteins and β-catenin in tissues of primary tumors and metastases of ovarian and breast cancer. Contents of p45 Ser β-catenin and the actin severing protein gelsolin were decreased in metastases of ovarian cancer relative to primary tumors. The level of the cofilin, functionally similar to gelsolin, was significantly higher in metastases compared to primary ovarian and breast tumor tissue. In breast cancer, significant increase in the number of an actin monomer binder protein thymosin-β4 was observed in metastases as compared to primary tumors. The data obtained suggest the involvement of locomotor proteins in metastases formation in ovarian and breast cancer.

  7. IGFBP3 mRNA expression in benign and malignant breast tumors

    OpenAIRE

    Ren, Zefang; Shin, Aesun; Cai, Qiuyin; Shu, Xiao-Ou; Gao, Yu-Tang; Zheng, Wei

    2007-01-01

    Introduction Most previous studies have focused on evaluating the association between circulating insulin-like growth factor binding protein 3 (IGFBP-3) levels and breast cancer risk. Emerging evidence over the past few years suggests that IGFBP-3 may act directly on mammary epithelial cells. Methods To understand the role of IGFBP-3 in breast tumorigenesis, we investigated IGFBP3 mRNA expression levels in benign and malignant breast tumors and their adjacent normal tissues using real-time qu...

  8. Prospective dual role of mesenchymal stem cells in breast tumor microenvironment.

    Science.gov (United States)

    Senst, Christiane; Nazari-Shafti, Timo; Kruger, Stefan; Höner Zu Bentrup, Kirstin; Dupin, Charles L; Chaffin, Abigail E; Srivastav, Sudesh K; Wörner, Philipp M; Abdel-Mageed, Asim B; Alt, Eckhard U; Izadpanah, Reza

    2013-01-01

    Breast cancer tissue is a heterogeneous cellular milieu comprising cancer and host cells. The interaction between breast malignant and non-malignant cells takes place in breast tumor microenvironment (TM), and has a crucial role in breast cancer progression. In addition to cellular component of TM, it mainly consists of cytokines released by tumor cells. The tumor-tropic capacity of mesenchymal stem cells (MSCs) and their interaction with breast TM is an active area of investigation. In the present communication, the interplay between the breast resident adipose tissue-derived MSCs (B-ASCs) and breast TM was studied. It was found that a distinct subset of B-ASCs display a strong affinity for conditioned media (CM) from two breast cancer cell lines, MDA-MB 231 (MDA-CM) and MCF-7 (MCF-CM). The expressions of several cytokines including angiogenin, GM-CSF, IL-6, GRO-α and IL-8 in MDA-CM and MCF-CM have been identified. Upon functional analysis a crucial role for GRO-α and IL-8 in B-ASCs migration was detected. The B-ASC migration was found to be via negative regulation of RECK and enhanced expression of MMPs. Furthermore, transcriptome analysis showed that migratory subpopulation express both pro- and anti-tumorigenic genes and microRNAs (miRNA). Importantly, we observed that the migratory cells exhibit similar gene and miRNA attributes as those seen in B-ASCs of breast cancer patients. These findings are novel and suggest that in breast cancer, B-ASCs migrate to the proximity of tumor foci. Characterization of the molecular mechanisms involved in the interplay between B-ASCs and breast TM will help in understanding the probable role of B-ASCs in breast cancer development, and could pave way for anticancer therapies.

  9. Chitosan-Based Thermoreversible Hydrogel as an in Vitro Tumor Microenvironment for Testing Breast Cancer Therapies

    OpenAIRE

    Tsao, Ching-Ting; Kievit, Forrest M.; Wang, Kui; Erickson, Ariane E.; Ellenbogen, Richard G.; Zhang, Miqin

    2014-01-01

    Breast cancer is a major health problem for women worldwide. Although in vitro culture of established breast cancer cell lines is the most widely used model for preclinical assessment, it poorly represents the behavior of breast cancers in vivo. Acceleration of the development of effective therapeutic strategies requires a cost-efficient in vitro model that can more accurately resemble the in vivo tumor microenvironment. Here, we report the use of a thermoreversible poly(ethylene glycol)-g-ch...

  10. Non-invasive estimation of the metabolic heat production of breast tumors using digital infrared imaging

    CERN Document Server

    González, Francisco Javier

    2011-01-01

    In this work the metabolic heat generated by breast tumors was estimated indirectly and noninvasively from digital infrared images and numerically simulating a simplified breast model and a cancerous tumor, this parameter can be of clinical importance since it has been related to the doubling volume's time and malignancy for that particular tumor. The results indicate that digital infrared imaging has the potential to estimate in a non-invasive way the malignancy of a tumor by calculating its metabolic heat generation from bioheat thermal transfer models.

  11. Molecular insights into the association of obesity with breast cancer risk: relevance to xenobiotic metabolism and CpG island methylation of tumor suppressor genes.

    Science.gov (United States)

    Naushad, Shaik Mohammad; Hussain, Tajamul; Al-Attas, Omar S; Prayaga, Aruna; Digumarti, Raghunadha Rao; Gottumukkala, Suryanarayana Raju; Kutala, Vijay Kumar

    2014-07-01

    Obesity, genetic polymorphisms of xenobiotic metabolic pathway, hypermethylation of tumor suppressor genes, and hypomethylation of proapoptotic genes are known to be independent risk factors for breast cancer. The objective of this study is to evaluate the combined effect of these environmental, genetic, and epigenetic risk factors on the susceptibility to breast cancer. PCR-RFLP and multiplex PCR were used for the genetic analysis of six variants of xenobiotic metabolic pathway. Methylation-specific PCR was used for the epigenetic analysis of four genetic loci. Multifactor dimensionality reduction analysis revealed a significant interaction between the body mass index (BMI) and catechol-O-methyl transferase H108L variant alone or in combination with cytochrome P450 (CYP) 1A1m1 variant. Women with "Luminal A" breast cancer phenotype had higher BMI compared to other phenotypes and healthy controls. There was no association between the BMI and tumor grade. The post-menopausal obese women exhibited lower glutathione levels. BMI showed a positive association with the methylation of extracellular superoxide dismutase (r = 0.21, p obesity increases the breast cancer susceptibility by two possible mechanisms: (i) by interacting with xenobiotic genetic polymorphisms in inducing increased oxidative DNA damage and (ii) by altering the methylome of several tumor suppressor genes.

  12. Breast tomosynthesis: Accuracy of tumor measurement compared with digital mammography and ultrasonography

    Energy Technology Data Exchange (ETDEWEB)

    Foernvik, Daniel; Svahn, Tony; Timberg, Pontus; Tingberg, Anders (Dept. of Medical Radiation Physics, Lund Univ., Malmoe (Sweden)), e-mail: daniel.fornvik@med.lu.se; Zackrisson, Sophia; Andersson, Ingvar (Diagnostic Centre of Imaging and Functional Medicine, Malmoe Univ. Hospital, Malmoe (Sweden)); Ljungberg, Otto (Dept. of Pathology, Malmoe Univ. Hospital, Malmoe (Sweden))

    2010-04-15

    Background: Mammographic tumor size measurement can be difficult because breast structures are superimposed onto a two-dimensional (2D) plane, potentially obscuring the tumor outline. Breast tomosynthesis (BT) is a 3D X-ray imaging technique in which low-dose images are acquired over a limited angular range at a total dose comparable to digital mammography (DM). These low-dose images are used to mathematically reconstruct a 3D image volume of the breast, thus reducing the problem of superimposed tissue. Purpose: To investigate whether breast cancer size can be more accurately assessed with breast tomosynthesis than with digital mammography and ultrasonography (United States), by reducing the disturbance effect of the projected anatomy. Material and Methods: A prototype BT system was used. The main inclusion criterion for BT examination was subtle but suspicious findings of breast cancer on 2D mammography. Sixty-two women with 73 breast cancers were included. BT, DM, and US sizes were measured independently by experienced radiologists without knowledge of the pathology results, which were used as reference. Results: The tumor outline could be determined in significantly more cases with BT (63) and US (60) than DM (49). BT and US size correlated well with pathology (R=0.86 and R=0.85, respectively), and significantly better than DM size (R=0.71). Accordingly, staging was significantly more accurate with BT than with DM. Conclusion: The study indicates that BT is superior to DM in the assessment of breast tumor size and stage

  13. Computational Model for Tumor Oxygenation Applied to Clinical Data on Breast Tumor Hemoglobin Concentrations Suggests Vascular Dilatation and Compression.

    Science.gov (United States)

    Welter, Michael; Fredrich, Thierry; Rinneberg, Herbert; Rieger, Heiko

    2016-01-01

    We present a computational model for trans-vascular oxygen transport in synthetic tumor and host tissue blood vessel networks, aiming at qualitatively explaining published data of optical mammography, which were obtained from 87 breast cancer patients. The data generally show average hemoglobin concentration to be higher in tumors versus host tissue whereas average oxy-to total hemoglobin concentration (vascular segment RBC-volume-weighted blood oxygenation) can be above or below normal. Starting from a synthetic arterio-venous initial network the tumor vasculature was generated by processes involving cooption, angiogenesis, and vessel regression. Calculations of spatially resolved blood flow, hematocrit, oxy- and total hemoglobin concentrations, blood and tissue oxygenation were carried out for ninety tumor and associated normal vessel networks starting from various assumed geometries of feeding arteries and draining veins. Spatial heterogeneity in the extra-vascular partial oxygen pressure distribution can be related to various tumor compartments characterized by varying capillary densities and blood flow characteristics. The reported higher average hemoglobin concentration of tumors is explained by growth and dilatation of tumor blood vessels. Even assuming sixfold metabolic rate of oxygen consumption in tumorous versus host tissue, the predicted oxygen hemoglobin concentrations are above normal. Such tumors are likely associated with high tumor blood flow caused by high-caliber blood vessels crossing the tumor volume and hence oxygen supply exceeding oxygen demand. Tumor oxy- to total hemoglobin concentration below normal could only be achieved by reducing tumor vessel radii during growth by a randomly selected factor, simulating compression caused by intra-tumoral solid stress due to proliferation of cells and extracellular matrix. Since compression of blood vessels will impede chemotherapy we conclude that tumors with oxy- to total hemoglobin concentration

  14. Cytokines secreted by macrophages isolated from tumor microenvironment of inflammatory breast cancer patients possess chemotactic properties

    OpenAIRE

    Mohamed, Mona M.; El-Ghonaimy, Eslam A.; Nouh, Mohamed A.; Schneider, Robert J.; Sloane, Bonnie F.; El-Shinawi, Mohamed

    2013-01-01

    Although there is a growing literature describing the role of macrophages in breast cancer, the role of macrophages in inflammatory breast cancer (IBC) is unclear. The aim of present study was to isolate and characterize tumor associated macrophages of IBC and non-IBC patients and define their role in IBC. Tumor infiltrating monocytes/macrophages (CD14+ and CD68+) were measured by immunohistochem-istry using specific monoclonal antibodies. Blood drained from axillary vein tributaries was coll...

  15. A Rare Case of Breast Malignant Phyllodes Tumor With Metastases to the Kidney

    OpenAIRE

    Karczmarek-Borowska, Bożenna; Bukala, Agnieszka; Syrek-Kaplita, Karolina; Ksiazek, Mariusz; Filipowska, Justyna; Gradalska-Lampart, Monika

    2015-01-01

    Abstract Phyllodes tumors are rare breast neoplasms. Surgery is the treatment of choice. The role of postoperative radiotherapy and chemotherapy is still under dispute, as there are no equivocal prognostic factors. Treatment failure results in the occurrence of distant metastasis—mainly to the lungs, bones, liver, and brain. We have described the case of a woman with a malignant phyllodes tumor of the breast that was surgically treated. She did not receive adjuvant therapy because there is no...

  16. Hypoxia-inducible factor 1α promotes primary tumor growth and tumor-initiating cell activity in breast cancer

    OpenAIRE

    Schwab, Luciana P; Peacock, Danielle L.; Majumdar, Debeshi; Ingels, Jesse F; Jensen, Laura C; Smith, Keisha D; Cushing, Richard C; Seagroves, Tiffany N

    2012-01-01

    Introduction Overexpression of the oxygen-responsive transcription factor hypoxia-inducible factor 1α (HIF-1α) correlates with poor prognosis in breast cancer patients. The mouse mammary tumor virus polyoma virus middle T (MMTV-PyMT) mouse is a widely utilized preclinical mouse model that resembles human luminal breast cancer and is highly metastatic. Prior studies in which the PyMT model was used demonstrated that HIF-1α is essential to promoting carcinoma onset and lung metastasis, although...

  17. Preliminary clinical observation of 99mTc-MIBI breast tumor imaging

    International Nuclear Information System (INIS)

    An effective, noninvasive diagnostic method of breast cancer is investigated. 99mTc-MIBI breast tumor imaging was performed in 78 patients with palpable breast mass. All was pathologically proved after operation. Of 78 patients, 42 were breast carcinoma, among them 35 were detected using 99MTc-MIBI scintigraphy. The smallest detectable mass was a infiltrating ductal carcinoma measuring 1.5 cm x 1.5 cm x 1.2 cm. Of 36 patients with benign lesions, 30 with negative result, among the 6 positive one, 5 were big adenoma, 1 was plasma cell mastitis. The sensitivity and specificity of 99mTc-MIBI imaging in detecting breast cancer wa 83.3% either. 99mTc-MIBI scintigraphy can be used as an accessory method in detecting breast cancer. But it was useless for differentiation between breast cancer and big adenoma

  18. Obesity and its impact on breast cancer: tumor incidence, recurrence, survival, and possible interventions.

    Science.gov (United States)

    Ligibel, Jennifer A; Strickler, Howard D

    2013-01-01

    A positive association between obesity and the risk of incident postmenopausal breast cancer has been consistently observed in epidemiologic studies. Although most studies of premenopausal women have not found a similar relationship between breast cancer and obesity, the prognosis for both pre- and postmenopausal breast cancer is substantially worse among obese than normal-weight individuals. Increasing evidence suggests that these associations may be mechanistically related to sex hormones, insulin, and certain adipokines. Insulin, for example, has important mitogenic/antiapoptotic activity in addition to its metabolic effects, and many breast tumors express high levels of the insulin receptor (IR)-A isoform. Further, the use of metformin, a diabetes medication that reduces insulin levels, has been epidemiologically associated with reduced breast cancer risk among patients with diabetes, and a recent observational study found a higher rate of pathologic complete responses among patients with diabetes and breast cancer who were using metformin. Formal clinical trials of metformin as adjuvant breast cancer therapy have been initiated and are ongoing. Similarly, the effect of lifestyle changes on breast cancer outcomes is actively being investigated. Several lifestyle intervention studies have demonstrated that weight loss, increased physical activity, and dietary changes are feasible in breast cancer populations, and that individuals who make lifestyle changes after breast cancer diagnosis experience several physical and psychologic benefits. In this article, the authors review the evidence linking obesity with breast cancer risk and outcomes and provide an overview of lifestyle intervention studies in patients with breast cancer.

  19. VAMP-associated protein B (VAPB) promotes breast tumor growth by modulation of Akt activity.

    Science.gov (United States)

    Rao, Meghana; Song, Wenqiang; Jiang, Aixiang; Shyr, Yu; Lev, Sima; Greenstein, David; Brantley-Sieders, Dana; Chen, Jin

    2012-01-01

    VAPB (VAMP- associated protein B) is an ER protein that regulates multiple biological functions. Although aberrant expression of VAPB is associated with breast cancer, its function in tumor cells is poorly understood. In this report, we provide evidence that VAPB regulates breast tumor cell proliferation and AKT activation. VAPB protein expression is elevated in primary and metastatic tumor specimens, and VAPB mRNA expression levels correlated negatively with patient survival in two large breast tumor datasets. Overexpression of VAPB in mammary epithelial cells increased cell growth, whereas VAPB knockdown in tumor cells inhibited cell proliferation in vitro and suppressed tumor growth in orthotopic mammary gland allografts. The growth regulation of mammary tumor cells controlled by VAPB appears to be mediated, at least in part, by modulation of AKT activity. Overexpression of VAPB in MCF10A-HER2 cells enhances phosphorylation of AKT. In contrast, knockdown of VAPB in MMTV-Neu tumor cells inhibited pAKT levels. Pharmacological inhibition of AKT significantly reduced three-dimensional spheroid growth induced by VAPB. Collectively, the genetic, functional and mechanistic analyses suggest a role of VAPB in tumor promotion in human breast cancer.

  20. VAMP-associated protein B (VAPB promotes breast tumor growth by modulation of Akt activity.

    Directory of Open Access Journals (Sweden)

    Meghana Rao

    Full Text Available VAPB (VAMP- associated protein B is an ER protein that regulates multiple biological functions. Although aberrant expression of VAPB is associated with breast cancer, its function in tumor cells is poorly understood. In this report, we provide evidence that VAPB regulates breast tumor cell proliferation and AKT activation. VAPB protein expression is elevated in primary and metastatic tumor specimens, and VAPB mRNA expression levels correlated negatively with patient survival in two large breast tumor datasets. Overexpression of VAPB in mammary epithelial cells increased cell growth, whereas VAPB knockdown in tumor cells inhibited cell proliferation in vitro and suppressed tumor growth in orthotopic mammary gland allografts. The growth regulation of mammary tumor cells controlled by VAPB appears to be mediated, at least in part, by modulation of AKT activity. Overexpression of VAPB in MCF10A-HER2 cells enhances phosphorylation of AKT. In contrast, knockdown of VAPB in MMTV-Neu tumor cells inhibited pAKT levels. Pharmacological inhibition of AKT significantly reduced three-dimensional spheroid growth induced by VAPB. Collectively, the genetic, functional and mechanistic analyses suggest a role of VAPB in tumor promotion in human breast cancer.

  1. Proficient Feature Extraction Strategy for Performance Enhancement of NN Based Early Breast Tumor Detection

    Directory of Open Access Journals (Sweden)

    Khondker Jahid Reza

    2014-01-01

    Full Text Available Ultra Wideband is one of the promising microwave imaging techniques for breast tumor prognosis. The basic principle of tumor detection depends on the dielectric properties discrepancies between healthy and tumorous tissue. Usually, the tumor affected tissues scatter more signal than the healthy one and are used for early tumor detection through received pulses. Feedforward backpropagation neural network(NN was so far used for some research works by showing its detection efficiency up to 1mm (radius size with 95.8% accuracy. This paper introduces an efficient feature extraction method to further improve the performance by considering four main features of backpropagation NN. This performance is being increased to 99.99%. This strategy is well justified for classifying the normal and tumor affected breast with 100% accuracy in its early stage. It also enhances the training and testing performances by reducing the required duration. The overall performance is 99.99% verified by using thirteen different tumor sizes.

  2. [Specific features of mammographic visualization of "small" breast tumors developing on the background of fibrocystic disease].

    Science.gov (United States)

    Bukharin, D G; Velichko, S A; Slonimskaia, E M; Frolova, I G; Luneva, S V; Garbukov, E Iu; Doroshenko, A V

    2011-01-01

    All complications diagnosed at early stages of breast cancer were associated with small tumors, especially with those arising in the aftermath of fibrocystic disease. Hence, our task was to study the XR-semiotics of lesions of less than 15 mm in diameter and of the same origin. 100 mammograms of breast cancer patients with benign disease of the breast were studied. The presence of moderate-to-severe fibrocystic disease significantly affected the visualization of lesions of less than 10 mm in diameter. Since the XR-semiotics of small tumors failed to reveal malignancy features, all lesions visualized by mammography required additional diagnostic procedures using ultrasound and invasive radiology.

  3. Alcohol and breast cancer tumor subtypes in a Spanish Cohort.

    Science.gov (United States)

    Gago-Dominguez, Manuela; Castelao, J Esteban; Gude, Francisco; Fernandez, Maite Peña; Aguado-Barrera, Miguel E; Ponte, Sara Miranda; Redondo, Carmen M; Castelo, Manuel Enguix; Dominguez, Alejandro Novo; Garzón, Víctor Muñoz; Carracedo, Angel; Martínez, María Elena

    2016-01-01

    Although alcohol intake is an established risk factor for overall breast cancer, few studies have looked at the relationship between alcohol use and breast cancer risk by the four major subtypes of breast cancer and very few data exist in the alcohol-breast cancer relationship in Spanish women. A population-based case-control study was conducted in Galicia, Spain. A total of 1766 women diagnosed with invasive breast cancer between 1997 and 2014 and 833 controls participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics were collected. We examined the alcohol-breast cancer association according to the major breast cancer subtypes [hormone-receptor-positive, HER2-negative (luminal A); hormone-receptor-positive, HER2-positive (luminal B); hormone-receptor-negative, HER2-negative (TNBC); and hormone-receptor-negative, HER2-positive (HER2 overexpressing)] as well as grade and morphology in Spanish women. With the exception of HER2 overexpressing, the risk of all subtypes of breast cancer significantly increased with increasing alcohol intake. The association was similar for hormonal receptor positive breast cancer, i.e., luminal A and luminal B breast cancer (odds ratio, OR 2.16, 95 % confidence interval, CI 1.55-3.02; and OR 1.98, 95 % CI 1.11-3.53, respectively), and for TNBC (TNBC: OR 1.93, 95 % CI 1.07-3.47). The alcohol-breast cancer association was slightly more pronounced among lobular breast cancer (OR 2.76, 95 % CI 1.62-4.69) than among ductal type breast cancers (OR 2.21, 95 % CI 1.61-3.03). In addition, significant associations were shown for all grades, I, II and III breast cancer (OR 1.98, 95 % CI 1.26-3.10; OR 2.34, 95 % CI 1.66-3.31; and OR 2.16, 95 % CI 1.44-3.25 for Grades I, II and III, respectively). To our knowledge, this is the first study to examine the association of breast cancer subtypes and alcohol intake in Spanish women. Our findings indicate that breast cancer risk increased

  4. Tumor markers and bone scan in breast cancer patients

    International Nuclear Information System (INIS)

    Full text: The objective of this study was to compare the levels of CA15-3 and CEA with the bone scan findings in patients with breast cancer. Retrospective analysis of 76 bone scans from 61 patients diagnosed with breast cancer in the last 5 years was performed by two nuclear medicine specialists. All bone scans were performed after surgical treatment of the disease. Patients with loco-regional residual disease or distant metastases in the liver, lung or the brain were excluded from the study. According to the bone scan the patients were divided in 5 groups: normal bone scan (N), equivocal bone scan (E), single metastasis (1MS), three metastases (3MS) and multiple metastases (MMS). Tumor markers were determined within a month before or after the bone scan was performed. Cut-off value for CA 15-3 was 35 U/ml, and for CEA 3 ng/ml. Statistical analysis was performed using descriptive statistic and Kolmogorov-Smirnov test. Bone metastases were revealed in 38% of the patients referred for bone scintigraphy out of which 26% had MMS, 7.8% had single MS and 4% had 3MS. The results of 6.5% of the patients were determined as equivocal. The values of CA15-3 were higher in all patient groups compared with the group that had normal bone scan, but this difference reached statistical significance only in groups with 3MS and MMS (p < 0.01). The values of CEA were significantly higher only in patients with multiple metastases when compared with group N (p < 0.01). Values higher than cut-off value for CA 15-3 was found in 9 patients out of 42 in the group with normal bone scan. The highest value of CA 15-3 in this group was 47 U/ml. Only one patient in this group showed elevated levels for CEA. Three patients in the group with single metastasis had normal CA 15-3, while CEA was elevated only in one patient. All patients in the group with 3MS had elevated levels of CA 15-3 while CEA was in the normal range. All patients with MMS had elevated CA 15-3 values while CEA was elevated in

  5. Oncofetal Epigenetic Bivalency in Breast Cancer Cells: H3K4 and H3K27 Tri-Methylation as a Biomarker for Phenotypic Plasticity.

    Science.gov (United States)

    Messier, Terri L; Boyd, Joseph R; Gordon, Jonathan A R; Stein, Janet L; Lian, Jane B; Stein, Gary S

    2016-11-01

    Alterations in the epigenetic landscape are fundamental drivers of aberrant gene expression that contribute to cancer progression and pathology. Understanding specific modes of epigenetic regulation can be used to identify novel biomarkers or targets for therapeutic intervention to clinically treat solid tumors and leukemias. The bivalent marking of gene promoters by H3K4me3 and H3K27me3 is a primary mechanism to poise genes for expression in pluripotent embryonic stem cells (ESC). In this study we interrogated three well-established mammary cell lines to model epigenetic programming observed among breast cancer subtypes. Evidence is provided for a distinct bivalent signature, activating and repressive histone marks co-residing at the same gene promoter, in the MCF7 (ESR/PGR+) luminal breast cancer cell line. We identified a subset of genes, enriched for developmental pathways that regulate cellular phenotype and signaling, and partially recapitulate the bivalent character observed in ESC. We validated the biological relevance of this "oncofetal epigenetic" signature using data from ESR/PGR+ tumor samples from breast cancer patients. This signature of oncofetal epigenetic control is an informative biomarker and may provide novel therapeutic targets, selective for both recurring and treatment-resistant cancers. J. Cell. Physiol. 231: 2474-2481, 2016. © 2016 Wiley Periodicals, Inc. PMID:26916849

  6. Nucleolin overexpression in breast cancer cell sub-populations with different stem-like phenotype enables targeted intracellular delivery of synergistic drug combination.

    Science.gov (United States)

    Fonseca, Nuno A; Rodrigues, Ana S; Rodrigues-Santos, Paulo; Alves, Vera; Gregório, Ana C; Valério-Fernandes, Ângela; Gomes-da-Silva, Lígia C; Rosa, Manuel Santos; Moura, Vera; Ramalho-Santos, João; Simões, Sérgio; Moreira, João Nuno

    2015-11-01

    Breast cancer stem cells (CSC) are thought responsible for tumor growth and relapse, metastization and active evasion to standard chemotherapy. The recognition that CSC may originate from non-stem cancer cells (non-SCC) through plastic epithelial-to-mesenchymal transition turned these into relevant cell targets. Of crucial importance for successful therapeutic intervention is the identification of surface receptors overexpressed in both CSC and non-SCC. Cell surface nucleolin has been described as overexpressed in cancer cells as well as a tumor angiogenic marker. Herein we have addressed the questions on whether nucleolin was a common receptor among breast CSC and non-SCC and whether it could be exploited for targeting purposes. Liposomes functionalized with the nucleolin-binding F3 peptide, targeted simultaneously, nucleolin-overexpressing putative breast CSC and non-SCC, which was paralleled by OCT4 and NANOG mRNA levels in cells from triple negative breast cancer (TNBC) origin. In murine embryonic stem cells, both nucleolin mRNA levels and F3 peptide-targeted liposomes cellular association were dependent on the stemness status. An in vivo tumorigenic assay suggested that surface nucleolin overexpression per se, could be associated with the identification of highly tumorigenic TNBC cells. This proposed link between nucleolin expression and the stem-like phenotype in TNBC, enabled 100% cell death mediated by F3 peptide-targeted synergistic drug combination, suggesting the potential to abrogate the plasticity and adaptability associated with CSC and non-SCC. Ultimately, nucleolin-specific therapeutic tools capable of simultaneous debulk multiple cellular compartments of the tumor microenvironment may pave the way towards a specific treatment for TNBC patient care. PMID:26283155

  7. Nucleolin overexpression in breast cancer cell sub-populations with different stem-like phenotype enables targeted intracellular delivery of synergistic drug combination.

    Science.gov (United States)

    Fonseca, Nuno A; Rodrigues, Ana S; Rodrigues-Santos, Paulo; Alves, Vera; Gregório, Ana C; Valério-Fernandes, Ângela; Gomes-da-Silva, Lígia C; Rosa, Manuel Santos; Moura, Vera; Ramalho-Santos, João; Simões, Sérgio; Moreira, João Nuno

    2015-11-01

    Breast cancer stem cells (CSC) are thought responsible for tumor growth and relapse, metastization and active evasion to standard chemotherapy. The recognition that CSC may originate from non-stem cancer cells (non-SCC) through plastic epithelial-to-mesenchymal transition turned these into relevant cell targets. Of crucial importance for successful therapeutic intervention is the identification of surface receptors overexpressed in both CSC and non-SCC. Cell surface nucleolin has been described as overexpressed in cancer cells as well as a tumor angiogenic marker. Herein we have addressed the questions on whether nucleolin was a common receptor among breast CSC and non-SCC and whether it could be exploited for targeting purposes. Liposomes functionalized with the nucleolin-binding F3 peptide, targeted simultaneously, nucleolin-overexpressing putative breast CSC and non-SCC, which was paralleled by OCT4 and NANOG mRNA levels in cells from triple negative breast cancer (TNBC) origin. In murine embryonic stem cells, both nucleolin mRNA levels and F3 peptide-targeted liposomes cellular association were dependent on the stemness status. An in vivo tumorigenic assay suggested that surface nucleolin overexpression per se, could be associated with the identification of highly tumorigenic TNBC cells. This proposed link between nucleolin expression and the stem-like phenotype in TNBC, enabled 100% cell death mediated by F3 peptide-targeted synergistic drug combination, suggesting the potential to abrogate the plasticity and adaptability associated with CSC and non-SCC. Ultimately, nucleolin-specific therapeutic tools capable of simultaneous debulk multiple cellular compartments of the tumor microenvironment may pave the way towards a specific treatment for TNBC patient care.

  8. Alcohol and breast cancer tumor subtypes in a Spanish Cohort

    OpenAIRE

    Gago-Dominguez, Manuela; Castelao, J.Esteban; Gude, Francisco; Fernandez, Maite Peña; Miguel E. Aguado-Barrera; Ponte, Sara Miranda; Carmen M Redondo; Castelo, Manuel Enguix; Dominguez, Alejandro Novo; Garzón, Víctor Muñoz; Carracedo, Angel; Martínez, María Elena

    2016-01-01

    Although alcohol intake is an established risk factor for overall breast cancer, few studies have looked at the relationship between alcohol use and breast cancer risk by the four major subtypes of breast cancer and very few data exist in the alcohol-breast cancer relationship in Spanish women. A population-based case-control study was conducted in Galicia, Spain. A total of 1766 women diagnosed with invasive breast cancer between 1997 and 2014 and 833 controls participated in the study. Data...

  9. Active adjoint modeling method in microwave induced thermoacoustic tomography for breast tumor.

    Science.gov (United States)

    Zhu, Xiaozhang; Zhao, Zhiqin; Wang, Jinguo; Chen, Guoping; Liu, Qing Huo

    2014-07-01

    To improve the model-based inversion performance of microwave induced thermoacoustic tomography for breast tumor imaging, an active adjoint modeling (AAM) method is proposed. It aims to provide a more realistic breast acoustic model used for tumor inversion as the background by actively measuring and reconstructing the structural heterogeneity of human breast environment. It utilizes the reciprocity of acoustic sensors, and adapts the adjoint tomography method from seismic exploration. With the reconstructed acoustic model of breast environment, the performance of model-based inversion method such as time reversal mirror is improved significantly both in contrast and accuracy. To prove the advantage of AAM, a checkerboard pattern model and anatomical realistic breast models have been used in full wave numerical simulations. PMID:24956614

  10. Molecular Subtyping of Serous Ovarian Tumors Reveals Multiple Connections to Intrinsic Breast Cancer Subtypes

    DEFF Research Database (Denmark)

    Jönsson, Jenny-Maria; Johansson, Ida; Dominguez-Valentin, Mev;

    2014-01-01

    with the well-established intrinsic molecular subtypes of breast cancer. METHODS: Global gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published...... to the luminal A breast cancer subtype. These findings remained when analyzed in an independent dataset, supporting links between the molecular subtypes of ovarian cancer and breast cancer beyond those recently acknowledged. CONCLUSIONS: These data link the transcriptional profiles of serous ovarian cancer...... to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast cancer, and suggest that biomarkers and targeted therapies may overlap between these tumor subsets. The link between benign and borderline...

  11. Sulfatase 1 and Sulfatase 2 in Hepatocellular Carcinoma: Associated Signaling Pathways, Tumor Phenotypes, and Survival

    OpenAIRE

    Yang, Ju Dong; Sun, Zhifu; Hu, Chunling; Lai, Jinping; Dove, Rebecca; Nakamura, Ikuo; Lee, Ju-Seog; Thorgeirsson, Snorri S.; Kang, Koo Jeong; Chu, In-Sun; Lewis R Roberts

    2011-01-01

    The heparin-degrading endosulfatases sulfatase 1 (SULF1) and sulfatase 2 (SULF2) have opposing effects in hepatocarcinogenesis despite structural similarity. Using mRNA expression arrays, we analyzed the correlations of SULF expression with signaling networks in human hepatocellular carcinomas (HCCs) and the associations of SULF expression with tumor phenotype and patient survival. Data from two mRNA microarray analyses of 139 and 36 HCCs and adjacent tissues were used as training and validat...

  12. Tumor suppressor microRNAs: Targeted molecules and signaling pathways in breast cancer.

    Science.gov (United States)

    Asghari, F; Haghnavaz, N; Baradaran, B; Hemmatzadeh, M; Kazemi, T

    2016-07-01

    Breast cancer is the most common type of cancer in women whose prevalence is increasing every year. Common strategies for diagnosis, prognosis and specific treatment of breast cancer need improvements to increase patients' survival. For this reason, there is growing number of efforts world-wide with molecular approaches. With the advent of microRNAs (miRNAs), they have been interested for almost all aspects of tumorgenesis and correlation of breast cancer and microRNAs was discovered for the first time in 2005. MiRNAs form a group of small noncoding RNAs which participate in regulation of gene expression and subsequently several biological processes and pathogenesis of various diseases. As other cancers, miRNAs involved in breast cancer are classified in two groups: the first group is tumor inducing miRNAs (also called oncomirs) that can induce tumor initiation and progression, and their expression is increased in cancerous cells. The second group is tumor suppressor miRNAs. In normal situation, tumor suppressor miRNAs prevent beginning and progression of breast cancer through suppressing the expression of various oncogenes. In this review we will give a general overview about miRNAs and breast cancer, and in the following, more discussion about tumor suppressor miRNAs, with focus on the best known of them and their targeted oncogenes and signaling pathways. Finally, we will point to application of this group of miRNAs in diagnosis, prognosis and treatment of patients.

  13. Locoregional Recurrence by Tumor Biology in Breast Cancer Patients after Preoperative Chemotherapy and Breast Conservation Treatment

    Science.gov (United States)

    Jwa, Eunjin; Shin, Kyung Hwan; Kim, Ja Young; Park, Young Hee; Jung, So-Youn; Lee, Eun Sook; Park, In Hae; Lee, Keun Seok; Ro, Jungsil; Kim, Yeon-Joo; Kim, Tae Hyun

    2016-01-01

    Purpose The purpose of this study is to determine whether breast cancer subtype can affect locoregional recurrence (LRR) and ipsilateral breast tumor recurrence (IBTR) after neoadjuvant chemotherapy (NAC) and breast-conserving therapy (BCT). Materials and Methods We evaluated 335 consecutive patients with clinical stage II-III breast cancer who received NAC plus BCT from 2002 to 2009. Patients were classified according to six molecular subtypes: luminal A (hormone receptor [HR]+/HER2–/Ki-67 < 15%, n=113), luminal B1 (HR+/HER2–/Ki-67 ≥ 15%, n=33), luminal B2 (HR+/HER2+, n=83), HER2 with trastuzumab (HER2[T+]) (HR–/HER2+/use of trastuzumab, n=14), HER2 without trastuzumab (HER2[T–]) (HR–/HER2+, n=31), and triple negative (TN) (HR–/HER2–, n=61). Results After a median follow-up period of 7.2 years, 26 IBTRs and 37 LRRs occurred. The 5-year LRR-free survival rates were luminal A, 96.4%; B1, 93.9%; B2, 90.3%; HER2(T+), 92.9%; HER2(T–), 78.3%; and TN, 79.6%. The 5-year IBTR-free survival rates were luminal A, 97.2%; B1, 93.9%; B2, 92.8%; HER2(T+), 92.9%; HER2(T–), 89.1%; and TN, 84.6%. In multivariate analysis, HER2(T–) (IBTR: hazard ratio, 4.2; p=0.04 and LRR: hazard ratio, 7.6; p < 0.01) and TN subtypes (IBTR: hazard ratio, 6.9; p=0.01 and LRR: hazard ratio, 8.1; p < 0.01) were associated with higher IBTR and LRR rates. A pathologic complete response (pCR) was found to show correlation with better LRR and a tendency toward improved IBTR controls in TN patients (IBTR, p=0.07; LRR, p=0.03). Conclusion The TN and HER2(T–) subtypes predict higher rates of IBTR and LRR after NAC and BCT. A pCR is predictive of improved IBTR or LRR in TN subtype. PMID:26910473

  14. Ethanol exposure induces the cancer-associated fibroblast phenotype and lethal tumor metabolism

    Science.gov (United States)

    Sanchez-Alvarez, Rosa; Martinez-Outschoorn, Ubaldo E.; Lin, Zhao; Lamb, Rebecca; Hulit, James; Howell, Anthony; Sotgia, Federica; Rubin, Emanuel; Lisanti, Michael P.

    2013-01-01

    Little is known about how alcohol consumption promotes the onset of human breast cancer(s). One hypothesis is that ethanol induces metabolic changes in the tumor microenvironment, which then enhances epithelial tumor growth. To experimentally test this hypothesis, we used a co-culture system consisting of human breast cancer cells (MCF7) and hTERT-immortalized fibroblasts. Here, we show that ethanol treatment (100 mM) promotes ROS production and oxidative stress in cancer-associated fibroblasts, which is sufficient to induce myofibroblastic differentiation. Oxidative stress in stromal fibroblasts also results in the onset of autophagy/mitophagy, driving the induction of ketone body production in the tumor microenvironment. Interestingly, ethanol has just the opposite effect in epithelial cancer cells, where it confers autophagy resistance, elevates mitochondrial biogenesis and induces key enzymes associated with ketone re-utilization (ACAT1/OXCT1). During co-culture, ethanol treatment also converts MCF7 cells from an ER(+) to an ER(-) status, which is thought to be associated with “stemness,” more aggressive behavior and a worse prognosis. Thus, ethanol treatment induces ketone production in cancer-associated fibroblasts and ketone re-utilization in epithelial cancer cells, fueling tumor cell growth via oxidative mitochondrial metabolism (OXPHOS). This “two-compartment” metabolic model is consistent with previous historical observations that ethanol is first converted to acetaldehyde (which induces oxidative stress) and then ultimately to acetyl-CoA (a high-energy mitochondrial fuel), or can be used to synthesize ketone bodies. As such, our results provide a novel mechanism by which alcohol consumption could metabolically convert “low-risk” breast cancer patients to “high-risk” status, explaining tumor recurrence or disease progression. Hence, our findings have clear implications for both breast cancer prevention and therapy. Remarkably, our results

  15. Fibroblast Activation Protein Expression by Stromal Cells and Tumor-Associated Macrophages in Human Breast Cancer

    Science.gov (United States)

    Julia, Tchou; Zhang Paul, J; Yingtao, Bi; Celine, Satija; Rajrupa, Marjumdar; Stephen, TL; Lo, A; Haiying, Chen; Carolyn, Mies; June, Carl H; Jose, Conejo-Garcia; Ellen, Puré

    2013-01-01

    Summary Fibroblast activation protein (FAP) has long been known to be expressed in the stroma of breast cancer. However, very little is known if the magnitude of FAP expression within the stroma may have prognostic value and reflect the heterogeneous biology of the tumor cell. An earlier study had suggested that stromal FAP expression in breast cancer was inversely proportional to prognosis. We, therefore, hypothesized that stromal FAP expression may correlate with clinicopathologic variables and may serve as an adjunct prognostic factor in breast cancer. We evaluated the expression of FAP in a panel of breast cancer tissues (n=52) using a combination of immunostain analyses at the tissue and single cell level using freshly frozen or freshly digested human breast tumor samples respectively. Our results showed that FAP expression was abundantly expressed in the stroma across all breast cancer subtypes without significant correlation with clinicopathologic factors. We further identified a subset of FAP positive or FAP+ stromal cells that also expressed CD45, a pan-leukocyte marker. Using freshly dissociated human breast tumor specimens (n=5), we demonstrated that some of these FAP+ CD45+ cells were CD11b+CD14+MHC-II+ indicating that they were likely tumor associated macrophages (TAMs). Although FAP+CD45+ cells have been demonstrated in the mouse tumor stroma, our results demonstrating that human breast TAMs expressed FAP was novel and suggested that existing and future FAP directed therapy may have dual therapeutic benefits targeting both stromal mesenchymal cells and immune cells such as TAMs. More work is needed to explore the role of FAP as a potential targetable molecule in breast cancer treatment. PMID:24074532

  16. Breast tumor characteristics of BRCA1 and BRCA2 gene mutation carriers on MRI

    NARCIS (Netherlands)

    J. Veltman; R. Mann; T. Kok (Theo); A.I.M. Obdeijn (Inge-Marie); N. Hoogerbrugge (Nicoline); J.G. Blickman; C. Boetes

    2008-01-01

    textabstractThe appearance of malignant lesions in BRCA1 and BRCA2 mutation carriers (BRCA-MCs) on mammography and magnetic resonance imaging (MRI) was evaluated. Thus, 29 BRCA-MCs with breast cancer were retrospectively evaluated and the results compared with an age, tumor size and tumor type match

  17. Breast tumor characteristics of BRCA1 and BRCA2 gene mutation carriers on MRI

    NARCIS (Netherlands)

    Veltman, J.; Mann, R.; Kok, T.; Obdeijn, I. M.; Hoogerbrugge, N.; Blickman, J. G.; Boetes, C.

    2008-01-01

    The appearance of malignant lesions in BRCA1 and BRCA2 mutation carriers (BRCA-MCs) on mammography and magnetic resonance imaging (MRI) was evaluated. Thus, 29 BRCA-MCs with breast cancer were retrospectively evaluated and the results compared with an age, tumor size and tumor type matched control g

  18. MED12 exon 2 mutations in phyllodes tumors of the breast

    International Nuclear Information System (INIS)

    Exon 2 of MED12, a subunit of the transcriptional mediator complex, has been frequently mutated in uterine leiomyomas and breast fibroadenomas; however, it has been rarely mutated in other tumors. Although the mutations were also found in uterine leiomyosarcomas, the frequency was significantly lower than in uterine leiomyomas. Here, we examined the MED12 mutation in phyllodes tumors, another biphasic tumor with epithelial and stromal components related to breast fibroadenomas. Mutations in MED12 exon 2 were analyzed in nine fibroadenomas and eleven phyllodes tumors via Sanger sequencing. A panel of cancer- and sarcoma-related genes was also analyzed using Ion Torrent next-generation sequencing. Six mutations in fibroadenomas, including those previously reported (6/9, 67%), and five mutations in phyllodes tumors (5/11, 45%) were observed. Three mutations in the phyllodes tumors were missense mutations at Gly44, which is common in uterine leiomyomas and breast fibroadenomas. In addition, two deletion mutations (in-frame c.133-144del12 and loss of splice acceptor c.100-68-137del106) were observed in the phyllodes tumors. No other recurrent mutation was observed with next-generation sequencing. Frequent mutations in MED12 exon 2 in the phyllodes tumors suggest that it may share genetic etiology with uterine leiomyoma, a subgroup of uterine leiomyosarcomas and breast fibroadenoma

  19. Electrical impedance scanning in breast tumor imaging: correlation with the growth pattern of lesion

    Institute of Scientific and Technical Information of China (English)

    WANG Kan; WANG Ting; FU Feng; JI Zhen-yu; LIU Rui-gang; LIAO Qi-mei; DONG Xiu-zhen

    2009-01-01

    Background This study researched the electric impedance properties of breast tissue and demonstrated the differentcharacteristic of electrical impedance scanning (EIS) images.Methods The impedance character of 40 malignant tumors, 34 benign tumors and some normal breast tissue from 69patients undergoing breast surgery was examined by EIS in vivo measurement and mammography screening, with aseries of frequencies set between 100 Hz-100 kHz in the ex vivo spectroscopy measurement.Results Of the 39 patients with 40 malignant tumors, 24 showed bright spots, 11 showed dark areas in EIS and 5showed no specific image. Of the 30 patients with 34 benign tumors there were almost no specific abnormality shown inthe EIS results. Primary ex vivo spectroscopy experiments showed that the resistivity of various breast tissue take thefollowing pattern: adipose tissue>cancerous tissue>mammary gland and benign tumor tissue.Conclusions There are significant differences in the electrical impedance properties between cancerous tissue andhealthy tissue. The impedivity of benign tumor is lower, and is at the same level with that of the mammary glandulartissue. The distinct growth pattern of breast lesions determined the different electrical impedance characteristics in theEIS results.

  20. Suppression of human breast tumors in NOD/SCID mice by CD44 shRNA gene therapy combined with doxorubicin treatment

    Directory of Open Access Journals (Sweden)

    Pham PV

    2012-05-01

    Full Text Available Phuc Van Pham1, Ngoc Bich Vu1, Thuy Thanh Duong1, Tam Thanh Nguyen1, Nhung Hai Truong1, Nhan Lu Chinh Phan1, Tue Gia Vuong1, Viet Quoc Pham1, Hoang Minh Nguyen1, Kha The Nguyen1, Nhung Thi Nguyen1, Khue Gia Nguyen1, Lam Tan Khat1, Dong Van Le2, Kiet Dinh Truong1, Ngoc Kim Phan11Laboratory of Stem Cell Research and Application, University of Science, Vietnam National University, HCM City, 2Military Medical University, Ha Noi, VietnamBackground: Breast cancer stem cells with a CD44+CD24- phenotype are the origin of breast tumors. Strong CD44 expression in this population indicates its important role in maintaining the stem cell phenotype. Previous studies show that CD44 down-regulation causes CD44+CD24- breast cancer stem cells to differentiate into non-stem cells that are sensitive to antitumor drugs and lose many characteristics of the original cells. In this study, we determined tumor suppression in non-obese severe combined immunodeficiency mice using CD44 shRNA therapy combined with doxorubicin treatment.Methods: Tumor-bearing non-obese severe combined immunodeficiency mice were established by injection of CD44+CD24- cells. To track CD44+CD24- cells, green fluorescence protein was stably transduced using a lentiviral vector prior to injection into mice. The amount of CD44 shRNA lentiviral vector used for transduction was based on CD44 down-regulation by in vitro CD44 shRNA transduction. Mice were treated with direct injection of CD44 shRNA lentiviral vector into tumors followed by doxorubicin administration after 48 hours. The effect was evaluated by changes in the size and weight of tumors compared with that of the control.Results: The combination of CD44 down-regulation and doxorubicin strongly suppressed tumor growth with significant differences in tumor sizes and weights compared with that of CD44 down-regulation or doxorubicin treatment alone. In the combination of CD44 down-regulation and doxorubicin group, the tumor weight was

  1. Differential Expression of Growth Factor Receptors and Membrane-Bound Tumor Markers for Imaging in Male and Female Breast Cancer

    OpenAIRE

    Vermeulen, Jeroen F.; Robert Kornegoor; Elsken van der Wall; Petra van der Groep; Paul J. van Diest

    2013-01-01

    INTRODUCTION: Male breast cancer accounts for 0.5-1% of all breast cancers and is generally diagnosed at higher stage than female breast cancers and therefore might benefit from earlier detection and targeted therapy. Except for HER2 and EGFR, little is known about expression of growth factor receptors in male breast cancer. We therefore investigated expression profiles of growth factor receptors and membrane-bound tumor markers in male breast cancer and gynecomastia, in comparison with femal...

  2. Induction of tumor necrosis factor expression and resistance in an human breast tumor cell line

    International Nuclear Information System (INIS)

    Tumor necrosis factor (TNF) is a polypeptide cytokine that is cytotoxic to some but not all tumor cells. The basis for resistance to the cytotoxic effects of this agent remains unclear. We have studied the development of TNF resistance in human ZR-75-1 breast carcinoma cells. ZR-75-1 cells have undetectable levels of TNF RNA and protein. However, TNF transcripts are transiently induced in these cells by exposure to recombinant human TNF. This induction of TNF RNA is associated with production of TNF-like protein in cell lysates and culture supernatants. Stable resistance to TNF-induced cytotoxicity develops when ZR-75-1 cells are exposed to increased concentrations of TNF. The TNF-resistant cells, designated ZR-75-1R, continuously express TNF transcripts and a TNF-like protein. Furthermore, ZR-75-1R cell supernatants contain cytotoxic activity that is abrogated by polyclonal antibody against TNF. The ZR-75-1R cells also possess TNF receptors that are occupied or down-regulated by the TNF-like protein. These findings thus suggest that (i) TNF induces TNF transcripts and production of a TNF-like protein in ZR-75-1 cells and (ii) resistance to TNF-induced cytotoxicity is associated with stable TNF expression

  3. Suppression of Spry1 inhibits triple-negative breast cancer malignancy by decreasing EGF/EGFR mediated mesenchymal phenotype

    OpenAIRE

    Qing He; Hongyu Jing; Lucy Liaw; Lindsey Gower; Calvin Vary; Shucheng Hua; Xuehui Yang

    2016-01-01

    Sprouty (Spry) proteins have been implicated in cancer progression, but their role in triple-negative breast cancer (TNBC), a subtype of lethal and aggressive breast cancer, is unknown. Here, we reported that Spry1 is significantly expressed in TNBC specimen and MDA-MB-231 cells. To understand Spry1 regulation of signaling events controlling breast cancer phenotype, we used lentiviral delivery of human Spry1 shRNAs to suppress Spry1 expression in MDA-MB-231, an established TNBC cell line. Spr...

  4. Solitary fibrous tumor of the male breast: a case report and review of the literature

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    Sessa Fausto

    2008-02-01

    Full Text Available Abstract Extrapleural solitary fibrous tumors are very rare and occasionally they appear in extraserosal soft tissues or parenchymatous organs. In such cases the right preoperative diagnosis is often difficult and challenging, because both radiological and cytological examinations are not exhaustive. For these reasons, surgical excision is frequently the only way to reach the correct diagnosis and to achieve definitive treatment. A few cases of solitary fibrous tumors have been also described in the breast. Although rare, this lesion opens difficulties in preoperative diagnosis entering in differential diagnosis with other benign lesions as well as with breast cancer. In this article we describe a case of a solitary fibrous tumor of the breast in a 49-year-old man. Problems related to differential diagnosis and the possible pitfalls that can be encountered in the diagnostic iter of such rare tumor are discussed.

  5. Differences in the tumor microenvironment between African-American and European-American breast cancer patients.

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    Damali N Martin

    Full Text Available BACKGROUND: African-American breast cancer patients experience higher mortality rates than European-American patients despite having a lower incidence of the disease. We tested the hypothesis that intrinsic differences in the tumor biology may contribute to this cancer health disparity. METHODS AND RESULTS: Using laser capture microdissection, we examined genome-wide mRNA expression specific to tumor epithelium and tumor stroma in 18 African-American and 17 European-American patients. Numerous genes were differentially expressed between these two patient groups and a two-gene signature in the tumor epithelium distinguished between them. To identify the biological processes in tumors that are different by race/ethnicity, Gene Ontology and disease association analyses were performed. Several biological processes were identified which may contribute to enhanced disease aggressiveness in African-American patients, including angiogenesis and chemotaxis. African-American tumors also contained a prominent interferon signature. The role of angiogenesis in the tumor biology of African-Americans was further investigated by examining the extent of vascularization and macrophage infiltration in an expanded set of 248 breast tumors. Immunohistochemistry revealed that microvessel density and macrophage infiltration is higher in tumors of African-Americans than in tumors of European-Americans. Lastly, using an in silico approach, we explored the potential of tailored treatment options for African-American patients based on their gene expression profile. This exploratory approach generated lists of therapeutics that may have specific antagonistic activity against tumors of African-American patients, e.g., sirolimus, resveratrol, and chlorpromazine in estrogen receptor-negative tumors. CONCLUSIONS: The gene expression profiles of breast tumors indicate that differences in tumor biology may exist between African-American and European-American patients beyond the

  6. Computer-Aided Evaluation of Breast MRI for the Residual Tumor Extent and Response Monitoring in Breast Cancer Patients Receiving Neoadjuvant Chemotherapy

    OpenAIRE

    Lyou, Chae Yeon; Cho, Nariya; Kim, Sun Mi; Jang, Mijung; Park, Jeong-Seon; Baek, Seung Yon; Moon, Woo Kyung

    2011-01-01

    Objective To evaluate the accuracy of a computer-aided evaluation program (CAE) of breast MRI for the assessment of residual tumor extent and response monitoring in breast cancer patients receiving neoadjuvant chemotherapy. Materials and Methods Fifty-seven patients with breast cancers who underwent neoadjuvant chemotherapy before surgery and dynamic contrast enhanced MRI before and after chemotherapy were included as part of this study. For the assessment of residual tumor extent after compl...

  7. Breast Cancer-Derived Extracellular Vesicles: Characterization and Contribution to the Metastatic Phenotype

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    Toni M. Green

    2015-01-01

    Full Text Available The study of extracellular vesicles (EVs in cancer progression is a complex and rapidly evolving field. Whole categories of cellular interactions in cancer which were originally presumed to be due solely to soluble secreted molecules have now evolved to include membrane-enclosed extracellular vesicles (EVs, which include both exosomes and shed microvesicles (MVs, and can contain many of the same molecules as those secreted in soluble form but many different molecules as well. EVs released by cancer cells can transfer mRNA, miRNA, and proteins to different recipient cells within the tumor microenvironment, in both an autocrine and paracrine manner, causing a significant impact on signaling pathways, mRNA transcription, and protein expression. The transfer of EVs to target cells, in turn, supports cancer growth, immunosuppression, and metastasis formation. This review focuses exclusively on breast cancer EVs with an emphasis on breast cancer-derived exosomes, keeping in mind that breast cancer-derived EVs share some common physical properties with EVs of other cancers.

  8. Monocytes mediate metastatic breast tumor cell adhesion to endothelium under flow

    OpenAIRE

    Evani, Shankar J.; Prabhu, Rajesh G.; Gnanaruban, V.; Finol, Ender A.; Anand K. Ramasubramanian

    2013-01-01

    Endothelial adhesion is necessary for the hematogenous dissemination of tumor cells. However, the metastatic breast tumor cell MDA-MB-231 does not bind to the endothelium under physiological flow conditions, suggesting alternate mechanisms of adhesion. Since monocytes are highly represented in the tumor microenvironment, and also bind to endothelium during inflammation, we hypothesized that the monocytes assist in the arrest of MDA-MB-231 on the endothelium. Using in vitro models of the dynam...

  9. Chronic inhibition of tumor cell-derived VEGF enhances the malignant phenotype of colorectal cancer cells

    International Nuclear Information System (INIS)

    Vascular endothelial growth factor-a (VEGF)-targeted therapies have become an important treatment for a number of human malignancies. The VEGF inhibitors are actually effective in several types of cancers, however, the benefits are transiently, and the vast majority of patients who initially respond to the therapies will develop resistance. One of possible mechanisms for the acquired resistance may be the direct effect(s) of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGFR). Thus, we investigated here the direct effect of chronic VEGF inhibition on phenotype changes in human colorectal cancer (CRC) cells. To chronically inhibit cancer cell-derived VEGF, human CRC cell lines (HCT116 and RKO) were chronically exposed (2 months) to an anti-VEGF monoclonal antibody (mAb) or were disrupted the Vegf gene (VEGF-KO). Effects of VEGF family members were blocked by treatment with a VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI). Hypoxia-induced apoptosis under VEGF inhibited conditions was measured by TUNEL assay. Spheroid formation ability was assessed using a 3-D spheroid cell culture system. Chronic inhibition of secreted/extracellular VEGF by an anti-VEGF mAb redundantly increased VEGF family member (PlGF, VEGFR1 and VEGFR2), induced a resistance to hypoxia-induced apoptosis, and increased spheroid formation ability. This apoptotic resistance was partially abrogated by a VEGFR-TKI, which blocked the compensate pathway consisted of VEGF family members, or by knockdown of Vegf mRNA, which inhibited intracellular function(s) of all Vegf gene products. Interestingly, chronic and complete depletion of all Vegf gene products by Vegf gene knockout further augmented these phenotypes in the compensate pathway-independent manner. These accelerated phenotypes were significantly suppressed by knockdown of hypoxia-inducible factor-1α that was up-regulated in the VEGF-KO cell lines. Our findings suggest that chronic inhibition of tumor cell-derived VEGF

  10. Upregulation of HYAL1 expression in breast cancer promoted tumor cell proliferation, migration, invasion and angiogenesis.

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    Jin-Xiang Tan

    Full Text Available Hyaluronic acid (HA is a component of the Extra-cellular matrix (ECM, it is closely correlated with tumor cell growth, proliferation, metastasis and angiogenesis, etc. Hyaluronidase (HAase is a HA-degrading endoglycosidase, levels of HAase are elevated in many cancers. Hyaluronidase-1 (HYAL1 is the major tumor-derived HAase. We previously demonstrated that HYAL1 were overexpression in human breast cancer. Breast cancer cells with higher HAase expression, exhibited significantly higher invasion ability through matrigel than those cells with lower HAase expression, and knockdown of HYAL1 expression in breast cancer cells resulted in decreased cell growth, adhesion, invasion and angiogenesis. Here, to further elucidate the function of HYAL1 in breast cancer, we investigated the consequences of forcing HYAL1 expression in breast cancer cells by transfection of expression plasmid. Compared with control, HYAL1 up-regulated cells showed increased the HAase activity, and reduced the expression of HA in vitro. Meantime, upregulation of HYAL1 promoted the cell growth, migration, invasion and angiogenesis in vitro. Moreover, in nude mice model, forcing HYAL1 expression induced breast cancer cell xenograft tumor growth and angiogenesis. Interestingly, the HA expression was upregulated by forcing HYAL1 expression in vivo. These findings suggested that HYAL1-HA system is correlated with the malignant behavior of breast cancer.

  11. The multifaceted mechanism of Leptin signaling within tumor microenvironment in driving breast cancer growth and progression.

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    Sebastiano eAndò

    2014-11-01

    Full Text Available Adipokines represent likely candidates to mediate the increased breast cancer risk and the enhanced progression associated with obesity. Other contributors to obesity-related cancer progression are insulin/IGF-1 pathways and hormones. Among these, the adipokine leptin is the most intensively studied in both metabolism in general and in cancer due to the fact that leptin levels increase in proportion of fat mass. Leptin is primarily synthesized from adipocytes, but it is also produced by other cells including fibroblasts. In this latter case, it has been well demonstrated how cancer-associated fibroblasts express leptin receptor and secrete leptin which sustains a short autocrine loop and is able to target tumor epithelial cells enhancing breast cancer cell motility and invasiveness. In addition, it has been reported that leptin may induce breast cancer to undergo a transition from epithelial to spindle-like mesenchymal morphology, activating the signaling pathways devoted to the EMT. Thus, it emerges how leptin may play a crucial role in mediating malignant cell and tumor microenvironment interactions. Here, we present an overview of the role of leptin in breast cancer, covering the following topics: 1 leptin as an amplifier of estrogen signaling in tumor epithelial cells contributing to the promotion of carcinogenesis; 2 leptin as a crucial player in mediating tumor-stroma interaction and influencing EMT-linked mechanisms, that may sustain breast cancer growth and progression; 3 leptin and leptin receptor targeting as novel therapeutic strategies for breast cancer treatment.

  12. Biopotential signals of breast cancer versus tumor types and proliferation stages

    Science.gov (United States)

    Hassan, Ahmed M.; El-Shenawee, Magda

    2012-02-01

    Clinical studies have shown compelling data of elevated biopotential signals recorded noninvasively from the breasts of women with breast cancer. While these data are compelling and show a strong potential for use in the noninvasive early detection of breast cancer, there remains significant knowledge gaps which must be addressed before this technology can be routinely used for breast cancer detection. A diffusion-drift model is developed to study the spatial and temporal characteristics of the biopotential signals of breast tumors taking into account the morphology and cell division stages. The electric signals of the most common tumor types—papillary, compact, and comedo—are also considered. The largest biopotential signal is observed from the compact tumor, while the smallest signal is observed from the papillary type. The results also show an increase in the time duration of the generated biopotential signals when cancer cells start their transitions at different time instants. The spatial and temporal variations of the biopotential signals are correlated with the tumor pattern which can have important implications for breast cancer detection.

  13. Automated detection of breast tumor in MRI and comparison of kinetic features for assessing tumor response to chemotherapy

    Science.gov (United States)

    Aghaei, Faranak; Tan, Maxine; Zheng, Bin

    2015-03-01

    Dynamic contrast-enhanced breast magnetic resonance imaging (DCE-MRI) is used increasingly in diagnosis of breast cancer and assessment of treatment efficacy in current clinical practice. The purpose of this preliminary study is to develop and test a new quantitative kinetic image feature analysis method and biomarker to predict response of breast cancer patients to neoadjuvant chemotherapy using breast MR images acquired before the chemotherapy. For this purpose, we developed a computer-aided detection scheme to automatically segment breast areas and tumors depicting on the sequentially scanned breast MR images. From a contrast-enhancement map generated by subtraction of two image sets scanned pre- and post-injection of contrast agent, our scheme computed 38 morphological and kinetic image features from both tumor and background parenchymal regions. We applied a number of statistical data analysis methods to identify effective image features in predicting response of the patients to the chemotherapy. Based on the performance assessment of individual features and their correlations, we applied a fusion method to generate a final image biomarker. A breast MR image dataset involving 68 patients was used in this study. Among them, 25 had complete response and 43 had partially response to the chemotherapy based on the RECIST guideline. Using this image feature fusion based biomarker, the area under a receiver operating characteristic curve is AUC = 0.850±0.047. This study demonstrated that a biomarker developed from the fusion of kinetic image features computed from breast MR images acquired pre-chemotherapy has potentially higher discriminatory power in predicting response of the patients to the chemotherapy.

  14. Magnetic Fluorescent Nanoformulation for Intracellular Drug Delivery to Human Breast Cancer, Primary Tumors, and Tumor Biopsies: Beyond Targeting Expectations.

    Science.gov (United States)

    El-Boubbou, Kheireddine; Ali, Rizwan; Bahhari, Hassan M; AlSaad, Khaled O; Nehdi, Atef; Boudjelal, Mohamed; AlKushi, Abdulmohsen

    2016-06-15

    We report the development of a chemotherapeutic nanoformulation made of polyvinylpyrrolidone-stabilized magnetofluorescent nanoparticles (Fl-PMNPs) loaded with anticancer drugs as a promising drug carrier homing to human breast cancer cells, primary tumors, and solid tumors. First, nanoparticle uptake and cell death were evaluated in three types of human breast cells: two metastatic cancerous MCF-7 and MDA-MB-231 cells and nontumorigenic MCF-10A cells. While Fl-PMNPs were not toxic to cells even at the highest concentrations used, Dox-loaded Fl-PMNPs showed significant potency, effectively killing the different breast cancer cells, albeit at different affinities. Interestingly and superior to free Dox, Dox-loaded Fl-PMNPs were found to be more effective in killing the metastatic cells (2- to 3-fold enhanced cytotoxicities for MDA-MB-231 compared to MCF-7), compared to the normal noncancerous MCF-10A cells (up to 8-fold), suggesting huge potentials as selective anticancer agents. Electron and live confocal microscopy imaging mechanistically confirmed that the nanoparticles were successfully endocytosed and packaged into vesicles inside the cytoplasm, where Dox is released and then translocated to the nucleus exerting its cytotoxic action and causing apoptotic cell death. Furthermore, commendable and enhanced penetration in 3D multilayered primary tumor cells derived from primary lesions as well as in patient breast tumor biopsies was observed, killing the tumor cells inside. The designed nanocarriers described here can potentially open new opportunities for breast cancer patients, especially in theranostic imaging and hyperthermia. While many prior studies have focused on targeting ligands to specific receptors to improve efficacies, we discovered that even with passive-targeted tailored delivery system enhanced toxic responses can be attained. PMID:27269304

  15. Claudin-2 promotes breast cancer liver metastasis by facilitating tumor cell interactions with hepatocytes.

    Science.gov (United States)

    Tabariès, Sébastien; Dupuy, Fanny; Dong, Zhifeng; Monast, Anie; Annis, Matthew G; Spicer, Jonathan; Ferri, Lorenzo E; Omeroglu, Atilla; Basik, Mark; Amir, Eitan; Clemons, Mark; Siegel, Peter M

    2012-08-01

    We previously identified claudin-2 as a functional mediator of breast cancer liver metastasis. We now confirm that claudin-2 levels are elevated in liver metastases, but not in skin metastases, compared to levels in their matched primary tumors in patients with breast cancer. Moreover, claudin-2 is specifically expressed in liver-metastatic breast cancer cells compared to populations derived from bone or lung metastases. The increased liver tropism exhibited by claudin-2-expressing breast cancer cells requires claudin-2-mediated interactions between breast cancer cells and primary hepatocytes. Furthermore, the reduction of the claudin-2 expression level, either in cancer cells or in primary hepatocytes, diminishes these heterotypic cell-cell interactions. Finally, we demonstrate that the first claudin-2 extracellular loop is essential for mediating tumor cell-hepatocyte interactions and the ability of breast cancer cells to form liver metastases in vivo. Thus, during breast cancer liver metastasis, claudin-2 shifts from acting within tight-junctional complexes to functioning as an adhesion molecule between breast cancer cells and hepatocytes.

  16. Evaluation of some ratio effects in 99mTc-MIBI imaging of breast tumors

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The effectiveness of using some ratios in 99mTc-MIBI imaging fbr the diagnosis of breast tumors was evaluated. After 100 patients with the breast tumor underwent 99mTc-MIBI imaging, the ratios of tunor to contralateral uptake (T/N). tumor to heart uptake (T/H), and tumor to sternum uptake (T/S) were obtained and then analysed about their reproducibility and values in differentiating benign breast lesion the from malignant tumor. To detect breast cancers, the sensitivity, specificit y and accuracy of T/N were 92%, 90% and 91%, respectively. However, those of T/S were 70% (p <0.01), 74% (p <0.05), 72% (p <0.01), and those of T/H were 74%(p <0.05). 76% (p >0.05). 75% (p <0.01). The average coefticients of variation(CV) of T/N, T/S and T/H were 9.439±9.712. 4.856+4.420 (p >0.05), and 3.736±3.489 (p <0.05). It was found that T/N had the best sensitivity, specificity and accuracy todetect the breast cancer, but its reproducibility is poor. On the other hand, T/H has better reproducibility.

  17. EXPERIENCE OF MANAGEMENT OF PHYLLODES TUMOR OF BREAST AT A TERTIARY CARE HOSPITAL: A PROSPECTIVE STUDY

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    Bharath

    2016-02-01

    Full Text Available BACKGROUND Phyllodes tumors of the breast are a rare fibroepithelial lesions, which is locally aggressive neoplasm. The aim of the study was to report our experience at ESIC MC PGIMSR Hospital (Rajajinagar, Bengaluru acquired during period of 3 years. METHODS It was a prospective observational study, which included documentation of clinical presentation, pre-operative workup, surgical treatment, complications, histopathological examination and the outcome in a series of 52 cases diagnosed as phyllodes tumor from January 2013 to December 2015. RESULTS The analysis of this series showed that mean time of onset was 12 months [6 – 18 months], the chief complaint was lump in the breast in all the patients; tumor size ranged between 4.5 – 22.5cm (mean: 13.5cm; the right breast was affected in 31 cases, surgical treatment was used in all cases which included 44 cases who underwent wide local excision and 8 cases simple mastectomy; the tumor was classified based on histopathological examination as benign in 44 cases (85%, borderline in 2 cases (4% and malignant in 6 cases (11%; all the patients were followed up, the rate of recurrence was 10%. None of the patient had distant metastasis and no deaths were reported during the study period. CONCLUSIONS Phyllodes tumors of the breast clinically resemble fibroadenoma and have an unpredictable outcome, thus a wide local excision, with an adequate margin of normal breast tissue is the preferred initial therapy.

  18. Unusual malignant tumors of the breast: MRI features and pathologic correlation

    Energy Technology Data Exchange (ETDEWEB)

    Linda, Anna, E-mail: annalinda33@gmail.co [Institute of Radiology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Pl.e Santa Maria della Misericordia, 33100 Udine (Italy); Zuiani, Chiara; Girometti, Rossano; Londero, Viviana [Institute of Radiology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Pl.e Santa Maria della Misericordia, 33100 Udine (Italy); Machin, Piernicola [Institute of Pathology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Pl.e Santa Maria della Misericordia, 33100 Udine (Italy); Brondani, Giovanni; Bazzocchi, Massimo [Institute of Radiology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Pl.e Santa Maria della Misericordia, 33100 Udine (Italy)

    2010-08-15

    Unusual malignant breast tumors are well-differentiated subtypes of invasive ductal carcinoma, including mucinous, tubular, medullary and papillary carcinomas, and account for about 10% of malignant breast tumors. They are increasingly being encountered during magnetic resonance imaging (MRI) examinations of the breast. Therefore, breast radiologists should be aware of their appearance on MRI. This review provides an overview of MRI characteristics of a range of unusual tumors (mucinous carcinoma, medullary carcinoma, tubular carcinoma, intraductal papillary carcinoma, intracystic papillary carcinoma and invasive papillary carcinoma), highlighting specific clues for diagnosis and correlating MRI and pathologic features. Many unusual breast tumors exhibit MRI features similar to those of benign or low suspicious lesions (oval shape, well-defined margins, high signal intensity on T2-weighted images, continuous increase kinetics, i.e. type I dynamic curve), leading to a possible misdiagnosis. Nevertheless, an understanding of pathologic features of these tumors, especially tissue content (mucinous, fibrous) and growth pattern, can help to define some specific clues for their diagnosis.

  19. Protective antitumor immunity induced by tumor cell lysates conjugated with diphtheria toxin and adjuvant epitope in mouse breast tumor models

    Institute of Scientific and Technical Information of China (English)

    Ze-Yu Wang; Rong-Yue Cao; Jie Wu; Tai-Ming LI; Jing-Jing Liu; Yun Xing; Bin Liu; Lei Lu; Xiao Huang; Chi-Yu Ge; Wen-Jun Yao; Mao-Lei Xu; Zhen-Qiu Gao

    2012-01-01

    Cancer cell vaccine-based immunotherapy has received increasing interest in many clinical trials involving patients with breast cancer.Combining with appropriate adjuvants can enhance the weak immunogenic properties of tumor cell lysates (TCL).In this study,diphtheria toxin (DT) and two tandem repeats of mycobacterial heat shock protein 70 (mHSP70) fragment 407-426 (M2) were conjugated to TCL with glutaraldehyde,and the constructed cancer cell vaccine was named DT-TCL-M2.Subcutaneous injection of DT-TCL-M2 in mice effectively elicited tumor-specific polyclonal immune responses,including humoral and cellular immune responses.High levels of antibodies against TCL were detected in the serum of immunized mice with ELISA and verified with Western blot analyses.The splenocytes from immunized mice showed potent cytotoxicity on Ehrlich ascites carcinoma cells.Moreover,the protective antitumor immunity induced by DT-TCL-M2 inhibited tumor growth in a mouse breast tumor model.DTTCL-M2 also attenuated tumor-induced angiogenesis and slowed tumor growth in a mouse intradermal tumor model.These findings demonstrate that TCL conjugated with appropriate adjuvants induced effective antitumor immunity in vivo.Improvements in potency could further make cancer cell vaccines a useful and safe method for preventing cancer recurrence after resection.

  20. Salinomycin efficiency assessment in non-tumor (HB4a) and tumor (MCF-7) human breast cells.

    Science.gov (United States)

    Niwa, Andressa Megumi; D Epiro, Gláucia Fernanda Rocha; Marques, Lilian Areal; Semprebon, Simone Cristine; Sartori, Daniele; Ribeiro, Lúcia Regina; Mantovani, Mário Sérgio

    2016-06-01

    The search for anticancer drugs has led researchers to study salinomycin, an ionophore antibiotic that selectively destroys cancer stem cells. In this study, salinomycin was assessed in two human cell lines, a breast adenocarcinoma (MCF-7) and a non-tumor breast cell line (HB4a), to verify its selective action against tumor cells. Real-time assessment of cell proliferation showed that HB4a cells are more resistant to salinomycin than MCF-7 tumor cell line, and these data were confirmed in a cytotoxicity assay. The half maximal inhibitory concentration (IC50) values show the increased sensitivity of MCF-7 cells to salinomycin. In the comet assay, only MCF-7 cells showed the induction of DNA damage. Flow cytometric analysis showed that cell death by apoptosis/necrosis was only induced in the MCF-7 cells. The increased expression of GADD45A and CDKN1A genes was observed in all cell lines. Decreased expression of CCNA2 and CCNB1 genes occurred only in tumor cells, suggesting G2/M cell cycle arrest. Consequently, cell death was activated in tumor cells through strong inhibition of the antiapoptotic genes BCL-2, BCL-XL, and BIRC5 genes in MCF-7 cells. These data demonstrate the selectivity of salinomycin in killing human mammary tumor cells. The cell death observed only in MCF-7 tumor cells was confirmed by gene expression analysis, where there was downregulation of antiapoptotic genes. These data contribute to clarifying the mechanism of action of salinomycin as a promising antitumor drug and, for the first time, we observed the higher resistance of HB4a non-tumor breast cells to salinomycin. PMID:26932586

  1. CoREST1 promotes tumor formation and tumor stroma interactions in a mouse model of breast cancer.

    Directory of Open Access Journals (Sweden)

    Sohini Mazumdar

    Full Text Available Regulators of chromatin structure and gene expression contribute to tumor formation and progression. The co-repressor CoREST1 regulates the localization and activity of associated histone modifying enzymes including lysine specific demethylase 1 (LSD1 and histone deacetylase 1 (HDAC1. Although several CoREST1 associated proteins have been reported to enhance breast cancer progression, the role of CoREST1 in breast cancer is currently unclear. Here we report that knockdown of CoREST1 in the basal-type breast cancer cell line, MDA-MB-231, led to significantly reduced incidence and diminished size of tumors compared to controls in mouse xenograft studies. Notably, CoREST1-depleted cells gave rise to tumors with a marked decrease in angiogenesis. CoREST1 knockdown led to a decrease in secreted angiogenic and inflammatory factors, and mRNA analysis suggests that CoREST1 promotes expression of genes related to angiogenesis and inflammation including VEGF-A and CCL2. CoREST1 knockdown decreased the ability of MDA-MB-231 conditioned media to promote endothelial cell tube formation and migration. Further, tumors derived from CoREST1-depleted cells had reduced macrophage infiltration and the secretome of CoREST1 knockdown cells was deficient in promoting macrophage migration and macrophage-mediated angiogenesis. Taken together, these findings reveal that the epigenetic regulator CoREST1 promotes tumorigenesis in a breast cancer model at least in part through regulation of gene expression patterns in tumor cells that have profound non-cell autonomous effects on endothelial and inflammatory cells in the tumor microenvironment.

  2. Nestin expression associates with poor prognosis and triple negative phenotype in locally advanced (T4 breast cancer

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    F. Piras

    2011-11-01

    Full Text Available Nestin, an intermediate filament protein, has traditionally been noted for its importance as a neural stem cell marker. However, in recent years, expression of nestin has shown to be associated with general proliferation of progenitor cell populations within neoplasms. There is no reported study addressing nestin expression in T4 breast cancer patients. Thus, the aim of the present study was to investigate, through immunohistochemistry, the expression and distribution of nestin in T4 breast cancer, in order to determine its association with clinical and pathological parameters as well as with patients’ outcome. Nestin was detectable in tumoral cells and in endothelial cells of blood microvessels, and it is significantly expressed in triple-negative and in inflammatory breast cancer (IBC subgroups of T4 breast tumours. The Kaplan-Meier analysis showed that the presence of nestin in tumoral cells significantly predicted poor prognosis at 5-years survival (P=0.02 and with borderline significance at 10-years of survival (P=0.05 in T4 breast cancer patients. On the basis of these observations, we speculate that nestin expression may characterize tumours with an aggressive clinical behavior, suggesting that the presence of nestin in tumoral cells and vessels may be considered an important factor that leads to a poor prognosis. Further studies are awaited to define the biological role of nestin in the etiology of these subgroups of breast cancers.

  3. Musashi1 regulates breast tumor cell proliferation and is a prognostic indicator of poor survival

    Directory of Open Access Journals (Sweden)

    Wang Xiao-Yang

    2010-08-01

    Full Text Available Abstract Background Musashi1 (Msi1 is a conserved RNA-binding protein that regulates the Notch and Wnt pathways, and serves as a stem cell marker in the breast and other tissues. It is unknown how Msi1 relates to other breast cancer markers, whether it denotes tumor initiating cells (TICs, and how it affects gene expression and tumor cell survival in breast cancer cells. Results Msi1 expression was analyzed in 20 breast cancer cell lines and in 140 primary breast tumors by western blotting and immunohistochemistry, respectively. Lentivirus RNA interference was used to reduce Msi1 expression in breast cancer cell lines MCF-7 and T47D grown as spheroid cultures and to assess stem cell gene expression and the growth of these cell lines as xenografts. In normal human breast tissue, Msi1 was expressed in 10.6% of myoepithelum and 1.2% of ductal epithelium in the terminal ductal lobular unit (TDLU, whereas, less than 0.05% of ductal epithelium and myoepithelium in large ducts outside the TDLU expressed Msi1. Msi1 was expressed in 55% of the breast cancer cell lines and correlated with ErbB2 expression in 50% of the cell lines. Msi1 was expressed in 68% of primary tumors and in 100% of lymph node metastases, and correlated with 5 year survival. Msi1 was enriched in CD133+ MCF-7 and T47D cells and in spheroid cultures of these cells, and Msi1 'knockdown' (KD with a lentivirus-expressed shRNA decreased the number and size of spheroid colonies. Msi1 KD reduced Notch1, c-Myc, ErbB2 and pERK1/2 expression, and increased p21CIP1 expression, which is consistent with known Msi1 target mRNAs. Msi1 KD also reduced the expression of the somatic and embryonic stem cell markers, CD133, Bmi1, Sox2, Nanog and Oct4. Xenografts of MCF-7 and T47D Msi1 KD cells resulted in a marked reduction of tumor growth, reduced Msi1 and Notch1 expression and increased p21CIP1 expression. Conclusion Msi1 is a negative prognostic indicator of breast cancer patient survival, and is

  4. Argyrophilic carcinoma of the male breast. A neuroendocrine tumor containing predominantly chromogranin B (secretogranin I).

    Science.gov (United States)

    Scopsi, L; Andreola, S; Saccozzi, R; Pilotti, S; Boracchi, P; Rosa, P; Conti, A R; Manzari, A; Huttner, W B; Rilke, F

    1991-11-01

    Argyrophilic tumors were diagnosed in 28 of 134 (20.8%) consecutive male patients who had a carcinoma of the breast removed between 1961 and 1990. Histologically, most argyrophilic tumors showed uniform cellularity and prevalent expansive growth. Ultrastructural observation disclosed the presence of electron-dense cored granules in the cytoplasm of the tumor cells. By immunocytochemistry, 17 of 28 argyrophilic tumors (60.7%) contained chromogranin B (secretogranin I)-immunoreactive cells, whereas chromogranin A was present in four of these 17 tumors only (14.2%). Immunoblotting studies showed chromogranin B immunoreactivity similar to that found in normal neuroendocrine cells. Despite these findings, which would argue for a distinct morphologic and immunochemical entity, no statistically significant differences between argyrophilic and common male breast carcinomas were found when a number of clinicopathologic features and relapse-free survival were considered.

  5. Automatic tumor detection in the constrained region for ultrasound breast CAD

    Science.gov (United States)

    Seong, Yeong Kyeong; Park, Moon Ho; Ko, Eun Young; Woo, Kyoung-Gu

    2012-03-01

    In this paper we propose a new method to segment a breast image into several regions. Tumor detection region is constrained to the region only in glandular tissue because the tumors usually occur at glandular tissue in the breast anatomy. We extract texture feature for each point and classify them as several layers using a random forest classifier. Classified points are merged into a large region and small regions are removed by postprocessing. The accuracy of glandular tissue detection rate was about 90%. We applied the conventional tumor detection method in this segmented glandular tissue. After several tests we obtained that tumor detection accuracy improved for 14% and detection time was also reduced. With this method, we can achieve the improvement both on tumor detection accuracy and on the processing time.

  6. Shigella mediated depletion of macrophages in a murine breast cancer model is associated with tumor regression.

    Directory of Open Access Journals (Sweden)

    Katharina Galmbacher

    Full Text Available A tumor promoting role of macrophages has been described for a transgenic murine breast cancer model. In this model tumor-associated macrophages (TAMs represent a major component of the leukocytic infiltrate and are associated with tumor progression. Shigella flexneri is a bacterial pathogen known to specificly induce apotosis in macrophages. To evaluate whether Shigella-induced removal of macrophages may be sufficient for achieving tumor regression we have developed an attenuated strain of S. flexneri (M90TDeltaaroA and infected tumor bearing mice. Two mouse models were employed, xenotransplantation of a murine breast cancer cell line and spontanous breast cancer development in MMTV-HER2 transgenic mice. Quantitative analysis of bacterial tumor targeting demonstrated that attenuated, invasive Shigella flexneri primarily infected TAMs after systemic administration. A single i.v. injection of invasive M90TDeltaaroA resulted in caspase-1 dependent apoptosis of TAMs followed by a 74% reduction in tumors of transgenic MMTV-HER-2 mice 7 days post infection. TAM depletion was sustained and associated with complete tumor regression.These data support TAMs as useful targets for antitumor therapy and highlight attenuated bacterial pathogens as potential tools.

  7. Phenotypical Reversion and Differentiation of Breast Cancer in vitro by Sodium Phenylacetate

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective To evaluate the effect of a nontoxic differentiation inducer, sodium phenylacetate (NaPA) on breast cancer MCF-7 and MDA-453 cells in vitro. Methods The anchorage growth assay, ELISA, immunofluorescence analysis and electron microscopy were used to study the effect of NaPA on MCF-7 and MDA-453 cells. Results NaPA treatment resulted in a dose-dependent inhibition of MCF-7 or MDA-453 cell growth, including anchorage-dependent and anchorage-independent growth, but il did not significantly inhibit the growth of normal amnion tissue Wish cells and adult hepatic cells L-02. In addition, NaPA could enhance the expressions of intercellular adhesion molecule-1(ICAM-1), human leukocyte antigen ( HLA ) class Ⅰ and Ⅱ molecules on the surface of MCF-7 and MDA-453 cells. Electron micrographs demonstrated richer rough endoplasmic reticulum,mitochondria in NaPA-treated MCF-7 and MDA-453 cells, in contrast to the scant before-mentwned structures but scattered cytoplasmic polyribosomes in the untreated ones. Conclusion NaPA is effective in inducing phenotype reversion and differentiation of breast cancer, and potential in cancer intervention.

  8. Electric Field Analysis of Human Breast Tumors for Treatment by Electroporation

    OpenAIRE

    Agoramurthy, Poornima

    2011-01-01

    Breast cancer is a frequently diagnosed disease in women, second only to cancers of the skin. According to the American Cancer Society there were approximately 210,000 new cases of breast cancer estimated in 2010 in the US, 20 % of which resulted in death. With such a high rate of incidence, there is clearly a need for alternate treatments, especially for in-operable tumors and chemo- and radio-resistive patients. Electrochemotherapy, a method by which high intensity, short duration electri...

  9. Cancer Associated Fibroblasts express pro-inflammatory factors in human breast and ovarian tumors

    Energy Technology Data Exchange (ETDEWEB)

    Erez, Neta, E-mail: netaerez@post.tau.ac.il [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Glanz, Sarah [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Raz, Yael [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Department of Obstetrics and Gynecology, LIS Maternity Hospital, Tel Aviv Sourasky Medical Center, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Avivi, Camilla [Department of Pathology, Sheba Medical Center, Tel Hashomer, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Barshack, Iris [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Department of Pathology, Sheba Medical Center, Tel Hashomer, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel)

    2013-08-02

    Highlights: •CAFs in human breast and ovarian tumors express pro-inflammatory factors. •Expression of pro-inflammatory factors correlates with tumor invasiveness. •Expression of pro-inflammatory factors is associated with NF-κb activation in CAFs. -- Abstract: Inflammation has been established in recent years as a hallmark of cancer. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation and invasion. We previously demonstrated that CAFs also mediate tumor-enhancing inflammation in a mouse model of skin carcinoma. Breast and ovarian carcinomas are amongst the leading causes of cancer-related mortality in women and cancer-related inflammation is linked with both these tumor types. However, the role of CAFs in mediating inflammation in these malignancies remains obscure. Here we show that CAFs in human breast and ovarian tumors express high levels of the pro-inflammatory factors IL-6, COX-2 and CXCL1, previously identified to be part of a CAF pro-inflammatory gene signature. Moreover, we show that both pro-inflammatory signaling by CAFs and leukocyte infiltration of tumors are enhanced in invasive ductal carcinoma as compared with ductal carcinoma in situ. The pro-inflammatory genes expressed by CAFs are known NF-κB targets and we show that NF-κB is up-regulated in breast and ovarian CAFs. Our data imply that CAFs mediate tumor-promoting inflammation in human breast and ovarian tumors and thus may be an attractive target for stromal-directed therapeutics.

  10. Mammographic density and histopathologic characteristics of screen-detected tumors in the Norwegian Breast Cancer Screening Program

    International Nuclear Information System (INIS)

    High mammographic density might mask breast tumors, resulting in delayed diagnosis or missed cancers. To investigate the association between mammographic density and histopathologic tumor characteristics (histologic type, size, grade, and lymph node status) among women screened in the Norwegian Breast Cancer Screening Program. Information about 1760 screen-detected ductal carcinoma in situ (DCIS) and 7366 invasive breast cancers diagnosed among women aged 50–69 years, 1996–2010, was analyzed. The screening mammograms were classified subjectively according to the amount of fibroglandular tissue into fatty, medium dense, and dense by breast radiologists. Chi-square test was used to compare the distribution of tumor characteristics by mammographic density. Odds ratio (OR) of tumor characteristics by density was estimated by means of logistic regression, adjusting for screening mode (screen-film and full-field digital mammography), and age. Mean and median tumor size of invasive breast cancers was 13.8 and 12 mm, respectively, for women with fatty breasts, and 16.2 and 14 mm for those with dense breasts. Lymph node positive tumors were identified among 20.6% of women with fatty breasts compared with 27.2% of those with dense breasts (P < 0.001). The proportion of DCIS was significantly lower for women with fatty (15.8%) compared with dense breasts (22.0%). Women with dense breasts had an increased risk of large (OR, 1.44; 95% CI, 1.18–1.73) and lymph node positive tumors (OR, 1.26; 95% CI, 1.05–1.51) compared with women with fatty and medium dense breasts. High mammographic density was positively associated with tumor size and lymph node positive tumors

  11. UP-REGULATION OF CYCLOOXYGENASE-2 GENE EXPRESSION CORRELATES WITH TUMOR ANGIOGENESIS IN HUMAN BREAST CANCER

    Institute of Scientific and Technical Information of China (English)

    代志军; 王西京; 刘小旭; 康华峰; 姜建涛; 管海涛; 张淑群; 薛兴欢; 薛锋杰

    2003-01-01

    Objective: To study the relationship between cyclooxygenase-2 (COX-2) expression and tumor angiogenesis in human breast cancer. Methods: Archival primary breast carcinomas (n = 62), adjacent ductal carcinoma in situ (DCIS, n = 13) and DCIS alone (n = 5) were analyzed for COX-2 and VEGF expression by immunohistochemistry using specific monoclonal antibodies. Microvessel density (MVD) was also examined the using CD34 staining. Results: A significant correlation was found between COX-2 and VEGF expression (P<0.01). Both COX-2 and VEGF were significantly correlated with MVD (P<0.05) and P<0.01, respectively). COX-2 and VEGF genes were overexpressed in tumor specimens as compared with normal epithelia. Conclusion: COX-2 is related to tumor angiogenesis in breast cancer. It is likely that VEGF is one of the most important mediators of the COX-2 angiogenic pathway.

  12. A novel 3-D mineralized tumor model to study breast cancer bone metastasis.

    Directory of Open Access Journals (Sweden)

    Siddharth P Pathi

    Full Text Available BACKGROUND: Metastatic bone disease is a frequent cause of morbidity in patients with advanced breast cancer, but the role of the bone mineral hydroxyapatite (HA in this process remains unclear. We have developed a novel mineralized 3-D tumor model and have employed this culture system to systematically investigate the pro-metastatic role of HA under physiologically relevant conditions in vitro. METHODOLOGY/PRINCIPAL FINDINGS: MDA-MB231 breast cancer cells were cultured within non-mineralized or mineralized polymeric scaffolds fabricated by a gas foaming-particulate leaching technique. Tumor cell adhesion, proliferation, and secretion of pro-osteoclastic interleukin-8 (IL-8 was increased in mineralized tumor models as compared to non-mineralized tumor models, and IL-8 secretion was more pronounced for bone-specific MDA-MB231 subpopulations relative to lung-specific breast cancer cells. These differences were pathologically significant as conditioned media collected from mineralized tumor models promoted osteoclastogenesis in an IL-8 dependent manner. Finally, drug testing and signaling studies with transforming growth factor beta (TGFbeta confirmed the clinical relevance of our culture system and revealed that breast cancer cell behavior is broadly affected by HA. CONCLUSIONS/SIGNIFICANCE: Our results indicate that HA promotes features associated with the neoplastic and metastatic growth of breast carcinoma cells in bone and that IL-8 may play an important role in this process. The developed mineralized tumor models may help to reveal the underlying cellular and molecular mechanisms that may ultimately enable more efficacious therapy of patients with advanced breast cancer.

  13. Step-wise and punctuated genome evolution drive phenotype changes of tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Stepanenko, Aleksei, E-mail: a.a.stepanenko@gmail.com [Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv 03680 (Ukraine); Andreieva, Svitlana; Korets, Kateryna; Mykytenko, Dmytro [Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv 03680 (Ukraine); Huleyuk, Nataliya [Institute of Hereditary Pathology, National Academy of Medical Sciences of Ukraine, Lviv 79008 (Ukraine); Vassetzky, Yegor [CNRS UMR8126, Université Paris-Sud 11, Institut de Cancérologie Gustave Roussy, Villejuif 94805 (France); Kavsan, Vadym [Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv 03680 (Ukraine)

    2015-01-15

    Highlights: • There are the step-wise continuous and punctuated phases of cancer genome evolution. • The system stresses during the different phases may lead to very different responses. • Stable transfection of an empty vector can result in genome and phenotype changes. • Functions of a (trans)gene can be opposite/versatile in cells with different genomes. • Contextually, temozolomide can both promote and suppress tumor cell aggressiveness. - Abstract: The pattern of genome evolution can be divided into two phases: the step-wise continuous phase (step-wise clonal evolution, stable dominant clonal chromosome aberrations (CCAs), and low frequency of non-CCAs, NCCAs) and punctuated phase (marked by elevated NCCAs and transitional CCAs). Depending on the phase, system stresses (the diverse CIN promoting factors) may lead to the very different phenotype responses. To address the contribution of chromosome instability (CIN) to phenotype changes of tumor cells, we characterized CCAs/NCCAs of HeLa and HEK293 cells, and their derivatives after genotoxic stresses (a stable plasmid transfection, ectopic expression of cancer-associated CHI3L1 gene or treatment with temozolomide) by conventional cytogenetics, copy number alterations (CNAs) by array comparative genome hybridization, and phenotype changes by cell viability and soft agar assays. Transfection of either the empty vector pcDNA3.1 or pcDNA3.1-CHI3L1 into 293 cells initiated the punctuated genome changes. In contrast, HeLa-CHI3L1 cells demonstrated the step-wise genome changes. Increased CIN correlated with lower viability of 293-pcDNA3.1 cells but higher colony formation efficiency (CFE). Artificial CHI3L1 production in 293-CHI3L1 cells increased viability and further contributed to CFE. The opposite growth characteristics of 293-CHI3L1 and HeLa-CHI3L1 cells were revealed. The effect and function of a (trans)gene can be opposite and versatile in cells with different genetic network, which is defined by

  14. Step-wise and punctuated genome evolution drive phenotype changes of tumor cells

    International Nuclear Information System (INIS)

    Highlights: • There are the step-wise continuous and punctuated phases of cancer genome evolution. • The system stresses during the different phases may lead to very different responses. • Stable transfection of an empty vector can result in genome and phenotype changes. • Functions of a (trans)gene can be opposite/versatile in cells with different genomes. • Contextually, temozolomide can both promote and suppress tumor cell aggressiveness. - Abstract: The pattern of genome evolution can be divided into two phases: the step-wise continuous phase (step-wise clonal evolution, stable dominant clonal chromosome aberrations (CCAs), and low frequency of non-CCAs, NCCAs) and punctuated phase (marked by elevated NCCAs and transitional CCAs). Depending on the phase, system stresses (the diverse CIN promoting factors) may lead to the very different phenotype responses. To address the contribution of chromosome instability (CIN) to phenotype changes of tumor cells, we characterized CCAs/NCCAs of HeLa and HEK293 cells, and their derivatives after genotoxic stresses (a stable plasmid transfection, ectopic expression of cancer-associated CHI3L1 gene or treatment with temozolomide) by conventional cytogenetics, copy number alterations (CNAs) by array comparative genome hybridization, and phenotype changes by cell viability and soft agar assays. Transfection of either the empty vector pcDNA3.1 or pcDNA3.1-CHI3L1 into 293 cells initiated the punctuated genome changes. In contrast, HeLa-CHI3L1 cells demonstrated the step-wise genome changes. Increased CIN correlated with lower viability of 293-pcDNA3.1 cells but higher colony formation efficiency (CFE). Artificial CHI3L1 production in 293-CHI3L1 cells increased viability and further contributed to CFE. The opposite growth characteristics of 293-CHI3L1 and HeLa-CHI3L1 cells were revealed. The effect and function of a (trans)gene can be opposite and versatile in cells with different genetic network, which is defined by

  15. Monte Carlo simulation of breast tumor imaging properties with compact, discrete gamma cameras

    International Nuclear Information System (INIS)

    The authors describe Monte Carlo simulation results for breast tumor imaging using a compact, discrete gamma camera. The simulations were designed to analyze and optimize camera design, particularly collimator configuration and detector pixel size. Simulated planar images of 5--15 mm diameter tumors in a phantom patient (including a breast, torso, and heart) were generated for imaging distances of 5--55 mm, pixel sizes of 2 x 2--4 x 4 mm2, and hexagonal and square hole collimators with sensitivities from 4,000 to 16,000 counts/mCi/sec. Other factors considered included T/B (tumor-to-background tissue uptake ratio) and detector energy resolution. Image properties were quantified by computing the observed tumor fwhm (full-width at half-maximum) and S/N (sum of detected tumor events divided by the statistical noise). Results suggest that hexagonal and square hole collimators perform comparably, that higher sensitivity collimators provide higher tumor S/N with little increase in the observed tumor fwhm, that smaller pixels only slightly improve tumor fwhm and S/N, and that improved detector energy resolution has little impact on either the observed tumor fwhm or the observed tumor S/N

  16. Pathological predictive factors for tumor response in locally advanced breast carcinomas treated with anthracyclin-based neoadjuvant chemotherapy

    Directory of Open Access Journals (Sweden)

    Trupti Patel

    2013-01-01

    Conclusion: Pathological parameters like type of tumor, presence of LVE and tumor necrosis in the core biopsy can predict the response to NACT in routine stain. Tumor necrosis and type of breast carcinoma are predictive parameters for tumor responsiveness to NACT. LVE was reliable in predicting axillary lymph node metastasis.

  17. Mesenchymal and stemness circulating tumor cells in early breast cancer diagnosis

    International Nuclear Information System (INIS)

    Epithelial mesenchymal transition (EMT) is a crucial event likely involved in dissemination of epithelial cancer cells. This process enables them to acquire migratory/invasive properties, contributing to tumor and metastatic spread. To know if this event is an early one in breast cancer, we developed a clinical trial. The aim of this protocol was to detect circulating tumor cells endowed with mesenchymal and/or stemness characteristics, at the time of initial diagnosis. Breast cancer patients (n = 61), without visceral or bone metastasis were enrolled and analysis of these dedifferentiated circulating tumor cells (ddCTC) was realized. AdnaGen method was used for enrichment cell selection. Then, ddCTC were characterized by RT-PCR study of the following genes: PI3Kα, Akt-2, Twist1 (EMT markers) and ALDH1, Bmi1 and CD44 (stemness indicators). Among the studied primary breast cancer cohort, presence of ddCTC was detected in 39% of cases. This positivity is independant from tumor clinicopathological factors apart from the lymph node status. Our data uniquely demonstrated that in vivo EMT occurs in the primary tumors and is associated with an enhanced ability of tumor cells to intravasate in the early phase of cancer disease. These results suggest that analysis of circulating tumor cells focused on cells showing mesenchymal or stemness characteristics might facilitate assessment of new drugs in clinical trials

  18. Malignant phyllodes tumor of the breast presenting with hypoglycemia: a case report and literature review

    Directory of Open Access Journals (Sweden)

    Pacioles T

    2014-12-01

    Full Text Available Toni Pacioles,1 Rahul Seth,2,3 Cesar Orellana,3 Ivy John,4 Veera Panuganty,3 Ruban Dhaliwal3,5 1Department of Hematology and Oncology, Edwards Comprehensive Cancer Center, Marshall University, Huntington, WV, USA; 2Division of Hematology and Oncology, 3Department of Medicine, 4Department of Pathology, 5Division of Endocrinology, SUNY Upstate Medical University, Syracuse, NY, USA Abstract: Phyllodes tumors are rare fibroepithelial neoplasms that account for less than 1% of all breast tumors and are typically found in middle-aged women. Phyllodes tumors that present with hypoglycemia are even rarer. No one morphologic finding is reliable in predicting the clinical behavior of this tumor. Surgery has been the primary mode of treatment to date. However, the extent of resection and the role of adjuvant radiotherapy or chemotherapy are still controversial. Here, we present a challenging case of malignant phyllodes tumor of the breast associated with hypoglycemia, and review the literature regarding clinical findings, pathologic risk factors for recurrence, and treatment recommendations. Keywords: breast cancer, fibroepithelial neoplasm, neuroendocrine tumor, adjuvant treatment, non-islet cell tumor-induced hypoglycemia

  19. Knockdown of c-Myc expression by RNAi inhibits MCF-7 breast tumor cells growth in vitro and in vivo

    International Nuclear Information System (INIS)

    Breast cancer is the leading cause of cancer death in women worldwide. Elevated expression of c-Myc is a frequent genetic abnormality seen in this malignancy. For a better understanding of its role in maintaining the malignant phenotype, we used RNA interference (RNAi) directed against c-Myc in our study. RNAi provides a new, reliable method to investigate gene function and has the potential for gene therapy. The aim of the study was to examine the anti-tumor effects elicited by a decrease in the protein level of c-Myc by RNAi and its possible mechanism of effects in MCF-7 cells. A plasmid-based polymerase III promoter system was used to deliver and express short interfering RNA (siRNA) targeting c-myc to reduce its expression in MCF-7 cells. Western blot analysis was used to measure the protein level of c-Myc. We assessed the effects of c-Myc silencing on tumor growth by a growth curve, by soft agar assay and by nude mice experiments in vivo. Standard fluorescence-activated cell sorter analysis and TdT-mediated dUTP nick end labelling assay were used to determine apoptosis of the cells. Our data showed that plasmids expressing siRNA against c-myc markedly and durably reduced its expression in MCF-7 cells by up to 80%, decreased the growth rate of MCF-7 cells, inhibited colony formation in soft agar and significantly reduced tumor growth in nude mice. We also found that depletion of c-Myc in this manner promoted apoptosis of MCF-7 cells upon serum withdrawal. c-Myc has a pivotal function in the development of breast cancer. Our data show that decreasing the c-Myc protein level in MCF-7 cells by RNAi could significantly inhibit tumor growth both in vitro and in vivo, and imply the therapeutic potential of RNAi on the treatment of breast cancer by targeting overexpression oncogenes such as c-myc, and c-myc might be a potential therapeutic target for human breast cancer

  20. Significance of Epithelial-mesenchaymal Transition Phenotype in Invasive Tumor Front Cells of Lung Squamous Cell Carcinoma

    OpenAIRE

    Song, Yinghua; Caiqing ZHANG; Zhixin CAO; XU, Jiawen; Wang, Lingcheng; Lin, Xiaoyan

    2014-01-01

    Background and objective The invasive tumor front (ITF) refers to cells or invasive nests in the junctional region of a tumor and its host. The ITF contains the most invasive cells of a tumor, and has a high prognostic value in carcinoma. The aim of this study is to investigate the epithelial-mesenchymal transformation phenotype in ITF cells of lung squamous cell carcinoma (SCC), and analyze the relationship between clinicopathological features and clinical outcomes of patients. Methods Semiq...

  1. Activated FXR Inhibits Leptin Signaling and Counteracts Tumor-promoting Activities of Cancer-Associated Fibroblasts in Breast Malignancy

    OpenAIRE

    Cinzia Giordano; Ines Barone; Valentina Vircillo; Salvatore Panza; Rocco Malivindi; Luca Gelsomino; Michele Pellegrino; Vittoria Rago; Loredana Mauro; Marilena Lanzino; Maria Luisa Panno; Daniela Bonofiglio; Stefania Catalano; Sebastiano Andò

    2016-01-01

    Cancer-associated fibroblasts (CAFs), the principal components of the tumor stroma, play a central role in cancer development and progression. As an important regulator of the crosstalk between breast cancer cells and CAFs, the cytokine leptin has been associated to breast carcinogenesis. The nuclear Farnesoid X Receptor-(FXR) seems to exert an oncosuppressive role in different tumors, including breast cancer. Herein, we demonstrated, for the first time, that the synthetic FXR agonist GW4064,...

  2. Breast tumor segmentation in high resolution x-ray phase contrast analyzer based computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Brun, E., E-mail: emmanuel.brun@esrf.fr [European Synchrotron Radiation Facility (ESRF), Grenoble 380000, France and Department of Physics, Ludwig-Maximilians University, Garching 85748 (Germany); Grandl, S.; Sztrókay-Gaul, A.; Gasilov, S. [Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, 81377 Munich (Germany); Barbone, G. [Department of Physics, Harvard University, Cambridge, Massachusetts 02138 (United States); Mittone, A.; Coan, P. [Department of Physics, Ludwig-Maximilians University, Garching 85748, Germany and Institute for Clinical Radiology, Ludwig-Maximilians-University Hospital Munich, 81377 Munich (Germany); Bravin, A. [European Synchrotron Radiation Facility (ESRF), Grenoble 380000 (France)

    2014-11-01

    Purpose: Phase contrast computed tomography has emerged as an imaging method, which is able to outperform present day clinical mammography in breast tumor visualization while maintaining an equivalent average dose. To this day, no segmentation technique takes into account the specificity of the phase contrast signal. In this study, the authors propose a new mathematical framework for human-guided breast tumor segmentation. This method has been applied to high-resolution images of excised human organs, each of several gigabytes. Methods: The authors present a segmentation procedure based on the viscous watershed transform and demonstrate the efficacy of this method on analyzer based phase contrast images. The segmentation of tumors inside two full human breasts is then shown as an example of this procedure’s possible applications. Results: A correct and precise identification of the tumor boundaries was obtained and confirmed by manual contouring performed independently by four experienced radiologists. Conclusions: The authors demonstrate that applying the watershed viscous transform allows them to perform the segmentation of tumors in high-resolution x-ray analyzer based phase contrast breast computed tomography images. Combining the additional information provided by the segmentation procedure with the already high definition of morphological details and tissue boundaries offered by phase contrast imaging techniques, will represent a valuable multistep procedure to be used in future medical diagnostic applications.

  3. A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds.

    Science.gov (United States)

    Bruna, Alejandra; Rueda, Oscar M; Greenwood, Wendy; Batra, Ankita Sati; Callari, Maurizio; Batra, Rajbir Nath; Pogrebniak, Katherine; Sandoval, Jose; Cassidy, John W; Tufegdzic-Vidakovic, Ana; Sammut, Stephen-John; Jones, Linda; Provenzano, Elena; Baird, Richard; Eirew, Peter; Hadfield, James; Eldridge, Matthew; McLaren-Douglas, Anne; Barthorpe, Andrew; Lightfoot, Howard; O'Connor, Mark J; Gray, Joe; Cortes, Javier; Baselga, Jose; Marangoni, Elisabetta; Welm, Alana L; Aparicio, Samuel; Serra, Violeta; Garnett, Mathew J; Caldas, Carlos

    2016-09-22

    The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance. PMID:27641504

  4. CD44+/CD24- breast cancer cells exhibit phenotypic reversion in three-dimensional self-assembling peptide RADA16 nanofiber scaffold

    Directory of Open Access Journals (Sweden)

    Mi K

    2015-04-01

    Full Text Available Kun Mi,1 Zhihua Xing2 1Department of Biochemistry and Molecular Biology, Sichuan Cancer Hospital and Institute, 2Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China Background: Self-assembling peptide nanofiber scaffolds have been shown to be a ­permissive biological material for tissue repair, cell proliferation, differentiation, etc. Recently, a subpopulation (CD44+/CD24- of breast cancer cells has been reported to have stem/progenitor cell properties. The aim of this study was to investigate whether this subpopulation of cancer cells have different phenotypes in self-assembling COCH3-RADARADARADARADA-CONH2 (RADA16 peptide nanofiber scaffold compared with Matrigel® (BD Biosciences, Two Oak Park, Bedford, MA, USA and collagen I.Methods: CD44 and CD24 expression was determined by flow cytometry. Cell proliferation was measured by 5-bromo-2'-deoxyuridine assay and DNA content measurement. Immunostaining was used to indicate the morphologies of cells in three-dimensional (3D cultures of different scaffolds and the localization of β-catenin in the colonies. Western blot was used to determine the expression of signaling proteins. In vitro migration assay and inoculation into nude mice were used to evaluate invasion and tumorigenesis in vivo.Results: The breast cancer cell line MDA-MB-435S contained a high percentage (>99% of CD44+/CD24- cells, which exhibited phenotypic reversion in 3D RADA16 nanofiber scaffold compared with collagen I and Matrigel. The newly formed reverted acini-like colonies reassembled a basement membrane and reorganized their cytoskeletons. At the same time, cells cultured and embedded in RADA16 peptide scaffold exhibited growth arrest. Also, they exhibited different migration potential, which links their migration ability with their cellular morphology. Consistent with studies in vitro, the in vivo tumor

  5. Frondoside A inhibits human breast cancer cell survival, migration, invasion and the growth of breast tumor xenografts.

    Science.gov (United States)

    Al Marzouqi, Nadia; Iratni, Rabah; Nemmar, Abderrahim; Arafat, Kholoud; Ahmed Al Sultan, Mahmood; Yasin, Javed; Collin, Peter; Mester, Jan; Adrian, Thomas E; Attoub, Samir

    2011-10-01

    Breast cancer is a major challenge for pharmacologists to develop new drugs to improve the survival of cancer patients. Frondoside A is a triterpenoid glycoside isolated from the sea cucumber, Cucumaria frondosa. It has been demonstrated that Frondoside A inhibited the growth of pancreatic cancer cells in vitro and in vivo. We investigated the impact of Frondoside A on human breast cancer cell survival, migration and invasion in vitro, and on tumor growth in nude mice, using the human estrogen receptor-negative breast cancer cell line MDA-MB-231. The non-tumorigenic MCF10-A cell line derived from normal human mammary epithelium was used as control. Frondoside A (0.01-5 μM) decreased the viability of breast cancer cells in a concentration- and time-dependent manner, with 50%-effective concentration (EC50) of 2.5 μM at 24h. MCF10-A cells were more resistant to the cytotoxic effect of Frondoside A (EC50 superior to 5 μM at 24 h). In the MDA-MB-231 cells, Frondoside A effectively increased the sub-G1 (apoptotic) cell fraction through the activation of p53, and subsequently the caspases 9 and 3/7 cell death pathways. In addition, Frondoside A induced a concentration-dependent inhibition of MDA-MB-231 cell migration and invasion. In vivo, Frondoside A (100 μg/kg/dayi.p. for 24 days) strongly decreased the growth of MDA-MB-231 tumor xenografts in athymic mice, without manifest toxic side-effects. Moreover, we found that Frondoside A could enhance the killing of breast cancer cells induced by the chemotherapeutic agent paclitaxel. These findings identify Frondoside A as a promising novel therapeutic agent for breast cancer. PMID:21741966

  6. Evaluating mononuclear cells as nanoparticle delivery vehicles for the treatment of breast tumors

    Science.gov (United States)

    Murton, Jaclyn K.; Hu, Chelin; Ahmed, Mona M.; Hathaway, Helen J.; Nysus, Monique; Anderson Daniels, Tamara; Norenberg, Jeffrey P.; Adolphi, Natalie L.

    2015-08-01

    In breast cancer, certain types of circulating immune cells respond to long-range chemical signals from tumors by leaving the blood stream to actively infiltrate tumor tissue. The aim of this study was to evaluate whether immune cells could be used to deliver therapeutic nanoparticles into breast tumors in mice. Mononuclear splenocytes (MS) were harvested from donor mice, labeled with Indium-111, injected intravenously into immune-competent recipient mice (3 tumor-bearing and 3 control), and imaged longitudinally by SPECT/CT. For comparison, the biodistribution of bonemarrow derived macrophages (BMDM) in one pair of mice was also imaged. Quantitative analysis of the SPECT images demonstrates that, after 24 hours, the concentration of MS detected in mammary tumors is more than 3-fold higher than the concentration detected in normal mammary glands. The ratio of MS concentration in mammary tissue to MS concentration in non-target tissues (muscle, lung, heart, liver, spleen, and kidney) was enhanced in tumor-bearing mice (compared to controls), with statistical significance achieved for mammary/muscle (p<0.01), mammary/lung (p<0.05), and mammary/kidney (p<0.05). By contrast, BMDM did not show a different affinity for tumors relative to normal mammary tissue. MS were incubated with 100 nm red fluorescent nanoparticles, and flow cytometry demonstrated that ~35% of the MS population exhibited strong phagocytic uptake of the nanoparticles. After intravenous injection into tumor-bearing mice, fluorescence microscopy images of tumor sections show qualitatively that nanoparticle-loaded MS retain the ability to infiltrate mammary tumors. Taken together, these results suggest that MS carriers are capable of actively targeting therapeutic nanoparticles to breast tumors.

  7. Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression.

    Science.gov (United States)

    Ibrahim, Safaa A; Katara, Gajendra K; Kulshrestha, Arpita; Jaiswal, Mukesh K; Amin, Magdy A; Beaman, Kenneth D

    2015-10-20

    In invasive breast cancer, tumor associated neutrophils (TAN) represent a significant portion of the tumor mass and are associated with increased angiogenesis and metastasis. Identifying the regulatory factors that control TAN behavior will help in developing ideal immunotherapies. Vacuolar ATPases (V-ATPases), multi-subunit proton pumps, are highly expressed in metastatic breast cancer cells. A cleaved peptide from a2 isoform V-ATPase (a2NTD) has immunomodulatory role in tumor microenvironment. Here, we report for the first time the role of V-ATPase in neutrophils modulation. In invasive breast cancer cells, a2NTD was detected and a2V was highly expressed on the surface. Immunohistochemical analysis of invasive breast cancer tissues revealed that increased neutrophil recruitment and blood vessel density correlated with increased a2NTD levels. In order to determine the direct regulatory role of a2NTD on neutrophils, recombinant a2NTD was used for the treatment of neutrophils isolated from the peripheral blood of healthy volunteers. Neutrophils treated with a2NTD (a2Neuɸ) showed increased secretion of IL-1RA, IL-10, CCL-2 and IL-6 that are important mediators in cancer related inflammation. Moreover, a2Neuɸ exhibited an increased production of protumorigenic factors including IL-8, matrix metaloprotinase-9 and vascular endothelial growth factor. Further, functional characterization of a2Neuɸ revealed that a2Neuɸ derived products induce in vitro angiogenesis as well as increase the invasiveness of breast cancer cells. This study establishes the modulatory effect of breast cancer associated a2V on neutrophils, by the action of a2NTD, which has a positive impact on tumor progression, supporting that a2V can be a potential selective target for breast cancer therapy.

  8. Nectin-4 is a new histological and serological tumor associated marker for breast cancer

    Directory of Open Access Journals (Sweden)

    Sauvan Richard

    2007-05-01

    Full Text Available Abstract Introduction Breast cancer is a complex and heterogeneous disease at the molecular level. Evolution is difficult to predict according to classical histoclinical prognostic factors. Different studies highlight the importance of large-scale molecular expression analyses to improve taxonomy of breast cancer and prognostic classification. Identification of new molecular markers that refine this taxonomy and improve patient management is a priority in the field of breast cancer research. Nectins are cell adhesion molecules involved in the regulation of epithelial physiology. We present here Nectin-4/PVRL4 as a new histological and serological tumor associated marker for breast carcinoma. Methods Expression of Nectin-4 protein was measured on a panel of 78 primary cells and cell lines from different origins and 57 breast tumors by FACS analysis and immunohistochemistry (IHC, respectively. mRNA expression was measured by quantitative PCR. Serum Nectin-4 was detected by ELISA and compared with CEA and CA15.3 markers, on panels of 45 sera from healthy donors, 53 sera from patients with non-metastatic breast carcinoma (MBC at diagnosis, and 182 sera from patients with MBC. Distribution of histological/serological molecular markers and histoclinical parameters were compared using the standard Chi-2 test. Results Nectin-4 was not detected in normal breast epithelium. By contrast, Nectin-4 was expressed in 61% of ductal breast carcinoma vs 6% in lobular type. Expression of Nectin-4 strongly correlated with the basal-like markers EGFR, P53, and P-cadherin, and negatively correlated with the luminal-like markers ER, PR and GATA3. All but one ER/PR-negative tumors expressed Nectin-4. The detection of Nectin-4 in serum improves the follow-up of patients with MBC: the association CEA/CA15.3/Nectin-4 allowed to monitor 74% of these patients compared to 67% with the association CEA/CA15.3. Serum Nectin-4 is a marker of disease progression, and levels

  9. Prostate-specific membrane antigen expression in tumor-associated vasculature of breast cancers.

    Science.gov (United States)

    Wernicke, Alla Gabriella; Varma, Sonal; Greenwood, Eleni A; Christos, Paul J; Chao, K S Clifford; Liu, He; Bander, Neil H; Shin, Sandra J

    2014-06-01

    Prostate-specific membrane antigen (PSMA) has been found to be expressed in the tumor-associated neovasculature of multiple solid tumor types including breast cancers. However, thus far, the number of cases studied from some tumor types has been limited. In this study, we set out to assess PSMA expression in the tumor-associated vasculature associated with invasive breast carcinomas in a sizable cohort of patients. One hundred and six patients with AJCC stage 0-IV breast cancer were identified. Ninety-two of these patients had primary breast cancer [invasive breast carcinoma with or without co-existing ductal carcinoma in situ (DCIS) (74) or DCIS alone (18)]. In addition, 14 patients with breast cancer metastases to the brain were identified. Immunohistochemical staining for PSMA and CD31 was performed on parallel representative tumor sections in each case. Tumor-associated vascular endothelial cell PSMA immunoreactivity was semi-quantitatively assessed based on two parameters: overall percent of endothelial positivity and staining intensity. PSMA expression for tumor-associated vascular endothelial cells was scored 0 if there was no detectable PSMA expression, 1 if PSMA staining was detectable in 5-50%, and 2 if PSMA expression was positive in >50% of microvessels. CD 31 staining was concurrently reviewed to confirm the presence of vasculature in each case. Tumor-associated vasculature was PSMA-positive in 68/92 (74%) of primary breast cancers and in 14/14 (100%) of breast cancers metastatic to brain. PSMA was not detected in normal breast tissue or carcinoma cells. All but 2 cases (98%) showed absence of PSMA expression in normal breast tissue-associated vasculature. The 10-year overall survival was 88.7% (95% CI = 80.0%, 93.8%) in patients without brain metastases. When overall survival (OS) was stratified based on PSMA score group, patients with PSMA scores of 0, 1, and 2 had 10-year OS of 95.8%, 96.0%, and 79.7%, respectively (p = 0.12). When PSMA scores

  10. Loss of membranous VEGFR1 expression is associated with an adverse phenotype and shortened survival in breast cancer.

    Science.gov (United States)

    Lebok, Patrick; Huber, Julia; Burandt, Eike-Christian; Lebeau, Annette; Marx, Andreas Holger; Terracciano, Luigi; Heilenkötter, Uwe; Jänicke, Fritz; Müller, Volkmar; Paluchowski, Peter; Geist, Stefan; Wilke, Christian; Simon, Ronald; Sauter, Guido; Quaas, Alexander

    2016-08-01

    Angiogenesis is a key process in tumor growth and progression, which is controlled by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs). In order to better understand the prevalence and prognostic value of VEGFR1 expression in breast cancer, a tissue microarray containing >2,100 breast cancer specimens, with clinical follow‑up data, was analyzed by immunohistochemistry using an antibody directed against the membrane‑bound full‑length receptor protein. The results demonstrated that membranous VEGFR1 staining was detected in all (5 of 5) normal breast specimens. In carcinoma specimens, membranous staining was negative in 3.1%, weak in 6.3%, moderate in 10.9%, and strong in 79.7% of the 1,630 interpretable tissues. Strong staining was significantly associated with estrogen receptor and progesterone receptor expression, but was inversely associated with advanced tumor stage (P=0.0431), high Bloom-Richardson-Ellis Score for Breast Cancer grade and low Ki67 labeling index (both Ptamoxifen as the sole therapy (P=0.001). In conclusion, these data indicated that membrane‑bound VEGFR1 is frequently expressed in normal and cancerous breast epithelium. In addition, reduced or lost VEGFR1 expression may serve as a marker for poor prognosis in patients with breast cancer, who might not optimally benefit from endocrine therapy. PMID:27357606

  11. Renal cell carcinoma primary cultures maintain genomic and phenotypic profile of parental tumor tissues

    International Nuclear Information System (INIS)

    Clear cell renal cell carcinoma (ccRCC) is characterized by recurrent copy number alterations (CNAs) and loss of heterozygosity (LOH), which may have potential diagnostic and prognostic applications. Here, we explored whether ccRCC primary cultures, established from surgical tumor specimens, maintain the DNA profile of parental tumor tissues allowing a more confident CNAs and LOH discrimination with respect to the original tissues. We established a collection of 9 phenotypically well-characterized ccRCC primary cell cultures. Using the Affymetrix SNP array technology, we performed the genome-wide copy number (CN) profiling of both cultures and corresponding tumor tissues. Global concordance for each culture/tissue pair was assayed evaluating the correlations between whole-genome CN profiles and SNP allelic calls. CN analysis was performed using the two CNAG v3.0 and Partek software, and comparing results returned by two different algorithms (Hidden Markov Model and Genomic Segmentation). A very good overlap between the CNAs of each culture and corresponding tissue was observed. The finding, reinforced by high whole-genome CN correlations and SNP call concordances, provided evidence that each culture was derived from its corresponding tissue and maintained the genomic alterations of parental tumor. In addition, primary culture DNA profile remained stable for at least 3 weeks, till to third passage. These cultures showed a greater cell homogeneity and enrichment in tumor component than original tissues, thus enabling a better discrimination of CNAs and LOH. Especially for hemizygous deletions, primary cultures presented more evident CN losses, typically accompanied by LOH; differently, in original tissues the intensity of these deletions was weaken by normal cell contamination and LOH calls were missed. ccRCC primary cultures are a reliable in vitro model, well-reproducing original tumor genetics and phenotype, potentially useful for future functional approaches

  12. Population prevalence of hereditary breast cancer phenotypes and implementation of a genetic cancer risk assessment program in southern Brazil

    Directory of Open Access Journals (Sweden)

    Edenir I. Palmero

    2009-01-01

    Full Text Available In 2004, a population-based cohort (the Núcleo Mama Porto Alegre - NMPOA Cohort was started in Porto Alegre, southern Brazil and within that cohort, a hereditary breast cancer study was initiated, aiming to determine the prevalence of hereditary breast cancer phenotypes and evaluate acceptance of a genetic cancer risk assessment (GCRA program. Women from that cohort who reported a positive family history of cancer were referred to GCRA. Of the 9218 women enrolled, 1286 (13.9% reported a family history of cancer. Of the 902 women who attended GCRA, 55 (8% had an estimated lifetime risk of breast cancer ³ 20% and 214 (23.7% had pedigrees suggestive of a breast cancer predisposition syndrome; an unexpectedly high number of these fulfilled criteria for Li-Fraumeni-like syndrome (122 families, 66.7%. The overall prevalence of a hereditary breast cancer phenotype was 6.2% (95%CI: 5.67-6.65. These findings identified a problem of significant magnitude in the region and indicate that genetic cancer risk evaluation should be undertaken in a considerable proportion of the women from this community. The large proportion of women who attended GCRA (72.3% indicates that the program was well-accepted by the community, regardless of the potential cultural, economic and social barriers.

  13. Malignant phyllodes tumor of the breast presenting with hypoglycemia: a case report and literature review

    OpenAIRE

    Pacioles T; Seth R; Orellana C; John I; Panuganty V; Dhaliwal R

    2014-01-01

    Toni Pacioles,1 Rahul Seth,2,3 Cesar Orellana,3 Ivy John,4 Veera Panuganty,3 Ruban Dhaliwal3,5 1Department of Hematology and Oncology, Edwards Comprehensive Cancer Center, Marshall University, Huntington, WV, USA; 2Division of Hematology and Oncology, 3Department of Medicine, 4Department of Pathology, 5Division of Endocrinology, SUNY Upstate Medical University, Syracuse, NY, USA Abstract: Phyllodes tumors are rare fibroepithelial neoplasms that account for less than 1% of all breast tumors a...

  14. Genetic and epigenetic silencing of the beclin 1 gene in sporadic breast tumors

    International Nuclear Information System (INIS)

    Beclin 1, an important autophagy-related protein in human cells, is involved in cell death and cell survival. Beclin 1 mapped to human chromosome 17q21. It is widely expressed in normal mammary epithelial cells. Although down-regulated expression with mono-allelic deletions of beclin 1 gene was frequently observed in breast tumors, whether there was other regulatory mechanism of beclin 1 was to be investigated. We studied the expression of beclin 1 and explored the possible regulatory mechanisms on its expression in breast tumors. 20 pairs of tumors and adjacent normal tissues from patients with sporadic breast invasive ductal cancer (IDCs) were collected. The mRNA expression of beclin 1 was detected by real-time quantitative RT-PCR. Loss of heterozygosity (LOH) was determined by real-time quantitative PCR and microsatellite methods. The protein expression of beclin 1, p53, BRCA1 and BRCA2 was assessed by immunohistochemistry. CpG islands in 5' genomic region of beclin 1 gene were identified using MethylPrimer Program. Sodium bisulfite sequencing was used in examining the methylation status of each CpG island. Decreased beclin 1 mRNA expression was detected in 70% of the breast tumors, and the protein levels were co-related to the mRNA levels. Expression of beclin 1 mRNA was demonstrated to be much higher in the BRCA1 positive tumors than that in the BRCA1 negative ones. Loss of heterozygosity was detected in more than 45% of the breast tumors, and a dense cluster of CpG islands was found from the 5' end to the intron 2 of the beclin 1 gene. Methylation analysis showed that the promoter and the intron 2 of beclin 1 were aberrantly methylated in the tumors with decreased expression. These data indicated that LOH and aberrant DNA methylation might be the possible reasons of the decreased expression of beclin 1 in the breast tumors. The findings here shed some new light on the regulatory mechanisms of beclin 1 in breast cancer

  15. Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models

    Science.gov (United States)

    Liu, Huiping; Patel, Manishkumar R.; Prescher, Jennifer A.; Patsialou, Antonia; Qian, Dalong; Lin, Jiahui; Wen, Susanna; Chang, Ya-Fang; Bachmann, Michael H.; Shimono, Yohei; Dalerba, Piero; Adorno, Maddalena; Lobo, Neethan; Bueno, Janet; Dirbas, Frederick M.; Goswami, Sumanta; Somlo, George; Condeelis, John; Contag, Christopher H.; Gambhir, Sanjiv Sam; Clarke, Michael F.

    2010-01-01

    To examine the role of breast cancer stem cells (BCSCs) in metastasis, we generated human-in-mouse breast cancer orthotopic models using patient tumor specimens, labeled with optical reporter fusion genes. These models recapitulate human cancer features not captured with previous models, including spontaneous metastasis in particular, and provide a useful platform for studies of breast tumor initiation and progression. With noninvasive imaging approaches, as few as 10 cells of stably labeled BCSCs could be tracked in vivo, enabling studies of early tumor growth and spontaneous metastasis. These advances in BCSC imaging revealed that CD44+ cells from both primary tumors and lung metastases are highly enriched for tumor-initiating cells. Our metastatic cancer models, combined with noninvasive imaging techniques, constitute an integrated approach that could be applied to dissect the molecular mechanisms underlying the dissemination of metastatic CSCs (MCSCs) and to explore therapeutic strategies targeting MCSCs in general or to evaluate individual patient tumor cells and predict response to therapy. PMID:20921380

  16. Prevention of Distant Lung Metastasis After Photodynamic Therapy Application in a Breast Cancer Tumor Model.

    Science.gov (United States)

    Longo, João Paulo Figueiró; Muehlmann, Luis Alexandre; Miranda-Vilela, Ana Luisa; Portilho, Flávia Arruda; de Souza, Ludmilla Regina; Silva, Jaqueline Rodrigues; Lacava, Zulmira Guerrero Marques; Bocca, Anamelia Lorenzetti; Chaves, Sacha Braun; Azevedo, Ricardo Bentes

    2016-04-01

    The objective of this study was to investigate the activity of photodynamic therapy mediated by aluminum-chlorophthalocyanine contained in a polymeric nanostructured carrier composed by methyl vinyl ether-co-maleic anhydride (PVM/MA) against local subcutaneous breast cancer tumors and its effects against distant metastasis in a mouse tumor model. In our results, we observed a decrease in breast cancer tumor growth, prevention of distant lung metastases, and a significant increased survival in mice treated with photodynamic therapy. In addition to these results, we observed that tumor-bearing mice without treatment developed a significant extension of liver hematopoiesis that was significantly reduced in mice treated with photodynamic therapy. We hypothesized and showed that this reduction in (1) metastasis and (2) liver hematopoiesis may be related to the systemic activity of immature hematopoietic cells, specifically the myeloid-derived suppressor cells, which were suppressed in mice treated with photodynamic therapy. These cells produce a tolerogenic tumor environment that protects tumor tissues from immunological surveillance. Therefore, we suggest that photodynamic therapy could be employed in combination with other conventional therapies; such as surgery and radiotherapy, to improve the overall survival of patients diagnosed with breast cancer, as observed in our experimental resuIts. PMID:27301195

  17. Expression of the Circadian Clock Genes Pert, Per2 in Sporadic, Familial Breast Tumors

    Directory of Open Access Journals (Sweden)

    Sherry L. Winter

    2007-10-01

    Full Text Available There is a growing body of evidence implicating aberrant circadian clock expression in the development of cancer. Based on our initial experiments identifying a putative interaction between BRCA1, the clock proteins Per1, Per2, as well as the reported involvement of the circadian clock in the development of cancer, we have performed an expression analysis of the circadian clock genes Per1, Per2 in both sporadic, familial primary breast tumors, normal breast tissues using real-time polymerase chain reaction. Significantly decreased levels of Per1 were observed between sporadic tumors, normal samples (P < .00001, as well as a further significant decrease between familial, sporadic breast tumors for both Per1 (P < .00001, Per2 (P < .00001. Decreased Per1 was also associated with estrogen receptor negativity (53% vs 15%, P = .04. These results suggest a role for both Perl, Per2 in normal breast function, show for the first time that deregulation of the circadian clock may be an important factor in the development of familial breast cancer. Aberrant expression of circadian clock genes could have important consequences on the transactivation of downstream targets that control the cell cycle, on the ability of cells to undergo apoptosis, potentially promoting carcinogenesis.

  18. Pit-1 inhibits BRCA1 and sensitizes human breast tumors to cisplatin and vitamin D treatment

    Science.gov (United States)

    Seoane, Samuel; Arias, Efigenia; Sigueiro, Rita; Sendon-Lago, Juan; Martinez-Ordoñez, Anxo; Castelao, Esteban; Eiró, Noemí; Garcia-Caballero, Tomás; Macia, Manuel; Lopez-Lopez, Rafael; Maestro, Miguel; Vizoso, Francisco; Mouriño, Antonio; Perez-Fernandez, Roman

    2015-01-01

    The POU class 1 homeobox 1 (POU1F1, also known as Pit-1), pertaining to the Pit-Oct-Unc (POU) family of transcription factors, has been related to tumor growth and metastasis in breast. However, its role in response to breast cancer therapy is unknown. We found that Pit-1 down-regulated DNA-damage and repair genes, and specifically inhibited BRCA1 gene expression, sensitizing breast cancer cells to DNA-damage agents. Administration of 1α, 25-dihydroxy-3-epi-vitamin D3 (3-Epi, an endogenous low calcemic vitamin D metabolite) reduced Pit-1 expression, and synergized with cisplatin, thus, decreasing cell proliferation and apoptosis in vitro, and reducing tumor growth in vivo. In addition, fifteen primary cultures of human breast tumors showed significantly decreased proliferation when treated with 3-Epi+cisplatin, compared to cisplatin alone. This response positively correlated with Pit-1 levels. Our findings demonstrate that high levels of Pit-1 and reduced BRCA1 levels increase breast cancer cell susceptibility to 3-Epi+cisplatin therapy. PMID:25992773

  19. Mutational myriad of tumor suppressor p53 in Filipino breast cancer: results and perspectives in molecular pathology and epidemiology

    International Nuclear Information System (INIS)

    .093) as compared to late-presenting tumors (age of diagnosis ≥ 50 yrs.). Incidentally, exon 7 encodes the L3 domain of p53 that interacts with the DNA minor groove while forming a stabilized complex with zinc and its mutations are correlated with poor prognosis and resistance to radiotherapy and chemotherapy, specifically, but not limited to, doxorubicin and cisplatinum (Aas et al., 1997). Whereas, residency in rural or urban regions fail to elicit any significantly disparate mutational profile, women from Manila have slightly higher p53 mutation rates (43% of the total cases) when compared with those referred from provincial hospitals (33% of the total cases). Social class appears to affect p53 at exons 6 (p=0.050: biased to the 'high-income' bracket) and 8 (p=0.052): biased to the 'low-income' bracket). The mutational myriad of tumor suppressor p53 in Filipino breast cancer in this thesis underscores the important fine-structured biophysical correlates of the p53 core domain (exons 5-8) with that of the neoplasm's cell biology, pathology and epidemiology. In future studies, p53 analysis will be used to identify the underlying causes of the unusually high breast cancer incidence in Manila by offering a possible glimpse into the temporal interactions of genetics (WT, GST, NMT, MSH1/2, PTEN, BRCA1/2, ETC), hormonal and environmental cues leading to a tumor phenotype). (Author)

  20. Interplay of Stem Cell Characteristics, EMT, and Microtentacles in Circulating Breast Tumor Cells

    International Nuclear Information System (INIS)

    Metastasis, not the primary tumor, is responsible for the majority of breast cancer-related deaths. Emerging evidence indicates that breast cancer stem cells (CSCs) and the epithelial-to-mesenchymal transition (EMT) cooperate to produce circulating tumor cells (CTCs) that are highly competent for metastasis. CTCs with both CSC and EMT characteristics have recently been identified in the bloodstream of patients with metastatic disease. Breast CSCs have elevated tumorigenicity required for metastatic outgrowth, while EMT may promote CSC character and endows breast cancer cells with enhanced invasive and migratory potential. Both CSCs and EMT are associated with a more flexible cytoskeleton and with anoikis-resistance, which help breast carcinoma cells survive in circulation. Suspended breast carcinoma cells produce tubulin-based extensions of the plasma membrane, termed microtentacles (McTNs), which aid in reattachment. CSC and EMT-associated upregulation of intermediate filament vimentin and increased detyrosination of α-tubulin promote the formation of McTNs. The combined advantages of CSCs and EMT and their associated cytoskeletal alterations increase metastatic efficiency, but understanding the biology of these CTCs also presents new therapeutic targets to reduce metastasis

  1. Interplay of Stem Cell Characteristics, EMT, and Microtentacles in Circulating Breast Tumor Cells

    Energy Technology Data Exchange (ETDEWEB)

    Charpentier, Monica [Program in Molecular Medicine, University of Maryland School of Medicine, 655 W. Baltimore St., Bressler Bldg., Rm 10-20, Baltimore, MD 21201 (United States); Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, 655 W. Baltimore St., Bressler Bldg., Rm 10-29, Baltimore, MD 21201 (United States); Martin, Stuart, E-mail: ssmartin@som.umaryland.edu [Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, 655 W. Baltimore St., Bressler Bldg., Rm 10-29, Baltimore, MD 21201 (United States); Department of Physiology, University of Maryland School of Medicine, 655 W. Baltimore St., Bressler Bldg., Rm 10-29, Baltimore, MD 21201 (United States)

    2013-11-14

    Metastasis, not the primary tumor, is responsible for the majority of breast cancer-related deaths. Emerging evidence indicates that breast cancer stem cells (CSCs) and the epithelial-to-mesenchymal transition (EMT) cooperate to produce circulating tumor cells (CTCs) that are highly competent for metastasis. CTCs with both CSC and EMT characteristics have recently been identified in the bloodstream of patients with metastatic disease. Breast CSCs have elevated tumorigenicity required for metastatic outgrowth, while EMT may promote CSC character and endows breast cancer cells with enhanced invasive and migratory potential. Both CSCs and EMT are associated with a more flexible cytoskeleton and with anoikis-resistance, which help breast carcinoma cells survive in circulation. Suspended breast carcinoma cells produce tubulin-based extensions of the plasma membrane, termed microtentacles (McTNs), which aid in reattachment. CSC and EMT-associated upregulation of intermediate filament vimentin and increased detyrosination of α-tubulin promote the formation of McTNs. The combined advantages of CSCs and EMT and their associated cytoskeletal alterations increase metastatic efficiency, but understanding the biology of these CTCs also presents new therapeutic targets to reduce metastasis.

  2. Application of imaging mass spectrometry for the molecular diagnosis of human breast tumors.

    Science.gov (United States)

    Mao, Xinxin; He, Jiuming; Li, Tiegang; Lu, Zhaohui; Sun, Jian; Meng, Yunxiao; Abliz, Zeper; Chen, Jie

    2016-01-01

    Distinguishing breast invasive ductal carcinoma (IDC) and breast ductal carcinoma in situ (DCIS) is a key step in breast surgery, especially to determine whether DCIS is associated with tumor cell micro-invasion. However, there is currently no reliable method to obtain molecular information for breast tumor analysis during surgery. Here, we present a novel air flow-assisted ionization (AFAI) mass spectrometry imaging method that can be used in ambient environments to differentiate breast cancer by analyzing lipids. In this study, we demonstrate that various subtypes and histological grades of IDC and DCIS can be discriminated using AFAI-MSI: phospholipids were more abundant in IDC than in DCIS, whereas fatty acids were more abundant in DCIS than in IDC. The classification of specimens in the subtype and grade validation sets showed 100% and 78.6% agreement with the histopathological diagnosis, respectively. Our work shows the rapid classification of breast cancer utilizing AFAI-MSI. This work suggests that this method could be developed to provide surgeons with nearly real-time information to guide surgical resections. PMID:26868906

  3. Expression of Fas (CD95/APO-1) Ligand by Human Breast Cancers: Significance for Tumor Immune Privilege

    OpenAIRE

    O’Connell, Joe; Bennett, Michael W; O’Sullivan, Gerald C.; O’Callaghan, Jim; Collins, J. Kevin; Shanahan, Fergus

    1999-01-01

    Breast cancers have been shown to elicit tumor-specific immune responses. As in other types of cancer, the antitumor immune response fails to contain breast tumor growth, and a reduction in both the quantity and cytotoxic effectiveness of tumor-infiltrating lymphocytes (TILs) is associated with a poorer prognosis. Fas ligand (FasL) induces apoptotic death of activated lymphocytes that express its cell surface receptor, FasR (CD95/APO-1). FasL-mediated apoptosis of acti...

  4. Non-invasive thermal IR detection of breast tumor development in vivo

    Science.gov (United States)

    Case, Jason R.; Young, Madison A.; Dréau, D.; Trammell, Susan R.

    2015-03-01

    Lumpectomy coupled with radiation therapy and/or chemotherapy comprises the treatment of breast cancer for many patients. We are developing an enhanced thermal IR imaging technique that can be used in real-time to guide tissue excision during a lumpectomy. This novel enhanced thermal imaging method is a combination of IR imaging (8- 10 μm) and selective heating of blood (~0.5 °C) relative to surrounding water-rich tissue using LED sources at low powers. Post-acquisition processing of these images highlights temporal changes in temperature and is sensitive to the presence of vascular structures. In this study, fluorescent and enhanced thermal imaging modalities were used to estimate breast cancer tumor volumes as a function of time in 19 murine subjects over a 30-day study period. Tumor volumes calculated from fluorescent imaging follow an exponential growth curve for the first 22 days of the study. Cell necrosis affected the tumor volume estimates based on the fluorescent images after Day 22. The tumor volumes estimated from enhanced thermal imaging show exponential growth over the entire study period. A strong correlation was found between tumor volumes estimated using fluorescent imaging and the enhanced IR images, indicating that enhanced thermal imaging is capable monitoring tumor growth. Further, the enhanced IR images reveal a corona of bright emission along the edges of the tumor masses. This novel IR technique could be used to estimate tumor margins in real-time during surgical procedures.

  5. A comparative study of four serological tumor markers for the detection of breast cancer.

    Science.gov (United States)

    Clinton, Shawn R; Beason, Kevin L; Bryant, Sabrina; Johnson, James T; Jackson, Margaret; Wilson, Cynthia; Holifield, Kay; Vincent, Charlton; Hall, Margot

    2003-01-01

    Breast cancer is currently the third most common cause of cancer in the world. Circulating tumor antigens are often used as a minimally invasive tool for noting breast cancer progression. The objective of this study was to compare four tumor antigens (CA 15-3, CA 27.29, alpha-fetoprotein [AFP], and carcinoembryonic antigen [CEA]) for their diagnostic efficacy in breast cancer patients. It was hypothesized that CA 15-3 would proved to be superior to CA 27.29, CEA, and AFP in assay performance. Tumor marker assays were performed according to the manufacturers' directions. Assays used in this study were CA 15-3 and CA 27.29 (Fujirebio Diagnostics/Centocor Inc.), AFP (Abbott Inc.), and CEA (Hybritech Inc.). A total of 554 patient samples were obtained from an area hospital, plus 200 healthy adult samples which were used for the determination of normal reference intervals. The patients included patients with no disease (184), with non-malignant disease (11), with breast cancer (87), and with other types of cancer (272). Diagnostic percent sensitivities for each marker were: CA 15-3 (63%), CA 27.29 (39%), CEA (22%), and AFP (22%). Diagnostic specificities for each marker were comparable, ranging from 80-88%. Analytical parameters were evaluated for the assays and compared favorably. We concluded that CA 15-3 was the best tumor antigen for use as a diagnostic aid and monitoring agent.

  6. Annexin A1 expression in a pooled breast cancer series : Association with tumor subtypes and prognosis

    NARCIS (Netherlands)

    Sobral-Leite, Marcelo; Wesseling, Jelle; Smit, Vincent T H B M; Nevanlinna, Heli; van Miltenburg, Martine H.; Sanders, Joyce; Hofland, Ingrid; Blows, Fiona M.; Coulson, Penny; Patrycja, Gazinska; Schellens, Jan H M; Fagerholm, Rainer; Heikkilä, Päivi; Aittomäki, Kristiina; Blomqvist, Carl; Provenzano, Elena; Ali, Hamid Raza; Figueroa, Jonine; Sherman, Mark; Lissowska, Jolanta; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli Matti; Hartikainen, Jaana M.; Phillips, Kelly Anne; Couch, Fergus J.; Olson, Janet E.; Vachon, Celine; Visscher, Daniel; Brenner, Hermann; Butterbach, Katja; Arndt, Volker; Holleczek, Bernd; Hooning, Maartje J.; Hollestelle, Antoinette; Martens, John W M; van Deurzen, Carolien H M; van de Water, Bob; Broeks, Annegien; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Easton, Douglas F.; Pharoah, Paul D P; García-Closas, Montserrat; de Graauw, Marjo; Schmidt, Marjanka K.; Aghmesheh, Morteza; Amor, David; Andrews, Lesley; Antill, Yoland; Armitage, Shane; Arnold, Leanne; Balleine, Rosemary; Bankier, Agnes; Bastick, Patti; Beesley, Jonathan; Beilby, John; Bennett, Barbara; Bennett, Ian; Berry, Geoffrey; Blackburn, Anneke; Bogwitz, Michael; Brennan, Meagan; Brown, Melissa; Buckley, Michael; Burgess, Matthew; Burke, Jo; Butow, Phyllis; Byron, Keith; Callen, David; Campbell, Ian; Chauhan, Deepa; Chauhan, Manisha; Christian, Alice; Clarke, Christine; Colley, Alison; Cotton, Dick; Crook, Ashley; Cui, James; Culling, Bronwyn; Cummings, Margaret; Dawson, Sarah Jane; deFazio, Anna; Delatycki, Martin; Dickson, Rebecca; Dixon, Joanne; Dobrovic, Alexander; Dudding, Tracy; Edkins, Ted; Edwards, Stacey; Eisenbruch, Maurice; Farshid, Gelareh; Fawcett, Susan; Fellows, Andrew; Fenton, Georgina; Field, Michael; Firgaira, Frank; Flanagan, James; Fleming, Jean; Fong, Peter; Forbes, John; Fox, Stephen; French, Juliet; Friedlander, Michael; Gaff, Clara; Gardner, Mac; Gattas, Mike; George, Peter; Giles, Graham; Gill, Grantley; Goldblatt, Jack; Greening, Sian; Grist, Scott; Haan, Eric; Hardie, Kate; Harris, Marion; Hart, Stewart; Hayward, Nick; Healey, Sue; Heiniger, Louise; Hopper, John; Humphrey, Evelyn; Hunt, Clare; James, Paul; Jenkins, Mark; Jones, Alison; Kefford, Rick; Kidd, Alexa; Kiely, Belinda; Kirk, Judy; Koehler, Jessica; Kollias, James; Kovalenko, Serguei; Lakhani, Sunil; Leaming, Amanda; Leary, Jennifer; Lim, Jacqueline; Lindeman, Geoff; Lipton, Lara; Lobb, Liz; Mann, Graham; Marsh, Deborah; McLachlan, Sue Anne; Meiser, Bettina; Meldrum, Cliff; Milne, Roger; Mitchell, Gillian; Newman, Beth; Niedermayr, Eveline; Nightingale, Sophie; O'Connell, Shona; O'Loughlin, Imelda; Osborne, Richard; Pachter, Nick; Patterson, Briony; Peters, Lester; Phillips, Kelly; Price, Melanie; Purser, Lynne; Reeve, Tony; Reeve, Jeanne; Richards, Robert; Rickard, Edwina; Robinson, Bridget; Rudzki, Barney; Saleh, Mona; Salisbury, Elizabeth; Sambrook, Joe; Saunders, Christobel; Saunus, Jodi; Sayer, Robyn; Scott, Elizabeth; Scott, Rodney; Scott, Clare; Seshadri, Ram; Sexton, Adrienne; Sharma, Raghwa; Shelling, Andrew; Simpson, Peter; Southey, Melissa; Spurdle, Amanda; Suthers, Graeme; Sykes, Pamela; Tassell, Margaret; Taylor, Donna; Taylor, Jessica; Thierry, Benjamin; Thomas, Susan; Thompson, Ella; Thorne, Heather; Townshend, Sharron; Trainer, Alison; Tran, Lan; Tucker, Kathy; Tyler, Janet; Visvader, Jane; Walker, Logan; Walpole, Ian; Ward, Robin; Waring, Paul; Warner, Bev; Warren, Graham; Williams, Rachael; Wilson, Judy; Winship, Ingrid; Wu, Kathy; Young, Mary Ann; Bowtell, D.; Green, A.; Webb, P.; de Fazio, A.; Gertig, D.

    2015-01-01

    Background: Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germl

  7. Tumor regression of multiple bone metastases from breast cancer after administration of strontium-89 chloride (Metastron)

    International Nuclear Information System (INIS)

    We report a case of tumor regression of multiple bone metastases from breast carcinoma after administration of strontium-89 chloride. This case suggests that strontium-89 chloride can not only relieve bone metastases pain not responsive to analgesics, but may also have a tumoricidal effect on bone metastases

  8. FGFR2 intronic SNPs and breast cancer risk; associations with tumor characteristics and interactions with exogenous exposures and other known breast cancer risk factors

    OpenAIRE

    Marian, Catalin; Ochs-Balcom, Heather M; Nie, Jing; Kallakury, Bhaskar V.; Ambrosone, Christine B; Trevisan, Maurizio; Edge, Stephen; Shields, Peter G.; Freudenheim, Jo L.

    2010-01-01

    Recent genome-wide association studies have revealed several new candidate genes for breast cancer, including FGFR2. The associations were also replicated in several other independent studies. The next important step is to study whether these common variants interact with known breast cancer risk factors, exogenous exposures, and tumor characteristics. In a population-based case-control study of 1170 breast cancer cases and 2115 controls, we examined genetic associations of four intronic FGFR...

  9. Validation of a Web-Based Tool to Predict the Ipsilateral Breast Tumor Recurrence (IBTR! 2.0) after Breast-Conserving Therapy for Korean Patients

    OpenAIRE

    Jung, Seung Pil; Hur, Sung Mo; Lee, Se Kyung; Kim, Sangmin; Choi, Min-Young; Bae, Soo Youn; Kim, Jiyoung; Kim, Min Kuk; Kil, Won Ho; Choe, Jun-Ho; Kim, Jung-Han; Kim, Jee Soo; Nam, Seok Jin; Bae, Jeoung Won; Lee, Jeong Eon

    2013-01-01

    Purpose IBTR! 2.0 is a web-based nomogram that predicts the 10-year ipsilateral breast tumor recurrence (IBTR) rate after breast-conserving therapy. We validated this nomogram in Korean patients. Methods The nomogram was tested for 520 Korean patients, who underwent breast-conserving surgery followed by radiation therapy. Predicted and observed 10-year outcomes were compared for the entire cohort and for each group, predefined by nomogram-predicted risks: group 1, 10%. Results In overall pati...

  10. Human Papillomavirus (HPV) in breast tumors: prevalence in a group of Mexican patients

    International Nuclear Information System (INIS)

    Breast cancer is one of the main health problems in developed countries, occupying first place in mortality in women. It is well-known that there are risk factors associated with breast cancer development. Nonetheless, in 50–80% of cases known risk factors have not been identified, this has generated the attempt to identify new factors related with this neoplasia as viral infections. The aim of this work is investigate the prevalence of HPV DNA in patients with breast lesions at the Instituto Nacional de Cancerologia de Mexico. Fifty-one cases of breast cancer were selected from the files of the institute and compared by age and tumor size with 43 cases of non malignant breast lesions (fibroadenoma, fibrocystic disease and phyllodes tumor). Paraffin embedded specimens were selected, HPV DNA was analyzed by polymerase chain reaction (PCR) and sequenced for different types of HPV in case of positivity for HPV-DNA. Descriptive analysis of clinical and pathological variables was performed and comparisons between positive and negative cases was done. All patients were mexican, mean age was 53.3, median age of menarche was 13 and median tumor size 9 cms. Cervicovaginal cytology was performed to all patients, 1 patient (1.9%) of cancer group had HPV and none in the other group, no cases were diagnosed with cervical dysplasia. In the group of carcinomas 36 (70.5%) were negative and 15 (29.4%) were positive to HPV-DNA, 10(66.6%) were positive for HPV 16, 3(20%) for HPV 18, two cases (13.4%) were positive for both. In the group of benign conditions all were negative to HPV-DNA. Presence of HPV in breast cancer in our group of cases is high in comparison to other authors; larger numbers of cases need to be analyzed in order to establish the exact role of this virus in the pathogenesis of breast cancer

  11. Human Papillomavirus (HPV in breast tumors: prevalence in a group of Mexican patients

    Directory of Open Access Journals (Sweden)

    Cetina Lucely

    2009-01-01

    Full Text Available Abstract Background Breast cancer is one of the main health problems in developed countries, occupying first place in mortality in women. It is well-known that there are risk factors associated with breast cancer development. Nonetheless, in 50–80% of cases known risk factors have not been identified, this has generated the attempt to identify new factors related with this neoplasia as viral infections. The aim of this work is investigate the prevalence of HPV DNA in patients with breast lesions at the Instituto Nacional de Cancerologia de Mexico. Methods Fifty-one cases of breast cancer were selected from the files of the institute and compared by age and tumor size with 43 cases of non malignant breast lesions (fibroadenoma, fibrocystic disease and phyllodes tumor. Paraffin embedded specimens were selected, HPV DNA was analyzed by polymerase chain reaction (PCR and sequenced for different types of HPV in case of positivity for HPV-DNA. Descriptive analysis of clinical and pathological variables was performed and comparisons between positive and negative cases was done. Results All patients were mexican, mean age was 53.3, median age of menarche was 13 and median tumor size 9 cms. Cervicovaginal cytology was performed to all patients, 1 patient (1.9% of cancer group had HPV and none in the other group, no cases were diagnosed with cervical dysplasia. In the group of carcinomas 36 (70.5% were negative and 15 (29.4% were positive to HPV-DNA, 10(66.6% were positive for HPV 16, 3(20% for HPV 18, two cases (13.4% were positive for both. In the group of benign conditions all were negative to HPV-DNA. Conclusion Presence of HPV in breast cancer in our group of cases is high in comparison to other authors; larger numbers of cases need to be analyzed in order to establish the exact role of this virus in the pathogenesis of breast cancer.

  12. Lack of association between level of Plasminogen Activator Inhibitor-1 and estimates of tumor angiogenesis in early breast cancer

    DEFF Research Database (Denmark)

    Offersen, Birgitte Vrou; Riisbro, Rikke; Knoop, Ann;

    2007-01-01

    Plasminogen Activator Inhibitor type-1 (PAI-1) is involved in tumor invasion and progression. High levels of PAI-1 are associated with poor prognosis in breast cancer, and PAI-1 has been shown to play a role in angiogenic processes. Since estimates of tumor angiogenesis may predict poor prognosis...... we studied the relationship between PAI-1 and estimates of angiogenesis in breast cancer. Tumor tissue specimens from 438 breast cancer patients were included. Median follow-up was 10.3 years. Protein levels of PAI-1 were measured using an ELISA. Angiogenesis scores were performed using a Chalkley.......009) were independent markers of death from breast cancer. This study confirms high PAI-1 or high Chalkley counts as markers of poor prognosis in breast cancer patients, and suggests that the prognostic impact of PAI-1 is independent of its supposed involvement in tumor angiogenesis. Udgivelsesdato: 2007...

  13. Steroid Tumor Environment in Male and Female Mice Model of Canine and Human Inflammatory Breast Cancer

    Directory of Open Access Journals (Sweden)

    Sara Caceres

    2016-01-01

    Full Text Available Canine inflammatory mammary cancer (IMC shares clinical and histopathological characteristics with human inflammatory breast cancer (IBC and has been proposed as a good model for studying the human disease. The aim of this study was to evaluate the capacity of female and male mice to reproduce IMC and IBC tumors and identify the hormonal tumor environment. To perform the study sixty 6–8-week-old male and female mice were inoculated subcutaneously with a suspension of 106 IPC-366 and SUM149 cells. Tumors and serum were collected and used for hormonal analysis. Results revealed that IPC-366 reproduced tumors in 90% of males inoculated after 2 weeks compared with 100% of females that reproduced tumor at the same time. SUM149 reproduced tumors in 40% of males instead of 80% of females that reproduced tumors after 4 weeks. Both cell lines produce distant metastasis in lungs being higher than the metastatic rates in females. EIA analysis revealed that male tumors had higher T and SO4E1 concentrations compared to female tumors. Serum steroid levels were lower than those found in tumors. In conclusion, IBC and IMC male mouse model is useful as a tool for IBC research and those circulating estrogens and intratumoral hormonal levels are crucial in the development and progression of tumors.

  14. Steroid Tumor Environment in Male and Female Mice Model of Canine and Human Inflammatory Breast Cancer.

    Science.gov (United States)

    Caceres, Sara; Peña, Laura; Silvan, Gema; Illera, Maria J; Woodward, Wendy A; Reuben, James M; Illera, Juan C

    2016-01-01

    Canine inflammatory mammary cancer (IMC) shares clinical and histopathological characteristics with human inflammatory breast cancer (IBC) and has been proposed as a good model for studying the human disease. The aim of this study was to evaluate the capacity of female and male mice to reproduce IMC and IBC tumors and identify the hormonal tumor environment. To perform the study sixty 6-8-week-old male and female mice were inoculated subcutaneously with a suspension of 10(6)IPC-366 and SUM149 cells. Tumors and serum were collected and used for hormonal analysis. Results revealed that IPC-366 reproduced tumors in 90% of males inoculated after 2 weeks compared with 100% of females that reproduced tumor at the same time. SUM149 reproduced tumors in 40% of males instead of 80% of females that reproduced tumors after 4 weeks. Both cell lines produce distant metastasis in lungs being higher than the metastatic rates in females. EIA analysis revealed that male tumors had higher T and SO4E1 concentrations compared to female tumors. Serum steroid levels were lower than those found in tumors. In conclusion, IBC and IMC male mouse model is useful as a tool for IBC research and those circulating estrogens and intratumoral hormonal levels are crucial in the development and progression of tumors. PMID:27195300

  15. A novel thermal treatment modality for controlling breast tumor growth and progression.

    Science.gov (United States)

    Xie, Yifan; Liu, Ping; Xu, Lisa X

    2012-01-01

    The new concept of keeping primary tumor under control in situ to suppress distant foci sheds light on the novel treatment of metastatic tumor. Hyperthermia is considered as one of the means for controlling tumor growth. In this study, a novel thermal modality was built to introduce hyperthermia effect on tumor to suppress its growth and progression using 4T1 murine mammary carcinoma, a common animal model of metastatic breast cancer. A mildly raised temperature (i.e.39°C) was imposed on the skin surface of the implanted tumor using a thermal heating pad. Periodic heating (12 hours per day) was carried out for 3 days, 7 days, 14 days, and 21 days, respectively. The tumor growth rate was found significantly decreased in comparison to the control without hyperthermia. Biological evidences associated with tumor angiogenesis and metastasis were examined using histological analyses. Accordingly, the effect of mild hyperthermia on immune cell infiltration into tumors was also investigated. It was demonstrated that a delayed tumor growth and malignancy progression was achieved by mediating tumor cell apoptosis, vascular injury, degrading metastasis potential and as well as inhibiting the immunosuppressive cell myeloid derived suppressor cells (MDSCs) recruitment. Further mechanistic studies will be performed to explore the quantitative relationship between tumor progression and thermal dose in the near future. PMID:23367225

  16. Study of thermal effect on breast tumor metabolism and growth using metabonomics.

    Science.gov (United States)

    Dai, Guangchen; Jia, Wei; Hu, Xiaofang; Xu, Lisa X

    2013-01-01

    In this study, the biological effects of long-term mild hyperthermia treatment on tumor metabolism and growth were investigated using 4T1 murine mammary carcinoma, a common animal model of metastatic breast cancer. Periodic thermal treatment (12 hours per day) was applied to tumors and carried out for 3 days, 7 days, 14 days, and 21 days, respectively. The metabolites of tumor tissues were analyzed by gas chromatography-mass spectrometry. The results showed that the growth rate of thermally treated tumors was inversely related to the abundance of long chain fatty acids and acyl glycerols identified in tumor tissues. In the first two weeks, the growth of thermally treated tumors was significantly inhibited, while there was an obvious accumulation of long chain fatty acids and acyl glycerols in tumor tissues. In the third week, the thermally treated tumors adapted to the thermal environment and started to regrow, while the abundance of long chain fatty acids and acyl glycerols decreased in the tumor tissues. These observations suggested that the blockade of long chain fatty acid synthesis during mild hyperthermia treatment of tumors could improve the long-term treatment effect by limiting the supply of substance and energy for tumor re-growth. PMID:24110083

  17. Proteomic profiling of 13 paired ductal infiltrating breast carcinomas and non-tumoral adjacent counterparts.

    Science.gov (United States)

    Pucci-Minafra, Ida; Cancemi, Patrizia; Marabeti, Maria Rita; Albanese, Nadia Ninfa; Di Cara, Gianluca; Taormina, Pietra; Marrazzo, Antonio

    2007-01-01

    According to recent statistics, breast cancer remains one of the leading causes of death among women in Western countries. Breast cancer is a complex and heterogeneous disease, presently classified into several subtypes according to their cellular origin. Among breast cancer histotypes, infiltrating ductal carcinoma represents the most common and potentially aggressive form. Despite the current progress achieved in early cancer detection and treatment, including the new generation of molecular therapies, there is still need for identification of multiparametric biomarkers capable of discriminating between cancer subtypes and predicting cancer progression for personalized therapies. One established step in this direction is the proteomic strategy, expected to provide enough information on breast cancer profiling. To this aim, in the present study we analyzed 13 breast cancer tissues and their matched non-tumoral tissues by 2-DE. Collectively, we identified 51 protein spots, corresponding to 34 differentially expressed proteins, which may represent promising candidate biomarkers for molecular-based diagnosis of breast cancer and for pattern discovery. The relevance of these proteins as factors contributing to breast carcinogenesis is discussed. PMID:21136615

  18. Towards intraoperative assessment of tumor margins in breast surgery using optical coherence elastography (Conference Presentation)

    Science.gov (United States)

    Kennedy, Brendan F.; Wijesinghe, Philip; Allen, Wes M.; Chin, Lixin; Latham, Bruce; Saunders, Christobel M.; Sampson, David D.

    2016-03-01

    Surgical excision of tumor is a critical factor in the management of breast cancer. The most common surgical procedure is breast-conserving surgery. The surgeon's goal is to remove the tumor and a rim of healthy tissue surrounding the tumor: the surgical margin. A major issue in breast-conserving surgery is the absence of a reliable tool to guide the surgeon in intraoperatively assessing the margin. A number of techniques have been proposed; however, the re-excision rate remains high and has been reported to be in the range 30-60%. New tools are needed to address this issue. Optical coherence elastography (OCE) shows promise as a tool for intraoperative tumor margin assessment in breast-conserving surgery. Further advances towards clinical translation are limited by long scan times and small fields of view. In particular, scanning over sufficient areas to assess the entire margin in an intraoperative timeframe has not been shown to be feasible. Here, we present a protocol allowing ~75% of the surgical margins to be assessed within 30 minutes. To achieve this, we have incorporated a 65 mm-diameter (internal), wide-aperture annular piezoelectric transducer, allowing the entire surface of the excised tumor mass to be automatically imaged in an OCT mosaic comprised of 10 × 10 mm tiles. As OCT is effective in identifying adipose tissue, our protocol uses the wide-field OCT to selectively guide subsequent local OCE scanning to regions of solid tissue which often present low contrast in OCT images. We present promising examples from freshly excised human breast tissue.

  19. The molecular portraits of breast tumors are conserved across microarray platforms

    Directory of Open Access Journals (Sweden)

    Perreard Laurent

    2006-04-01

    Full Text Available Abstract Background Validation of a novel gene expression signature in independent data sets is a critical step in the development of a clinically useful test for cancer patient risk-stratification. However, validation is often unconvincing because the size of the test set is typically small. To overcome this problem we used publicly available breast cancer gene expression data sets and a novel approach to data fusion, in order to validate a new breast tumor intrinsic list. Results A 105-tumor training set containing 26 sample pairs was used to derive a new breast tumor intrinsic gene list. This intrinsic list contained 1300 genes and a proliferation signature that was not present in previous breast intrinsic gene sets. We tested this list as a survival predictor on a data set of 311 tumors compiled from three independent microarray studies that were fused into a single data set using Distance Weighted Discrimination. When the new intrinsic gene set was used to hierarchically cluster this combined test set, tumors were grouped into LumA, LumB, Basal-like, HER2+/ER-, and Normal Breast-like tumor subtypes that we demonstrated in previous datasets. These subtypes were associated with significant differences in Relapse-Free and Overall Survival. Multivariate Cox analysis of the combined test set showed that the intrinsic subtype classifications added significant prognostic information that was independent of standard clinical predictors. From the combined test set, we developed an objective and unchanging classifier based upon five intrinsic subtype mean expression profiles (i.e. centroids, which is designed for single sample predictions (SSP. The SSP approach was applied to two additional independent data sets and consistently predicted survival in both systemically treated and untreated patient groups. Conclusion This study validates the "breast tumor intrinsic" subtype classification as an objective means of tumor classification that should be

  20. Occurrence of thymosin beta4 in human breast cancer cells and in other cell types of the tumor microenvironment

    DEFF Research Database (Denmark)

    Larsson, L.-I.; Holck, Susanne

    2007-01-01

    that there is a considerable heterogeneity in the cellular distribution of thymosin beta4 in breast cancer. In most tumors examined, cancer cells showed low or intermediate reactivity for thymosin beta4, whereas leukocytes and macrophages showed intense reactivity. In addition, endothelial cells showed variable reactivity...... the tumor microenvironment produce thymosin beta4 and that such expression varies from tumor to tumor. Such heterogeneity of expression should be taken into account when the role of thymosin beta4 in tumor biology is assessed....

  1. The dissociation of tumor-induced weight loss from hypoglycemia in a transplantable pluripotent rat islet tumor results in the segregation of stable alpha- and beta-cell tumor phenotypes

    DEFF Research Database (Denmark)

    Madsen, O D; Karlsen, C; Nielsen, E;

    1993-01-01

    that of starved rats until death results from cachexia. After tumor resection, animals immediately resume normal feeding behavior. Comparative studies of hormone release and mRNA content in anorectic lines, MSL-G-AN and NHI-5B-AN, vs. those in the insulinoma line, MSL-G2-IN, revealed selective glucagon gene...... expression in both of the anorectic tumors, whereas insulin and islet amyloid polypeptide gene expression were confined to the insulinoma. Both tumor phenotypes produced cholecystokinin and gastrin in variable small amounts, making it unlikely that these hormones contribute to the anorectic phenotype. Tumor...

  2. Epigenetic regulation of multiple tumor-related genes leads to suppression of breast tumorigenesis by dietary genistein.

    Directory of Open Access Journals (Sweden)

    Yuanyuan Li

    Full Text Available Breast cancer is one of the most lethal diseases in women; however, the precise etiological factors are still not clear. Genistein (GE, a natural isoflavone found in soybean products, is believed to be a potent chemopreventive agent for breast cancer. One of the most important mechanisms for GE inhibition of breast cancer may involve its potential in impacting epigenetic processes allowing reversal of aberrant epigenetic events during breast tumorigenesis. To investigate epigenetic regulation for GE impedance of breast tumorigenesis, we monitored epigenetic alterations of several key tumor-related genes in an established breast cancer transformation system. Our results show that GE significantly inhibited cell growth in a dose-dependent manner in precancerous breast cells and breast cancer cells, whereas it exhibited little effect on normal human mammary epithelial cells. Furthermore, GE treatment increased expression of two crucial tumor suppressor genes, p21(WAF1 (p21 and p16(INK4a (p16, although it decreased expression of two tumor promoting genes, BMI1 and c-MYC. GE treatment led to alterations of histone modifications in the promoters of p21 and p16 as well as the binding ability of the c-MYC-BMI1 complex to the p16 promoter contributing to GE-induced epigenetic activation of these tumor suppressor genes. In addition, an orally-fed GE diet prevented breast tumorigenesis and inhibited breast cancer development in breast cancer mice xenografts. Our results suggest that genistein may repress early breast tumorigenesis by epigenetic regulation of p21 and p16 by impacting histone modifications as well as the BMI1-c-MYC complex recruitment to the regulatory region in the promoters of these genes. These studies will facilitate more effective use of soybean product in breast cancer prevention and also help elucidate the mechanisms during the process of early breast tumorigenesis.

  3. PDK1 promotes tumor growth and metastasis in a spontaneous breast cancer model.

    Science.gov (United States)

    Du, J; Yang, M; Chen, S; Li, D; Chang, Z; Dong, Z

    2016-06-23

    Because malignant cells have altered, usually accelerated, energy consumption, targeting metabolic signaling represents a prevailing strategy for tumor therapy. Phosphoinositide-dependent kinase 1 (PDK1) is a proximal signaling molecule of phosphatidylinositol 3-kinase, which is required for metabolic activation. It is still lacking definitive evidence whether inactivation of PDK1 can overwhelm tumorigenesis in vivo. Herein we revealed that mammary-specific ablation of PDK1 could delay tumor initiation, progression and metastasis in a spontaneous mouse tumor model. We also demonstrated that inducible deletion of PDK1 could noticeably shrink the growing breast tumors. However, a small portion of PDK1-deficient tumorigenic cells eventually established tumor lesions, albeit at a relatively later phase, most likely owing to compensatory upregulation of extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation. Consequently, simultaneous inhibition of PDK1 and Erk1/2 impeded the survival of breast cancer cells. Thus we identify PDK1 as a potential therapeutic target for breast cancer, particularly in combination with an Erk1/2 inhibitor. PMID:26455327

  4. NK Cells Preferentially Target Tumor Cells with a Cancer Stem Cell Phenotype.

    Science.gov (United States)

    Ames, Erik; Canter, Robert J; Grossenbacher, Steven K; Mac, Stephanie; Chen, Mingyi; Smith, Rachel C; Hagino, Takeshi; Perez-Cunningham, Jessica; Sckisel, Gail D; Urayama, Shiro; Monjazeb, Arta M; Fragoso, Ruben C; Sayers, Thomas J; Murphy, William J

    2015-10-15

    Increasing evidence supports the hypothesis that cancer stem cells (CSCs) are resistant to antiproliferative therapies, able to repopulate tumor bulk, and seed metastasis. NK cells are able to target stem cells as shown by their ability to reject allogeneic hematopoietic stem cells but not solid tissue grafts. Using multiple preclinical models, including NK coculture (autologous and allogeneic) with multiple human cancer cell lines and dissociated primary cancer specimens and NK transfer in NSG mice harboring orthotopic pancreatic cancer xenografts, we assessed CSC viability, CSC frequency, expression of death receptor ligands, and tumor burden. We demonstrate that activated NK cells are capable of preferentially killing CSCs identified by multiple CSC markers (CD24(+)/CD44(+), CD133(+), and aldehyde dehydrogenase(bright)) from a wide variety of human cancer cell lines in vitro and dissociated primary cancer specimens ex vivo. We observed comparable effector function of allogeneic and autologous NK cells. We also observed preferential upregulation of NK activation ligands MICA/B, Fas, and DR5 on CSCs. Blocking studies further implicated an NKG2D-dependent mechanism for NK killing of CSCs. Treatment of orthotopic human pancreatic cancer tumor-bearing NSG mice with activated NK cells led to significant reductions in both intratumoral CSCs and tumor burden. Taken together, these data from multiple preclinical models, including a strong reliance on primary human cancer specimens, provide compelling preclinical evidence that activated NK cells preferentially target cancer cells with a CSC phenotype, highlighting the translational potential of NK immunotherapy as part of a combined modality approach for refractory solid malignancies.

  5. Ultrasound Shear Wave Simulation of Breast Tumor Using Nonlinear Tissue Elasticity

    Directory of Open Access Journals (Sweden)

    Dae Woo Park

    2016-01-01

    Full Text Available Shear wave elasticity imaging (SWEI can assess the elasticity of tissues, but the shear modulus estimated in SWEI is often less sensitive to a subtle change of the stiffness that produces only small mechanical contrast to the background tissues. Because most soft tissues exhibit mechanical nonlinearity that differs in tissue types, mechanical contrast can be enhanced if the tissues are compressed. In this study, a finite element- (FE- based simulation was performed for a breast tissue model, which consists of a circular (D: 10 mm, hard tumor and surrounding tissue (soft. The SWEI was performed with 0% to 30% compression of the breast tissue model. The shear modulus of the tumor exhibited noticeably high nonlinearity compared to soft background tissue above 10% overall applied compression. As a result, the elastic modulus contrast of the tumor to the surrounding tissue was increased from 0.46 at 0% compression to 1.45 at 30% compression.

  6. Tumor cell phenotype is sustained by selective MAPK oxidation in mitochondria.

    Directory of Open Access Journals (Sweden)

    Soledad Galli

    Full Text Available Mitochondria are major cellular sources of hydrogen peroxide (H(2O(2, the production of which is modulated by oxygen availability and the mitochondrial energy state. An increase of steady-state cell H(2O(2 concentration is able to control the transition from proliferating to quiescent phenotypes and to signal the end of proliferation; in tumor cells thereby, low H(2O(2 due to defective mitochondrial metabolism can contribute to sustain proliferation. Mitogen-activated protein kinases (MAPKs orchestrate signal transduction and recent data indicate that are present in mitochondria and regulated by the redox state. On these bases, we investigated the mechanistic connection of tumor mitochondrial dysfunction, H(2O(2 yield, and activation of MAPKs in LP07 murine tumor cells with confocal microscopy, in vivo imaging and directed mutagenesis. Two redox conditions were examined: low 1 microM H(2O(2 increased cell proliferation in ERK1/2-dependent manner whereas high 50 microM H(2O(2 arrested cell cycle by p38 and JNK1/2 activation. Regarding the experimental conditions as a three-compartment model (mitochondria, cytosol, and nuclei, the different responses depended on MAPKs preferential traffic to mitochondria, where a selective activation of either ERK1/2 or p38-JNK1/2 by co-localized upstream kinases (MAPKKs facilitated their further passage to nuclei. As assessed by mass spectra, MAPKs activation and efficient binding to cognate MAPKKs resulted from oxidation of conserved ERK1/2 or p38-JNK1/2 cysteine domains to sulfinic and sulfonic acids at a definite H(2O(2 level. Like this, high H(2O(2 or directed mutation of redox-sensitive ERK2 Cys(214 impeded binding to MEK1/2, caused ERK2 retention in mitochondria and restricted shuttle to nuclei. It is surmised that selective cysteine oxidations adjust the electrostatic forces that participate in a particular MAPK-MAPKK interaction. Considering that tumor mitochondria are dysfunctional, their inability to

  7. Basal cytokeratin phenotypes of myoepithelial cells indicates the origin of ductal carcinomas in situ of the breast.

    Science.gov (United States)

    Chen, Ling; Yin, Xiaona; Lu, Shanshan; Chen, Guorong; Dong, Lei

    2015-09-01

    Terminal duct lobular unit (TDLU) is widely accepted as the origin of ductal carcinoma in situ of breast. The differentiation states of myoepithelial cells of breast ductal system hint the development of breast hyperplastic lesions. Basal cytokeratin (CK) phenotypes indicate the differentiation of myoepithelial cells. Using antibodies of CK5/6, CK14, and CK17, this study reports the basal CK phenotypes of myoepithelial cells in 20 foci of normal breast, 20 usual ductal hyperplasias, 36 ductal carcinomas in situ (DCIS), and 28 sclerosing adenosis (SA). The results showed that the positive staining of basal CKs of myoepithelial cells in normal ducts were significantly higher than those in normal lobules. The basal CK expression of myoepithelial cells of DCIS and usual ductal hyperplasia was similar to that of normal duct, whereas that of SA was similar to that of normal lobule. We propose a modified model of TDLU origin of intraductal carcinoma that most of DCIS originate from terminal ducts of TDLU, whereas most SA originate from lobules.

  8. HER4 selectively coregulates estrogen stimulated genes associated with breast tumor cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Han, Wen; Jones, Frank E., E-mail: fjones3@tulane.edu

    2014-01-10

    Highlights: •HER4/4ICD is an obligate coactivator for 37% of estrogen regulated genes. •HER4/4ICD coactivated genes selectively regulate estrogen stimulated proliferation. •Estrogen stimulated tumor cell migration occurs independent of HER4/4ICD. •Disrupting HER4/4ICD and ER coactivated gene expression may suppress breast cancer. -- Abstract: The EGFR-family member HER4 undergoes regulated intramembrane proteolysis (RIP) to generate an intracellular domain (4ICD) that functions as a transcriptional coactivator. Accordingly, 4ICD coactivates the estrogen receptor (ER) and associates with ER at target gene promoters in breast tumor cells. However, the extent of 4ICD coactivation of ER and the functional significance of the 4ICD/ER transcriptional complex is unclear. To identify 4ICD coactivated genes we performed a microarray gene expression analysis of β-estradiol treated cells comparing control MCF-7 breast cancer cells to MCF-7 cells where HER4 expression was stably suppressed using a shRNA. In the MCF-7 cell line, β-estradiol significantly stimulated or repressed by 2-fold or more 726 or 53 genes, respectively. Significantly, HER4/4ICD was an obligate coactivator for 277 or 38% of the β-estradiol stimulated genes. Ingenuity Pathway Analysis of β-estradiol regulated genes identified significant associations with multiple cellular functions regulating cellular growth and proliferation, cell cycle progression, cancer metastasis, decreased hypoplasia, tumor cell migration, apoptotic resistance of tumor cells, and increased transcription. Genes coactivated by 4ICD displayed functional specificity by only significantly contributing to cellular growth and proliferation, cell cycle progression, and decreased hypoplasia. In direct concordance with these in situ results we show that HER4 knockdown in MCF-7 cells results in a loss of estrogen stimulated tumor cell proliferation and cell cycle progression, whereas, estrogen stimulated tumor cell migration was

  9. Inhibition of autophagy stimulate molecular iodine-induced apoptosis in hormone independent breast tumors

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Preeti [Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow (India); Godbole, Madan, E-mail: madangodbole@yahoo.co.in [Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow (India); Rao, Geeta [Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow (India); Annarao, Sanjay [Centre of Biomedical Magnetic Resonance, Lucknow (India); Mitra, Kalyan [Electron Microscopy Unit, Central Drug Research Institute, Lucknow (India); Roy, Raja [Centre of Biomedical Magnetic Resonance, Lucknow (India); Ingle, Arvind [Advanced Centre for Treatment Research and Education in Cancer, Mumbai (India); Agarwal, Gaurav; Tiwari, Swasti [Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow (India)

    2011-11-11

    Highlights: Black-Right-Pointing-Pointer Molecular iodine (I{sub 2}) causes non-apoptotic cell death in MDA-MB231 breast tumor cells. Black-Right-Pointing-Pointer Autophagy is activated as a survival mechanism in response to I{sub 2} in MDA-MB231. Black-Right-Pointing-Pointer Autophagy inhibition sensitizes tumor cells to I{sub 2}-induced apoptotic cell death. Black-Right-Pointing-Pointer Autophagy inhibitor potentiates apoptosis and tumor regressive effects of I{sub 2} in mice. -- Abstract: Estrogen receptor negative (ER{sup -ve}) and p53 mutant breast tumors are highly aggressive and have fewer treatment options. Previously, we showed that molecular Iodine (I{sub 2}) induces apoptosis in hormone responsive MCF-7 breast cancer cells, and non-apoptotic cell death in ER{sup -ve}-p53 mutant MDA-MB231 cells (Shrivastava, 2006). Here we show that I{sub 2} (3 {mu}M) treatment enhanced the features of autophagy in MDA-MB231 cells. Since autophagy is a cell survival response to most anti-cancer therapies, we used both in vitro and in vivo systems to determine whether ER{sup -ve} mammary tumors could be sensitized to I{sub 2}-induced apoptosis by inhibiting autophagy. Autophagy inhibition with chloroquine (CQ) and inhibitors for PI3K (3MA, LY294002) and H+/ATPase (baflomycin) resulted in enhanced cell death in I{sub 2} treated MDA-MB231 cells. Further, CQ (20 {mu}M) in combination with I{sub 2}, showed apoptotic features such as increased sub-G1 fraction ({approx}5-fold), expression of cleaved caspase-9 and -3 compared to I{sub 2} treatment alone. Flowcytometry of I{sub 2} and CQ co-treated cells revealed increase in mitochondrial membrane permeability (p < 0.01) and translocation of cathepsin D activity to cytosol relative to I{sub 2} treatment. For in vivo studies ICRC mice were transplanted subcutaneously with MMTV-induced mammary tumors. A significant reduction in tumor volumes, as measured by MRI, was found in I{sub 2} and CQ co-treated mice relative to I{sub 2} or

  10. K5/K14-positive cells contribute to salivary gland-like breast tumors with myoepithelial differentiation

    DEFF Research Database (Denmark)

    Boecker, Werner; Stenman, Goeran; Loening, Thomas;

    2013-01-01

    different cell lineages and define their cellular hierarchy in tumors with myoepithelial differentiation. isTILT analysis of a series of 28 breast, salivary, and lacrimal gland tumors, including pleomorphic adenomas (n=8), epithelial-myoepithelial tumors (n=9), and adenoid cystic carcinomas (n=11) revealed...

  11. Effects of "Moxibustion Serum" on Proliferation and Phenotypes of Tumor Infiltrating Lvmphocytes

    Institute of Scientific and Technical Information of China (English)

    陈云飞; 赵粹英; 陈汉平; 秦慧莲; 方舫

    2003-01-01

    @@ Tumor infiltrating lymphocytes (TIL) were cultured with "moxibustion serum" (MS), and the results were examined by flow cytometry. The results indicated that MS could enhance the proliferation of TIL,accelerate it to reach the exponential growth phase, and assist recombinant interleukin 2 (rIL-2) to enhance successively the percentage of CD3+ positive cells, maintain the number of CD4+ positive T cells, promote greatly the percentage of CD8+ positive T cells among TILs, and reverse the CD4+/CD8+ ratio. Such cooperative effects rely on relative specificity of acupoints. It is suggested that MS is beneficial to the growth of TIL both in the aspects of proliferation and phenotypes.

  12. Local tumor control and cosmetic outcome following breast-conserving surgery and radiation up to a total dose of 56 Gy without boost in breast cancer patients

    International Nuclear Information System (INIS)

    Purpose: To evaluate overall survival, local tumor control and cosmetic outcome after breast-conserving surgery followed by radiotherapy without boost irradiation. Patients and Methods: In a retrospective study 270 breast cancer patients were treated with breast conserving surgery combined with a homogenous radiation of the tumor bearing breast up to a total dose of 56 Gy without local boost irradiation. Mean follow-up was 48 months. Local tumor control, side effects, cosmetic results and contentment with treatment were assessed using physical examinations and interviews based on a standardized questionnaire. Results: Cause-specific survival at 5 years after treatment was 88.3%, actuarial disease-free survival at 5 years was 76.1%. Within 23 to 78 months after treatment 12 patients suffered from ipsilateral breast recurrence. The actuarial freedom from local recurrence (single tumor manifestation) was 96.8% at 5 years after treatment, 89% at 10 years. The occurrence of local failures was not significantly correlated to tumor size, margins, grading, nodal status, age or lymphangiosis. 15.6% of the patients developed distant metastases. In all patients treatment was performed without interruption. Side effects were predominantly of mild degree, no severe side effects were detected. 73% of physicians and 81% of patients scored their cosmetic outcome as excellent or good. 93% of patients would again decide in favor of this procedure. Whereas, use of adjuvant chemotherapy as well as subcutaneous reconstruction of breast tissue did not significantly affect breast cosmesis, analysis demonstrated impaired cosmetic results related to a larger breast size. Conclusion: The data of this study show that tumor control achieved by breast conserving surgery in combination with a radiation technique up to a total dose of 56 Gy which omits boost irradiation is within the range of literature data. Side effects of the therapy were tolerable. The treatment displayed a good

  13. Lung metastasis genes couple breast tumor size and metastatic spread

    OpenAIRE

    Minn, Andy J.; Gupta, Gaorav P.; Padua, David; Bos, Paula; Nguyen, Don X.; Nuyten, Dimitry; Kreike, Bas; Zhang, Yi; Wang, Yixin; Ishwaran, Hemant; Foekens, John A; van de Vijver, Marc; Massagué, Joan

    2007-01-01

    The association between large tumor size and metastatic risk in a majority of clinical cancers has led to questions as to whether these observations are causally related or whether one is simply a marker for the other. This is partly due to an uncertainty about how metastasis-promoting gene expression changes can arise in primary tumors. We investigated this question through the analysis of a previously defined “lung metastasis gene-expression signature” (LMS) that mediates experimental breas...

  14. Role of Erbin in ErbB2-dependent breast tumor growth.

    Science.gov (United States)

    Tao, Yanmei; Shen, Chengyong; Luo, Shiwen; Traoré, Wilfried; Marchetto, Sylvie; Santoni, Marie-Josée; Xu, Linlin; Wu, Biao; Shi, Chao; Mei, Jinghong; Bates, Ryan; Liu, Xihui; Zhao, Kai; Xiong, Wen-Cheng; Borg, Jean-Paul; Mei, Lin

    2014-10-21

    ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2), a receptor tyrosine kinase of the ErbB family, is overexpressed in around 25% of breast cancers. In addition to forming a heterodimer with other ErbB receptors in response to ligand stimulation, ErbB2 can be activated in a ligand-independent manner. We report here that Erbin, an ErbB2-interacting protein that was thought to act as an antitumor factor, is specifically expressed in mammary luminal epithelial cells and facilitates ErbB2-dependent proliferation of breast cancer cells and tumorigenesis in MMTV-neu transgenic mice. Disruption of their interaction decreases ErbB2-dependent proliferation, and deletion of the PDZ domain in Erbin hinders ErbB2-dependent tumor development in MMTV-neu mice. Mechanistically, Erbin forms a complex with ErbB2, promotes its interaction with the chaperon protein HSP90, and thus prevents its degradation. Finally, ErbB2 and Erbin expression correlates in human breast tumor tissues. Together, these observations establish Erbin as an ErbB2 regulator for breast tumor formation and progression.

  15. Photoacoustic imaging of breast tumor vascularization: a comparison with MRI and histopathology

    Science.gov (United States)

    Heijblom, Michelle; Piras, Daniele; van den Engh, Frank M.; Klaase, Joost M.; Brinkhuis, Mariël.; Steenbergen, Wiendelt; Manohar, Srirang

    2013-06-01

    Breast cancer is the most common form of cancer and the leading cause of cancer death among females. Early diagnosis improves the survival chances for the disease and that is why there is an ongoing search for improved methods for visualizing breast cancer. One of the hallmarks of breast cancer is the increase in tumor vascularization that is associated with angiogenesis: a crucial factor for survival of malignancies. Photoacoustic imaging can visualize the malignancyassociated increased hemoglobin concentration with optical contrast and ultrasound resolution, without the use of ionizing radiation or contrast agents and is therefore theoretically an ideal method for breast imaging. Previous clinical studies using the Twente Photoacoustic Mammoscope (PAM), which works in forward mode using a single wavelength (1064 nm), showed that malignancies can indeed be identified in the photoacoustic imaging volume as high contrast areas. However, the specific appearance of the malignancies led to questions about the contrast mechanism in relation to tumor vascularization. In this study, the photoacoustic lesion appearance obtained with an updated version of PAM is compared with the lesion appearance on Magnetic Resonance Imaging (MRI), both in general (19 patients) and on an individual basis (7 patients). Further, in 3 patients an extended histopathology protocol is being performed in which malignancies are stained for vascularity using an endothelial antibody: CD31. The correspondence between PAM and MRI and between PAM and histopathology makes it likely that the high photoacoustic contrast at 1064 nm is indeed largely the consequence of the increased tumor vascularization.

  16. A superpixel-based framework for automatic tumor segmentation on breast DCE-MRI

    Science.gov (United States)

    Yu, Ning; Wu, Jia; Weinstein, Susan P.; Gaonkar, Bilwaj; Keller, Brad M.; Ashraf, Ahmed B.; Jiang, YunQing; Davatzikos, Christos; Conant, Emily F.; Kontos, Despina

    2015-03-01

    Accurate and efficient automated tumor segmentation in breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is highly desirable for computer-aided tumor diagnosis. We propose a novel automatic segmentation framework which incorporates mean-shift smoothing, superpixel-wise classification, pixel-wise graph-cuts partitioning, and morphological refinement. A set of 15 breast DCE-MR images, obtained from the American College of Radiology Imaging Network (ACRIN) 6657 I-SPY trial, were manually segmented to generate tumor masks (as ground truth) and breast masks (as regions of interest). Four state-of-the-art segmentation approaches based on diverse models were also utilized for comparison. Based on five standard evaluation metrics for segmentation, the proposed framework consistently outperformed all other approaches. The performance of the proposed framework was: 1) 0.83 for Dice similarity coefficient, 2) 0.96 for pixel-wise accuracy, 3) 0.72 for VOC score, 4) 0.79 mm for mean absolute difference, and 5) 11.71 mm for maximum Hausdorff distance, which surpassed the second best method (i.e., adaptive geodesic transformation), a semi-automatic algorithm depending on precise initialization. Our results suggest promising potential applications of our segmentation framework in assisting analysis of breast carcinomas.

  17. Tumor seeding after diagnostic vitrectomy for choroidal metastasis in breast cancer.

    Science.gov (United States)

    Kung, Ya-Hsin; Wu, Tsung-Tien; Lin, Chia-Shian

    2012-09-01

    Choroidal metastasis is the most common type of intraocular tumor in adults, and in females the most common primary site is the breast. We report a case of unilateral choroidal metastasis with exudative retinal detachment as the initial presentation of recurrent breast cancer, and subsequent ophthalmic metastasis following diagnostic vitrectomy. A 49-year-old woman with a 7-year-history of well-treated bilateral breast cancer had been suffering from blurred vision in the left eye for 1 week. Ocular examination was normal except for superotemporal retinal detachment in the left eye. Neither retinal break nor choroidal mass was seen. The patient received scleral buckling and pneumatic retinopexy without significant improvement. Fluorescein angiography revealed a suspected choroidal metastasis in the left eye, but ocular ultrasonography did not show a visible choroidal mass. Two consecutive diagnostic vitrectomies with cytology could not confirm malignancy. A systemic workup was also negative. Six months later, two tumor masses were noted over two of the sclerotomy wounds of the left eye. Pathology showed adenocarcinoma compatible with invasive ductal carcinoma of the breast. Ocular metastasis may present as infiltrative choroidal lesions with exudative retinal detachment without a visible mass. Invasive procedures, such as fine-needle aspiration biopsy and diagnostic vitrectomy, may risk tumor seeding.

  18. Mutational Profiling Can Establish Clonal or Independent Origin in Synchronous Bilateral Breast and Other Tumors.

    Directory of Open Access Journals (Sweden)

    Lei Bao

    Full Text Available Synchronous tumors can be independent primary tumors or a primary-metastatic (clonal pair, which may have clinical implications. Mutational profiling of tumor DNA is increasingly common in the clinic. We investigated whether mutational profiling can distinguish independent from clonal tumors in breast and other cancers, using a carefully defined test based on the Clonal Likelihood Score (CLS = 100 x # shared high confidence (HC mutations/ # total HC mutations.Statistical properties of a formal test using the CLS were investigated. A high CLS is evidence in favor of clonality; the test is implemented as a one-sided binomial test of proportions. Test parameters were empirically determined using 16,422 independent breast tumor pairs and 15 primary-metastatic tumor pairs from 10 cancer types using The Cancer Genome Atlas.We validated performance of the test with its established parameters, using five published data sets comprising 15,758 known independent tumor pairs (maximum CLS = 4.1%, minimum p-value = 0.48 and 283 known tumor clonal pairs (minimum CLS 13%, maximum p-value 0.99, supporting independence. A plausible molecular mechanism for the shift from hormone receptor positive to triple negative was identified in the clonal pair.We have developed the statistical properties of a carefully defined Clonal Likelihood Score test from mutational profiling of tumor DNA. Under identified conditions, the test appears to reliably distinguish between synchronous tumors of clonal and of independent origin in several cancer types. This approach may have scientific and clinical utility.

  19. Is early dynamic lymphoscintigraphy for detection of sentinel lymph nodes always achievable in breast tumor?

    International Nuclear Information System (INIS)

    In this article, we will discuss the achievement of early dynamic lymphoscintigraphic protocol and compare detection of sentinel node between benign and malignant breast tumors, and whether pathologic factor is related or not. During a six-month period, consecutive fifty-nine patients were enrolled into our study. The average age of patients was 47.6±9.8 years and all of them were clinically suspected of having breast cancer. The average tumor was 2.1±1.1 cm in size. First, Tc-99m sulfur colloid was injected around corners of palpable mass or biopsy cavity by the hybrid injection method. Immediately thereafter, dynamic protocol of lymphoscintigraphy, with 10 sec per frame for 60 frames was performed by established simultaneous dual-head vertical angle imaging technique. And delayed two-hour image was also acquired. All patients underwent surgery sixteen to twenty hours later and had a final pathological diagnosis. Among 59 patients, 14 of them were diagnosed with fibroadenoma and the other 45 cases with malignant conditions, infiltrating duct carcinoma mostly. The average age of the two groups was similar. From the summation image of dynamic study, identified axillary sentinel nodal activity was found as 80% in the group of benign breast tumor, but only 48% in the group of malignant breast tumor. In more than 88% of patients, sentinel lymph node was detectable on the delayed two-hour image between the two groups. Early dynamic protocol of pre-operative lymphoscintigraphy is helpful to clarify the relationship between the local lymphatic drainage basin and sentinel nodal uptake. However, this short period of protocol is not always achievable to detect sentinel node, especially in the group with breast malignant lesions. (author)

  20. Surface-enhanced Raman spectroscopy of saliva proteins for the noninvasive differentiation of benign and malignant breast tumors.

    Science.gov (United States)

    Feng, Shangyuan; Huang, Shaohua; Lin, Duo; Chen, Guannan; Xu, Yuanji; Li, Yongzeng; Huang, Zufang; Pan, Jianji; Chen, Rong; Zeng, Haishan

    2015-01-01

    The capability of saliva protein analysis, based on membrane protein purification and surface-enhanced Raman spectroscopy (SERS), for detecting benign and malignant breast tumors is presented in this paper. A total of 97 SERS spectra from purified saliva proteins were acquired from samples obtained from three groups: 33 healthy subjects; 33 patients with benign breast tumors; and 31 patients with malignant breast tumors. Subtle but discernible changes in the mean SERS spectra of the three groups were observed. Tentative assignments of the saliva protein SERS spectra demonstrated that benign and malignant breast tumors led to several specific biomolecular changes of the saliva proteins. Multiclass partial least squares-discriminant analysis was utilized to analyze and classify the saliva protein SERS spectra from healthy subjects, benign breast tumor patients, and malignant breast tumor patients, yielding diagnostic sensitivities of 75.75%, 72.73%, and 74.19%, as well as specificities of 93.75%, 81.25%, and 86.36%, respectively. The results from this exploratory work demonstrate that saliva protein SERS analysis combined with partial least squares-discriminant analysis diagnostic algorithms has great potential for the noninvasive and label-free detection of breast cancer.

  1. Targeting breast cancer stem cells by dendritic cell vaccination in humanized mice with breast tumor: preliminary results

    Directory of Open Access Journals (Sweden)

    Pham PV

    2016-07-01

    Full Text Available Phuc Van Pham,1 Hanh Thi Le,1 Binh Thanh Vu,1 Viet Quoc Pham,1 Phong Minh Le,1 Nhan Lu-Chinh Phan,1 Ngu Van Trinh,1 Huyen Thi-Lam Nguyen,1 Sinh Truong Nguyen,1 Toan Linh Nguyen,2 Ngoc Kim Phan1 1Laboratory of Stem Cell Research and Application, University of Science, Vietnam National University, Ho Chi Minh City, 2Vietnam Military Medical University, Ha Dong, Ha Noi, Vietnam Background: Breast cancer (BC is one of the leading cancers in women. Recent progress has enabled BC to be cured with high efficiency. However, late detection or metastatic disease often renders the disease untreatable. Additionally, relapse is the main cause of death in BC patients. Breast cancer stem cells (BCSCs are considered to cause the development of BC and are thought to be responsible for metastasis and relapse. This study aimed to target BCSCs using dendritic cells (DCs to treat tumor-bearing humanized mice models. Materials and methods: NOD/SCID mice were used to produce the humanized mice by transplantation of human hematopoietic stem cells. Human BCSCs were injected into the mammary fat pad to produce BC humanized mice. Both hematopoietic stem cells and DCs were isolated from the human umbilical cord blood, and immature DCs were produced from cultured mononuclear cells. DCs were matured by BCSC-derived antigen incubation for 48 hours. Mature DCs were vaccinated to BC humanized mice with a dose of 106 cells/mice, and the survival percentage was monitored in both treated and untreated groups. Results: The results showed that DC vaccination could target BCSCs and reduce the tumor size and prolong survival. Conclusion: These results suggested that targeting BCSCs with DCs is a promising therapy for BC. Keywords: breast cancer, breast cancer stem cells, targeting cancer therapy, humanized mice, targeting cancer stem cells 

  2. Downregulation of miR-342 is associated with tamoxifen resistant breast tumors

    Directory of Open Access Journals (Sweden)

    Richer Jennifer K

    2010-12-01

    Full Text Available Abstract Background Tumor resistance to the selective estrogen receptor modulator tamoxifen remains a serious clinical problem especially in patients with tumors that also overexpress HER2. We have recently demonstrated that the clinically important isoform of HER2, HERΔ16, promotes therapeutically refractory breast cancer including resistance to endocrine therapy. Likewise additional breast tumor cell models of tamoxifen resistance have been developed that do not involve HER2 overexpression. However, a unifying molecular mechanism of tamoxifen resistance has remained elusive. Results Here we analyzed multiple cell models of tamoxifen resistance derived from MCF-7 cells to examine the influence of microRNAs (miRNAs on tamoxifen resistance. We compared miRNA expression profiles of tamoxifen sensitive MCF-7 cells and tamoxifen resistant MCF-7/HER2Δ16 cells. We observed significant and dramatic downregulation of miR-342 in the MCF-7/HER2Δ16 cell line as well as the HER2 negative but tamoxifen resistant MCF-7 variants TAMR1 and LCC2. Restoring miR-342 expression in the MCF-7/HER2Δ16 and TAMR1 cell lines sensitized these cells to tamoxifen-induced apoptosis with a dramatic reduction in cell growth. Expression of miR-342 was also reduced in a panel of tamoxifen refractory human breast tumors, underscoring the potential clinical importance of miR-342 downregulation. Towards the goal of identifying direct and indirect targets of miR-342 we restored miR-342 expression in MCF-7/HER2Δ16 cells and analyzed changes in global gene expression by microarray. The impact of miR-342 on gene expression in MCF-7/HER2Δ16 cells was not limited to miR-342 in silica predicted targets. Ingenuity Pathways Analysis of the dataset revealed a significant influence of miR-342 on multiple tumor cell cycle regulators. Conclusions Our findings suggest that miR-342 regulates tamoxifen response in breast tumor cell lines and our clinical data indicates a trend towards

  3. Tumor stromal vascular endothelial growth factor A is predictive of poor outcome in inflammatory breast cancer

    International Nuclear Information System (INIS)

    Inflammatory breast cancer (IBC) is a highly angiogenic disease; thus, antiangiogenic therapy should result in a clinical response. However, clinical trials have demonstrated only modest responses, and the reasons for these outcomes remain unknown. Therefore, the purpose of this retrospective study was to determine the prognostic value of protein levels of vascular endothelial growth factor (VEGF-A), one of the main targets of antiangiogenic therapy, and its receptors (VEGF-R1 and -R2) in IBC tumor specimens. Specimens from IBC and normal breast tissues were obtained from Algerian patients. Tumor epithelial and stromal staining of VEGF-A, VEGF-R1, and VEGF-R2 was evaluated by immunohistochemical analysis in tumors and normal breast tissues; this expression was correlated with clinicopathological variables and breast cancer-specific survival (BCSS) and disease-free survival (DFS) duration. From a set of 117 IBC samples, we evaluated 103 ductal IBC tissues and 25 normal specimens. Significantly lower epithelial VEGF-A immunostaining was found in IBC tumor cells than in normal breast tissues (P <0.01), cytoplasmic VEGF-R1 and nuclear VEGF-R2 levels were slightly higher, and cytoplasmic VEGF-R2 levels were significantly higher (P = 0.04). Sixty-two percent of IBC tumors had high stromal VEGF-A expression. In univariate analysis, stromal VEGF-A levels predicted BCSS and DFS in IBC patients with estrogen receptor-positive (P <0.01 for both), progesterone receptor-positive (P = 0.04 and P = 0.03), HER2+ (P = 0.04 and P = 0.03), and lymph node involvement (P <0.01 for both). Strikingly, in a multivariate analysis, tumor stromal VEGF-A was identified as an independent predictor of poor BCSS (hazard ratio [HR]: 5.0; 95% CI: 2.0-12.3; P <0.01) and DFS (HR: 4.2; 95% CI: 1.7-10.3; P <0.01). To our knowledge, this is the first study to demonstrate that tumor stromal VEGF-A expression is a valuable prognostic indicator of BCSS and DFS at diagnosis and can therefore be used to

  4. Tumor selective cytotoxic action of a thiomorpholin hydroxamate inhibitor (TMI-1 in breast cancer.

    Directory of Open Access Journals (Sweden)

    Lynda Mezil

    Full Text Available BACKGROUND: Targeted therapies, associated with standard chemotherapies, have improved breast cancer care. However, primary and acquired resistances are frequently observed and the development of new concepts is needed. High-throughput approaches to identify new active and safe molecules with or without an "a priori" are currently developed. Also, repositioning already-approved drugs in cancer therapy is of growing interest. The thiomorpholine hydroxamate compound TMI-1 has been previously designed to inhibit metalloproteinase activity for the treatment of rheumatoid arthritis. We present here the repositioning of TMI-1 drug in breast cancer. METHODOLOGY/PRINCIPAL FINDINGS: We tested the effect of TMI-1 on luminal, basal and ERBB2-overexpressing breast tumor cell lines and on MMTV-ERBB2/neu tumor evolution. We measured the effects on i cell survival, ii cell cycle, iii extrinsic and intrinsic apoptotic pathways, iv association with doxorubicin, docetaxel and lapatinib, v cancer stem cells compartment. In contrast with conventional cytotoxic drugs, TMI-1 was highly selective for tumor cells and cancer stem cells at submicromolar range. All non-malignant cells tested were resistant even at high concentration. TMI-1 was active on triple negative (TN and ERBB2-overexpressing breast tumor cell lines, and was also highly efficient on human and murine "primary" ERBB2-overexpressing cells. Treatment of transgenic MMTV-ERBB2/neu mice with 100 mg/kg/day TMI-1 alone induced tumor apoptosis, inhibiting mammary gland tumor occurrence and development. No adverse effects were noticed during the treatment. This compound had a strong synergistic effect in association with docetaxel, doxorubicin and lapatinib. We showed that TMI-1 mediates its selective effects by caspase-dependent apoptosis. TMI-1 was efficient in 34/40 tumor cell lines of various origins (ED50: 0.6 µM to 12.5 µM. CONCLUSIONS/SIGNIFICANCE: This is the first demonstration of the tumor selective

  5. Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model.

    Directory of Open Access Journals (Sweden)

    Debbie Liao

    Full Text Available BACKGROUND: Local inflammation associated with solid tumors commonly results from factors released by tumor cells and the tumor stroma, and promotes tumor progression. Cancer associated fibroblasts comprise a majority of the cells found in tumor stroma and are appealing targets for cancer therapy. Here, our aim was to determine the efficacy of targeting cancer associated fibroblasts for the treatment of metastatic breast cancer. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate that cancer associated fibroblasts are key modulators of immune polarization in the tumor microenvironment of a 4T1 murine model of metastatic breast cancer. Elimination of cancer associated fibroblasts in vivo by a DNA vaccine targeted to fibroblast activation protein results in a shift of the immune microenvironment from a Th2 to Th1 polarization. This shift is characterized by increased protein expression of IL-2 and IL-7, suppressed recruitment of tumor-associated macrophages, myeloid derived suppressor cells, T regulatory cells, and decreased tumor angiogenesis and lymphangiogenesis. Additionally, the vaccine improved anti-metastatic effects of doxorubicin chemotherapy and enhanced suppression of IL-6 and IL-4 protein expression while increasing recruitment of dendritic cells and CD8(+ T cells. Treatment with the combination therapy also reduced tumor-associated Vegf, Pdgfc, and GM-CSF mRNA and protein expression. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that cancer associated fibroblasts promote tumor growth and metastasis through their role as key modulators of immune polarization in the tumor microenvironment and are valid targets for therapy of metastatic breast cancer.

  6. Breast cancer tumor growth is efficiently inhibited by dendritic cell transfusion in a murine model

    Directory of Open Access Journals (Sweden)

    Viet Quoc Pham

    2014-03-01

    Full Text Available The ability of dendritic cells to efficiently present tumor-derived antigens when primed with tumor cell lysates makes them attractive as an approach for cancer treatment. This study aimed to evaluate the effects of dendritic cell transfusion dose on breast cancer tumor growth in a murine model. Dendritic cells were produced from allogeneic bone marrow-derived mononuclear cells that were cultured in RPMI 1640 medium supplemented with 20 ng/mL GM-CSF and 20 ng/mL IL-4 for 7 days. These cells were checked for maturation before being primed with a cancer cell-derived antigen. Cancer cell antigens were produced by a rapid freeze-thaw procedure using a 4T1 cell line. Immature dendritic cells were loaded with 4T1 cellderived antigens. Dendritic cells were transfused into mice bearing tumors at three different doses, included 5.104, 105, and 106 cells/mouse with a control consisting of RPMI 1640 media alone. The results showed that dendritic cell therapy inhibited breast cancer tumors in a murine model; however, this effect depended on dendritic cell dose. After 17 days, in the treated groups, tumor size decreased by 43%, 50%, and 87.5% for the doses of 5 and times; 104, 105, and 106 dendritic cells, respectively, while tumor size in the control group decreased by 44%. This result demonstrated that dendritic cell therapy is a promising therapy for breast cancer treatment. [Biomed Res Ther 2014; 1(3.000: 85-92

  7. Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer.

    Science.gov (United States)

    Jardim-Perassi, Bruna Victorasso; Arbab, Ali S; Ferreira, Lívia Carvalho; Borin, Thaiz Ferraz; Varma, Nadimpalli R S; Iskander, A S M; Shankar, Adarsh; Ali, Meser M; de Campos Zuccari, Debora Aparecida Pires

    2014-01-01

    As neovascularization is essential for tumor growth and metastasis, controlling angiogenesis is a promising tactic in limiting cancer progression. Melatonin has been studied for their inhibitory properties on angiogenesis in cancer. We performed an in vivo study to evaluate the effects of melatonin treatment on angiogenesis in breast cancer. Cell viability was measured by MTT assay after melatonin treatment in triple-negative breast cancer cells (MDA-MB-231). After, cells were implanted in athymic nude mice and treated with melatonin or vehicle daily, administered intraperitoneally 1 hour before turning the room light off. Volume of the tumors was measured weekly with a digital caliper and at the end of treatments animals underwent single photon emission computed tomography (SPECT) with Technetium-99m tagged vascular endothelial growth factor (VEGF) C to detect in vivo angiogenesis. In addition, expression of pro-angiogenic/growth factors in the tumor extracts was evaluated by membrane antibody array and collected tumor tissues were analyzed with histochemical staining. Melatonin in vitro treatment (1 mM) decreased cell viability (pbreast cancer xenografts nude mice treated with melatonin showed reduced tumor size and cell proliferation (Ki-67) compared to control animals after 21 days of treatment (p0.05) images. In addition, there was a decrease of micro-vessel density (Von Willebrand Factor) in melatonin treated mice (pmelatonin treatment showed effectiveness in reducing tumor growth and cell proliferation, as well as in the inhibition of angiogenesis. PMID:24416386

  8. Mutational analysis of single circulating tumor cells by next generation sequencing in metastatic breast cancer

    Science.gov (United States)

    Galardi, Francesca; Pestrin, Marta; Gabellini, Stefano; Simi, Lisa; Mancini, Irene; Vannucchi, Alessandro Maria; Pazzagli, Mario; Di Leo, Angelo; Pinzani, Pamela

    2016-01-01

    Circulating Tumor Cells (CTCs) represent a “liquid biopsy” of the tumor potentially allowing real-time monitoring of cancer biology and therapies in individual patients. The purpose of the study was to explore the applicability of a protocol for the molecular characterization of single CTCs by Next Generation Sequencing (NGS) in order to investigate cell heterogeneity and provide a tool for a personalized medicine approach. CTCs were enriched and enumerated by CellSearch in blood from four metastatic breast cancer patients and singularly isolated by DEPArray. Upon whole genome amplification 3–5 single CTCs per patient were analyzed by NGS for 50 cancer-related genes. We found 51 sequence variants in 25 genes. We observed inter- and intra-patient heterogeneity in the mutational status of CTCs. The highest number of somatic deleterious mutations was found in the gene TP53, whose mutation is associated with adverse prognosis in breast cancer. The discordance between the mutational status of the primary tumor and CTCs observed in 3 patients suggests that, in advanced stages of cancer, CTC characteristics are more closely linked to the dynamic modifications of the disease status. In one patient the mutational profiles of CTCs before and during treatment shared only few sequence variants. This study supports the applicability of a non-invasive approach based on the liquid biopsy in metastatic breast cancer patients which, in perspective, should allow investigating the clonal evolution of the tumor for the development of new therapeutic strategies in precision medicine. PMID:27034166

  9. Use of Raman Spectroscopy in Characterizing Formalin-Fixed, Paraffin-Embedded Breast Tumor Samples (abstract)

    Science.gov (United States)

    Downey, Frances; Cade, Nicholas; Cook, Richard; Springall, Robert; Gillet, Cheryl; Richards, David; Festy, Frederic

    2009-04-01

    Formalin-fixed, paraffin-embedded (FFPE) sections of breast tissue are used by pathologists to correctly type and grade the primary tumor and to assess the extent of a patient's disease. The cut sections represent a reproducible likeness of the morphology of the tissue when viewed through a microscope, although the fixation technique creates some artifacts. What is not known is how the sections differ chemically from how the tumor would look or behave within the breast. Raman spectroscopy is, like many other optical techniques, fast, noninvasive, and generally inexpensive. The advantage Raman has over other techniques is its powerful ability to identify specific chemicals, molecules, and bonds within a sample. Using Raman spectroscopy the chemicals present in both fresh tissue and FFPE sections can be identified and compared, allowing any differences between them to be identified. This information may be useful to the pathologist as an aid to further treatment regimes or novel molecular techniques, and as an aid to patient management. If these sections are found to be chemically similar to fresh tissue, they could be used to further characterize breast tumors, particularly rare tumors, using Raman spectroscopy.

  10. Computer-aided breast MR image feature analysis for prediction of tumor response to chemotherapy

    International Nuclear Information System (INIS)

    Purpose: To identify a new clinical marker based on quantitative kinetic image features analysis and assess its feasibility to predict tumor response to neoadjuvant chemotherapy. Methods: The authors assembled a dataset involving breast MR images acquired from 68 cancer patients before undergoing neoadjuvant chemotherapy. Among them, 25 patients had complete response (CR) and 43 had partial and nonresponse (NR) to chemotherapy based on the response evaluation criteria in solid tumors. The authors developed a computer-aided detection scheme to segment breast areas and tumors depicted on the breast MR images and computed a total of 39 kinetic image features from both tumor and background parenchymal enhancement regions. The authors then applied and tested two approaches to classify between CR and NR cases. The first one analyzed each individual feature and applied a simple feature fusion method that combines classification results from multiple features. The second approach tested an attribute selected classifier that integrates an artificial neural network (ANN) with a wrapper subset evaluator, which was optimized using a leave-one-case-out validation method. Results: In the pool of 39 features, 10 yielded relatively higher classification performance with the areas under receiver operating characteristic curves (AUCs) ranging from 0.61 to 0.78 to classify between CR and NR cases. Using a feature fusion method, the maximum AUC = 0.85 ± 0.05. Using the ANN-based classifier, AUC value significantly increased to 0.96 ± 0.03 (p < 0.01). Conclusions: This study demonstrated that quantitative analysis of kinetic image features computed from breast MR images acquired prechemotherapy has potential to generate a useful clinical marker in predicting tumor response to chemotherapy

  11. Computer-aided breast MR image feature analysis for prediction of tumor response to chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Aghaei, Faranak; Tan, Maxine; Liu, Hong; Zheng, Bin, E-mail: Bin.Zheng-1@ou.edu [School of Electrical and Computer Engineering, University of Oklahoma, Norman, Oklahoma 73019 (United States); Hollingsworth, Alan B. [Mercy Women’s Center, Mercy Health Center, Oklahoma City, Oklahoma 73120 (United States); Qian, Wei [Department of Electrical and Computer Engineering, University of Texas, El Paso, Texas 79968 (United States)

    2015-11-15

    Purpose: To identify a new clinical marker based on quantitative kinetic image features analysis and assess its feasibility to predict tumor response to neoadjuvant chemotherapy. Methods: The authors assembled a dataset involving breast MR images acquired from 68 cancer patients before undergoing neoadjuvant chemotherapy. Among them, 25 patients had complete response (CR) and 43 had partial and nonresponse (NR) to chemotherapy based on the response evaluation criteria in solid tumors. The authors developed a computer-aided detection scheme to segment breast areas and tumors depicted on the breast MR images and computed a total of 39 kinetic image features from both tumor and background parenchymal enhancement regions. The authors then applied and tested two approaches to classify between CR and NR cases. The first one analyzed each individual feature and applied a simple feature fusion method that combines classification results from multiple features. The second approach tested an attribute selected classifier that integrates an artificial neural network (ANN) with a wrapper subset evaluator, which was optimized using a leave-one-case-out validation method. Results: In the pool of 39 features, 10 yielded relatively higher classification performance with the areas under receiver operating characteristic curves (AUCs) ranging from 0.61 to 0.78 to classify between CR and NR cases. Using a feature fusion method, the maximum AUC = 0.85 ± 0.05. Using the ANN-based classifier, AUC value significantly increased to 0.96 ± 0.03 (p < 0.01). Conclusions: This study demonstrated that quantitative analysis of kinetic image features computed from breast MR images acquired prechemotherapy has potential to generate a useful clinical marker in predicting tumor response to chemotherapy.

  12. Mouse mammary tumor virus (MMTV-like DNA sequences in the breast tumors of father, mother, and daughter

    Directory of Open Access Journals (Sweden)

    Wiernik Peter H

    2008-02-01

    Full Text Available Abstract Background The diagnosis of late onset breast cancer in a father, mother, and daughter living in the same house for decades suggested the possibility of an environmental agent as a common etiological factor. Both molecular and epidemiological data have indicated a possible role for the mouse mammary tumor virus (MMTV, the etiological agent of breast cancer in mice, in a certain percentage of human breast tumors. The aim of this study was to determine if MMTV might be involved in the breast cancer of this cluster of three family members. Results MMTV-like envelope (env and long terminal repeat (LTR sequences containing the MMTV superantigen gene (sag were detected in the malignant tissues of all three family members. The amplified env gene sequences were 98.0%–99.6% homologous to the MMTV env sequences found in the GR, C3H, and BR6 mouse strains. The amplified LTR sequences containing sag sequences segregated to specific branches of the MMTV phylogenetic tree and did not form a distinct branch of their own. Conclusion The presence of MMTV-like DNA sequences in the malignant tissues of all three family members suggests the possibility of MMTV as an etiological agent. Phylogenetic data suggest that the MMTV-like DNA sequences are mouse and not human derived and that the ultimate reservoir of MMTV is most likely the mouse. Although the route by which these family members came to be infected with MMTV is unknown, the possibility exists that such infection may have resulted from a shared exposure to mice.

  13. Combining phenotypic and proteomic approaches to identify membrane targets in a ‘triple negative’ breast cancer cell type

    Directory of Open Access Journals (Sweden)

    Rust Steven

    2013-02-01

    Full Text Available Abstract Background The continued discovery of therapeutic antibodies, which address unmet medical needs, requires the continued discovery of tractable antibody targets. Multiple protein-level target discovery approaches are available and these can be used in combination to extensively survey relevant cell membranomes. In this study, the MDA-MB-231 cell line was selected for membranome survey as it is a ‘triple negative’ breast cancer cell line, which represents a cancer subtype that is aggressive and has few treatment options. Methods The MDA-MB-231 breast carcinoma cell line was used to explore three membranome target discovery approaches, which were used in parallel to cross-validate the significance of identified antigens. A proteomic approach, which used membrane protein enrichment followed by protein identification by mass spectrometry, was used alongside two phenotypic antibody screening approaches. The first phenotypic screening approach was based on hybridoma technology and the second was based on phage display technology. Antibodies isolated by the phenotypic approaches were tested for cell specificity as well as internalisation and the targets identified were compared to each other as well as those identified by the proteomic approach. An anti-CD73 antibody derived from the phage display-based phenotypic approach was tested for binding to other ‘triple negative’ breast cancer cell lines and tested for tumour growth inhibitory activity in a MDA-MB-231 xenograft model. Results All of the approaches identified multiple cell surface markers, including integrins, CD44, EGFR, CD71, galectin-3, CD73 and BCAM, some of which had been previously confirmed as being tractable to antibody therapy. In total, 40 cell surface markers were identified for further study. In addition to cell surface marker identification, the phenotypic antibody screening approaches provided reagent antibodies for target validation studies. This is illustrated

  14. Phenotypic profile of dendritic and T cells in the lymph node of Balb/C mice with breast cancer submitted to dendritic cells immunotherapy.

    Science.gov (United States)

    da Cunha, Alessandra; Antoniazi Michelin, Marcia; Cândido Murta, Eddie Fernando

    2016-09-01

    Breast cancer (BC) is the most common malignant neoplasm and the cause of death by cancer among women worldwide. Its development influenced by various mutations that occur in the tumor cell and by the immune system's status, which has a direct influence on the tumor microenvironment and, consequently, on interactions with non-tumor cells involved in the immunological response. Strategies using dendritic cells (DCs) or antigen-presenting cells (APCs), therapeutic mode, in cancer have been developed for some time. The proper interaction between DCs and T cells upon antigen presentation is of greatest importance for an antitumor immune response activation. Thus, various receptors on the surface of T cells must be able to recognize ligands that are located on the surface of APCs. However, little is known about the real behavior and interaction forms of CDs and T cells after vaccination. Due to the crucial importance of DCs in an effective anti-tumor immune response activation and the search for compliant results in inducing this response by immunotherapies with DCs, the phenotypic profile of DCs and T cells in lymph nodes obtained from female Balb/C mice with breast cancer induced by 4T1 cells and DCs treated with vaccines was investigated. We evaluated through flow cytometry based on the surface and intracellular molecules marking; as well as the presence of cytokines and chemokines, IL-2, IL-4, IL-10, IL-12, IFN-γ, TNF-α and TGF-β in the supernatant of the culture of Balb/C lymph nodes by ELISA. The results show that the vaccination with DCs, in the maturation parameters used in this study, was able to stimulate the secretion of cytokines such as IFN-γ and IL-12 and inhibit the secretion of TGF-β and IL-10 in nodal lymph infiltrates, as well as co-stimulatory activating (CD86) and adhesion molecules in DCs and T cells LFA-1/ICAM-1 and inhibit the secretion of CTLA-4 present in lymph nodes. Facts that led to aTh1 profile polarization, immuno competent in relation

  15. Molecular deficiency (ies) in MT1 melatonin signaling pathway underlies the melatonin-unresponsive phenotype in MDA-MB-231 human breast cancer cells

    OpenAIRE

    Mao, Lulu; YUAN, LIN; Xiang, Shulin; Zeringue, Samantha B.; Dauchy, Robert T; Blask, David E.; Hauch, Adam; Steven M. Hill

    2014-01-01

    Melatonin, has been shown repeatedly to inhibit the growth of human breast tumor cells in vitro and in vivo. Its anti-proliferative effects have been well-studied in MCF-7 human breast cancer cells and several other estrogen receptor α (ERα)-positive human breast cancer cell lines. However, the MDA-MB-231 breast cancer cell line, an ERα negative cell line widely used in breast cancer research, has been shown to be unresponsive to melatonin’s growth-suppressive effect in vitro. Here we examine...

  16. Effects of phenotype transformation of receptors of triple-negative breast cancer(TNBC on clinical prognosis of patients with breast cancer

    Directory of Open Access Journals (Sweden)

    Xin ZHAO

    2012-04-01

    Full Text Available Objective To evaluate the expression of estrogen receptor (ER, progesterone receptor (PR and human epidermis growth-factor receptor 2(HER-2, to determine the phenotype transformation of these receptors before and after recurrence and/or metastasis, and to explore the effects of expression and phenotype transformation of receptors on the treatment efficacy and clinical prognosis of patients with breast cancer. Methods Based on the phenotype transformation of ER, PR, and HER-2 receptor, 211 breast cancer patients were assigned to 3 groups. Twenty patients of Group A were with primary triple-negative breast cancer (TNBC, defined as lacking expression of ER, PR and HER2 which transformed into non-TNBC after recurrence and/ or metastasis, 73 of Group B were with primary non-TNBC which transformed into TNBC after recurrence and/or metastasis, and 118 of Group C were with primary TNBC which was still TNBC after recurrence and/or metastasis. The phenotype transformation of receptors, recurrence/metastasis, and efficacy and clinical prognosis were analyzed following collection of general information of the patients. Results The median age of 211 recurrent patients was 52 years (range, 22 to 78 years. Most of the patients exhibited solitary metastasis. The most common locations of the initial metastasis were lymph node, bone and skin. The median disease-free survival for Groups A, B, and C was 34.0, 25.0, and 20.0 months, respectively. The clinical effect of Groups B and C was better than that of Group A for first-line, second-line, and third-line rescuing therapy (P=0.030, 0.003, 0.001. However, the clinical benefit rate of Group A was higher than those of Groups B and C for rescuing endocrine therapy. The median follow-up time of the 211 patients was 68 months (range, 20 to 127 months, and the median survival after recurrence for Groups A, B, and C was 63.1, 33.7, and 25.8 months respectively (P=0.000. The median overall survival for Groups A, B

  17. At last: classification of human mammary cells elucidates breast cancer origins

    OpenAIRE

    Robert D Cardiff; Alexander D Borowsky

    2014-01-01

    Current breast cancer classification systems are based on molecular evaluation of tumor receptor status and do not account for distinct morphological phenotypes. In other types of cancer, taxonomy based on normal cell phenotypes has been extremely useful for diagnosis and treatment strategies. In this issue of the JCI, Santagata and colleagues developed a breast cancer classification scheme based on characterization of healthy mammary cells. Reclassification of breast cancer cells and breast ...

  18. Early metabolic response using FDG PET/CT and molecular phenotypes of breast cancer treated with neoadjuvant chemotherapy

    Directory of Open Access Journals (Sweden)

    Han Wonshik

    2011-10-01

    Full Text Available Abstract Background This study was aimed 1 to investigate the predictive value of FDG PET/CT (fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography for histopathologic response and 2 to explore the results of FDG PET/CT by molecular phenotypes of breast cancer patients who received neoadjuvant chemotherapy. Methods Seventy-eight stage II or III breast cancer patients who received neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this study. FDG PET/CTs were acquired before chemotherapy and after the first cycle of chemotherapy for evaluating early metabolic response. Results The mean pre- and post-chemotherapy standard uptake value (SUV were 7.5 and 3.9, respectively. The early metabolic response provided by FDG PET/CT after one cycle of neoadjuvant chemotherapy was correlated with the histopathologic response after completion of neoadjuvant chemotherapy (P = 0.002. Sensitivity and negative predictive value were 85.7% and 95.1%, respectively. The estrogen receptor negative phenotype had a higher pre-chemotherapy SUV (8.6 vs. 6.4, P = 0.047 and percent change in SUV (48% vs. 30%, P = 0.038. In triple negative breast cancer (TNBC, the pre-chemotherapy SUV was higher than in non-TNBC (9.8 vs. 6.4, P = 0.008. Conclusions The early metabolic response using FDG PET/CT could have a predictive value for the assessment of histopathologic non-response of stage II/III breast cancer treated with neoadjuvant chemotherapy. Our findings suggest that the initial SUV and the decline in SUV differed based on the molecular phenotype. Trial Registration ClinicalTrials.gov: NCT01396655

  19. Correlation between dynamic contrast-enhanced MRI and histopathology in the measurement of tumor and breast volume and their ratio in breast cancer patients: a prospective study

    Institute of Scientific and Technical Information of China (English)

    LIU Qian; YE Jing-ming; XU Ling; DUAN Xue-ning; ZHAO Jian-xin; LIU Yin-hua

    2012-01-01

    Background Earlier studies have examined the association between the diameter of primary tumors measured by magnetic resonance imaging (MRI) and histopathology in breast cancer patients.However,the diameter does not completely describe the dimensions of the breast tumor or its volumetric proportion relative to the whole breast.The association between breast tumor volume/breast volume ratios measured by these two techniques has not been reported.Methods Seventy-three patients were recruited from female patients with primary breast tumors admitted to our center between January and December 2010.They were divided into two groups.Group A (n=46) underwent modified radical mastectomy (MRM),and Group B (n=27) underwent preoperative neoadjuvant chemotherapy before MRM.They were examined by dynamic-contrast enhanced MRI (DCE-MRI) to measure breast volumes (BVs),tumor volumes (TVs),and tumor volume/breast volume ratios (TV/BV).These measurements were compared with histopathology results after MRM,and the associations between MRI and pathology were analyzed by linear regression and Bland-Altman analysis.Results For Group A,the correlation coefficients for BVs,TVs,and TV/BV ratios measured by the two techniques were 0.938,0.921,and 0.897 (all P <0.001),respectively.For Group B,the correlation coefficients for BVs,TVs,and TV/BV ratios were 0.936,0.902,and 0.869 (all P<0.01),respectively.The results suggest statistically significant correlations between these parameters measured by the two techniques for both groups.Conclusion For these patients,BVs,TVs,and TV/BV ratios measured by DCE-MRI significantly correlated with those determined by histopathology.

  20. Identification of a panel of tumor-associated antigens from breast carcinoma cell lines, solid tumors and testis cDNA libraries displayed on lambda phage

    Directory of Open Access Journals (Sweden)

    Cianfriglia Maurizio

    2004-11-01

    Full Text Available Abstract Background Tumor-associated antigens recognized by humoral effectors of the immune system are a very attractive target for human cancer diagnostics and therapy. Recent advances in molecular techniques have led to molecular definition of immunogenic tumor proteins based on their reactivity with autologous patient sera (SEREX. Methods Several high complexity phage-displayed cDNA libraries from breast carcinomas, human testis and breast carcinoma cell lines MCF-7, MDA-MB-468 were constructed. The cDNAs were expressed in the libraries as fusion to bacteriophage lambda protein D. Lambda-displayed libraries were efficiently screened with sera from patients with breast cancer. Results A panel of 21 clones representing 18 different antigens, including eight proteins of unknown function, was identified. Three of these antigens (T7-1, T11-3 and T11-9 were found to be overexpressed in tumors as compared to normal breast. A serological analysis of the 21 different antigens revealed a strong cancer-related profile for at least five clones (T6-2, T6-7, T7-1, T9-21 and T9-27. Conclusions Preliminary results indicate that patient serum reactivity against five of the antigens is associated with tumor disease. The novel T7-1 antigen, which is overexpressed in breast tumors and recognized specifically by breast cancer patient sera, is potentially useful in cancer diagnosis.

  1. Early identification of non-responding locally advanced breast tumors receiving neoadjuvant chemotherapy

    Science.gov (United States)

    Van de Giessen, Martijn; Schaafsma, Boudewijn E.; Charehbili, Ayoub; Smit, Vincent T. H. B. M.; Kroep, Judith R.; Lelieveldt, Boudewijn P. F.; Liefers, Gerrit-Jan; Chan, Alan; Löwik, Clemens W. G. M.; Dijkstra, Jouke; van de Velde, Cornelis J. H.; Wasser, Martin N. J. M.; Vahrmeijer, Alexander L.

    2015-02-01

    Diffuse optical spectroscopy (DOS) may be advantageous for monitoring tumor response during chemotherapy treatment, particularly in the early treatment stages. In this paper we perform a second analysis on the data of a clinical trial with 25 breast cancer patients that received neoadjuvant chemotherapy. Patients were monitored using delayed contrast enhanced MRI and additionally with diffuse optical spectroscopy at baseline, after 1 cycle of chemotherapy, halfway therapy and before surgery. In this analysis hemoglobin content between tumor tissue and healthy tissue of the same breast is compared on all four monitoring time points. Furthermore, the predictive power of the tumor-healthy tissue difference of HbO2 for non-responder prediction is assessed. The difference in HbO2 content between tumor and healthy tissue was statistically significantly higher in responding tumors than in non-responding tumors at baseline (10.88 vs -0.57 μM, P=0.014) and after one cycle of chemotherapy (6.45 vs -1.31 μM, P=0.048). Before surgery this difference had diminished. In the data of this study, classification on the HbO2 difference between tumor and healthy tissue was able to predict tumor (non-)response at baseline and after 1 cycle with an area-under-curve of 0.95 and 0.88, respectively. While this result suggests that tumor response can be predicted before chemotherapy onset, one should be very careful with interpreting these results. A larger patient population is needed to confirm this finding.

  2. MTUS1 tumor suppressor and its miRNA regulators in fibroadenoma and breast cancer.

    Science.gov (United States)

    Kara, Murat; Kaplan, Mehmet; Bozgeyik, Ibrahim; Ozcan, Onder; Celik, Ozgur Ilhan; Bozgeyik, Esra; Yumrutas, Onder

    2016-08-10

    Breast cancer is major public health problem predominantly effects female population. Current therapeutic approaches to deal with breast cancer are still lack of effectiveness. Thus, identifying/developing novel strategies to fight against breast cancer is very important. The frequent deletions at 8p21.3-22 chromosomal location nearby D8S254 marker enabled the discovery of a novel tumor suppressor gene, MTUS1. Subsequently, MTUS1 was demonstrated to be less expressed in a variety cancer types including breast cancer. Also, it is obvious that gene expression is widely regulated by miRNAs. Here, we aimed to report differential expression of MTUS1 and its regulatory miRNAs in breast cancer and fibroadenoma tissues. Dynamic analysis of MTUS1 expression levels and its miRNAs regulators were attained by Fluidigm 96×96 Dynamic Array Expression chips and reactions were performed in Fluidigm BioMark™ HD System qPCR. Consequently, MTUS1 mRNA levels were significantly diminished in breast cancer tissues and elevated in fibroadenoma tissues. Also, among MTUS1 targeting miRNAs, miR-183-5p was identified to be overexpressed in breast cancer and down-regulated in fibroadenoma tissues. Also, expression levels of MTUS1 and miR-183-5p were well correlated with clinical parameters. In particular, MTUS1 expression was found to be diminished and miR-183-5p expression was elevated with the advancing stage. In conclusion, as a potential therapeutic target, miR-183-5p can be a chief regulator of MTUS1 and MTUS1-miR-183-5p axis may have significant influence in the pathology of breast cancer. PMID:27155522

  3. Expression of Fas (CD95/APO-1) ligand by human breast cancers: significance for tumor immune privilege.

    LENUS (Irish Health Repository)

    O'Connell, J

    2012-02-03

    Breast cancers have been shown to elicit tumor-specific immune responses. As in other types of cancer, the antitumor immune response fails to contain breast tumor growth, and a reduction in both the quantity and cytotoxic effectiveness of tumor-infiltrating lymphocytes (TILs) is associated with a poorer prognosis. Fas ligand (FasL) induces apoptotic death of activated lymphocytes that express its cell surface receptor, FasR (CD95\\/APO-1). FasL-mediated apoptosis of activated lymphocytes contributes to normal immune downregulation through its roles in tolerance acquisition, immune response termination, and maintenance of immune privilege in the eye, testis, and fetus. In this report, we demonstrate that breast carcinomas express FasL. Using in situ hybridization and immunohistochemistry, we show that breast tumors constitutively express FasL at both the mRNA and protein levels, respectively. FasL expression is prevalent in breast cancer: 100% of breast tumors (17 of 17) were found to express FasL, and expression occurred over more than 50% of the tumor area in all cases. By immunohistochemistry, FasR was found to be coexpressed with FasL throughout large areas of all the breast tumors. This suggests that the tumor cells had acquired intracellular defects in FasL-mediated apoptotic signaling. FasL and FasR expression were independent of tumor type or infiltrative capacity. FasL expressed by tumor cells has previously been shown to kill Fas-sensitive lymphoid cells in vitro and has been associated with apoptosis of TILs in vivo. We conclude that mammary carcinomas express FasL in vivo as a potential inhibitor of the antitumor immune response.

  4. TGFβ and Hypoxia Drive Breast Cancer Bone Metastases through Parallel Signaling Pathways in Tumor Cells and the Bone Microenvironment

    Institute of Scientific and Technical Information of China (English)

    Lauren K. DUNN; Pierrick G.J. FOURNIE; Khalid S. MOHAMMAD; C. Ryan MCKENNA; Holly W. DAVIS; Maria NIEWOLNA; Xianghong PENG; John M. CHIRGWIN; Theresa A.GUISE

    2009-01-01

    @@ Breast cancers frequently metastasize to bone, a site of hypoxia and high concentrations of active TGFβ. Skeletal metastases involve interactions between tumor and bone cells driven by locally secreted proteins, many of which are increased by hypoxia and TGFβ.

  5. Decreased Autocrine EGFR Signaling in Metastatic Breast Cancer Cells Inhibits Tumor Growth in Bone and Mammary Fat Pad

    OpenAIRE

    Nickerson, Nicole K.; Mohammad, Khalid S.; Gilmore, Jennifer L.; Crismore, Erin; Bruzzaniti, Angela; Guise, Theresa A.; Foley, John

    2012-01-01

    Breast cancer metastasis to bone triggers a vicious cycle of tumor growth linked to osteolysis. Breast cancer cells and osteoblasts express the epidermal growth factor receptor (EGFR) and produce ErbB family ligands, suggesting participation of these growth factors in autocrine and paracrine signaling within the bone microenvironment. EGFR ligand expression was profiled in the bone metastatic MDA-MB-231 cells (MDA-231), and agonist-induced signaling was examined in both breast cancer and oste...

  6. Tumor-targeting Salmonella typhimurium A1-R prevents experimental human breast cancer bone metastasis in nude mice

    OpenAIRE

    Miwa, Shinji; Yano, Shuya; Zhang, Yong; Matsumoto, Yasunori; Uehara, Fuminari; Yamamoto, Mako; Hiroshima, Yukihiko; Kimura, Hiroaki; Hayashi, Katsuhiro; Yamamoto, Norio; Bouvet, Michael; Tsuchiya, Hiroyuki; Hoffman, Robert M.; Ming ZHAO

    2014-01-01

    Bone metastasis is a lethal and morbid late stage of breast cancer that is currently treatment resistant. More effective mouse models and treatment are necessary. High bone-metastatic variants of human breast cancer cells were selected in nude mice by cardiac injection. After cardiac injection of a high bone-metastatic variant of breast cancer, all untreated mice had bone metastases compared to only 20% with parental cells. Treatment with tumor-targeting Salmonella typhimurium A1-R completely...

  7. Occurrence of thymosin ß4 in human breast cancer cells and in other cell types of the tumor microenvironment

    DEFF Research Database (Denmark)

    Larsson, Lars-Inge; Holck, Susanne

    2007-01-01

    that there is a considerable heterogeneity in the cellular distribution of thymosin ß4 in breast cancer. In most tumors examined, cancer cells showed low or intermediate reactivity for thymosin ß4, whereas leukocytes and macrophages showed intense reactivity. In addition, endothelial cells showed variable reactivity...... microenvironment produce thymosin ß4 and that such expression varies from tumor to tumor. Such heterogeneity of expression should be taken into account when the role of thymosin ß4 in tumor biology is assessed....

  8. Identification of genomic signatures in circulating tumor cells from breast cancer.

    Science.gov (United States)

    Kanwar, Nisha; Hu, Pingzhao; Bedard, Philippe; Clemons, Mark; McCready, David; Done, Susan J

    2015-07-15

    Levels of circulating tumor cells (CTCs) in blood have prognostic value in early and metastatic breast cancer. CTCs also show varying degrees of concordance with molecular markers of primary tumors they originate from. It is expected that individual cells reflect the heterogeneity and evolution of tumor cells as they acquire new functions and differential responses to chemotherapy. However, a degree of commonality is also plausible, highlighting alterations that allow tumor cells to perform CTC-defining activities such as invasion and intravasation. Using a matched tumor-normal approach, we performed high-resolution copy number profiling of CTCs from breast cancer to identify occult changes occurring during progression to metastasis. We identified a signature of recurrent gain in CTCs, consisting of 90 minimal common regions (MCRs) of copy number gain. These were predominantly found across chromosome 19 and were identified at low frequencies (3-4%) in 787 primary breast carcinomas examined. CTC genomic signatures clustered into two groups independent of subtype: a dormancy-related signature with 16 MCRs (AKT2, PTEN, CADM2); and a tumor-aggressiveness related signature with 358 MCRs (ANGPTL4, BSG, MIR-373). There were two MCRs in common between the groups on 19q13 and 21q21, containing genes involved in resistance to anoikis, TGFβ-signaling and metastasis (TFF3, LTBP4, NUMBL). Furthermore, a region harboring the ERBB2 gene was gained in a majority of patients. Regions 20q13 and 15q24 were associated with distant metastasis. The distinctiveness of CTC signatures highlights cell populations with different functional or metastatic potential. Such novel targets could help to specifically identify and block dissemination.

  9. Role of tumor-associated antigen expression in radioimmunoguided surgery for colorectal and breast cancer.

    Science.gov (United States)

    Bertoglio, S; Percivale, P; Schenone, F; Peressini, A; Murolo, C; Badellino, F

    1998-12-01

    One hundred thirty-six patients with colorectal and breast cancer were enrolled in a retrospective study using radioimmunoguided surgery (RIGS) with Iodine-125 (I125) radiolabeled B72.3 (Group A, 73 patients) and F023C5 (Group B, 63 patients) monoclonal antibodies (MAbs). The correlation between intraoperative tumor-to-normal tissue (T/NT) gamma-detecting probe (GDP) counts ratio and the expression of tumor-associated glycoprotein (TAG)-72 (GroupA patients) and carcinoembryonic antigen (CEA; Group B patients) tumor-associated antigens (TAA) expression of 209 resected or biopsy tumor specimens was assessed. Ex vivo radioimmunolocalization index (R.I.) was carried out on the same specimens as a control of intraoperative GDP ratio values. RIGS positive definition of tumor occurred in 80/113 (70.8%) tumor sites of Group A patients and in 84/96 (87.5%) tumor sites of Group B patients. Mean percent B72.3 TAA expression of 113 tumor sites of Group A patients was 62.74 +/- 28.79% vs. 73.00 +/- 26.28% of 96 tumor sites of Group B patients (P < 0.05). The higher incidence of positive RIGS results was observed in tumor sites with the higher expression of the relative TAA. A statistically significant correlation between RIGS ratios and B72.3 and CEA expression was observed in the 113 tumor sites of Group A (P < 0.05) and in the 96 tumor sites of Group B (P < 0.01), respectively. The role of a preoperative evaluation of TAA expression in patients undergoing RIGS is discussed. Its assessment, whenever possible, may help to select those patients who will benefit more from this immunodiagnostic technique.

  10. TIMP-1 as a tumor marker in breast cancer - an update

    DEFF Research Database (Denmark)

    Würtz, Sidse Ørnbjerg; Rasmussen, Anne-Sofie Schrohl; Mouridsen, Henning;

    2008-01-01

    Improvement of the management of breast cancer patients has high priority. In this regard, prognostic stratification needs to be improved in order to ensure proper medical treatment of all patients and furthermore predictors of response to chemotherapy are urgently needed. As new treatment...... the association between TIMP-1 and prognosis in breast cancer and new studies within this area have focused on the possibility of using blood samples or paraffin embedded tissue instead of tumor tissue extracts for measurements of TIMP-1. Interestingly, recent studies have investigated the association between...... TIMP-1 and response to treatment showing that TIMP-1 may also carry predictive information on response to treatment. In this regard, results from studies of the molecular functions of TIMP-1 point to a role of TIMP-1 in the inhibition of tumor cell apoptosis as an explanation for the clinical findings...

  11. Differential CARM1 Isoform Expression in Subcellular Compartments and among Malignant and Benign Breast Tumors.

    Directory of Open Access Journals (Sweden)

    David Shlensky

    Full Text Available Coactivator-associated arginine methyltransferase 1 (CARM1 is a coactivator for ERα and cancer-relevant transcription factors, and can methylate diverse cellular targets including histones. CARM1 is expressed in one of two alternative splice isoforms, full-length CARM1 (CARM1FL and truncated CARM1 (CARM1ΔE15. CARM1FL and CARM1ΔE15 function differently in transcriptional regulation, protein methylation, and mediation of pre-mRNA splicing in cellular models.To investigate the functional roles and the prognosis potential of CARM1 alternative spliced isoforms in breast cancer, we used recently developed antibodies to detect differential CARM1 isoform expression in subcellular compartments and among malignant and benign breast tumors.Immunofluorescence in MDA-MB-231 and BG-1 cell lines demonstrated that CARM1ΔE15 is the dominant isoform expressed in the cytoplasm, and CARM1FL is more nuclear localized. CARM1ΔE15 was found to be more sensitive to Hsp90 inhibition than CARM1FL, indicating that the truncated isoform may be the oncogenic form. Clinical cancer samples did not have significantly higher expression of CARM1FL or CARM1ΔE15 than benign breast samples at the level of mRNA or histology. Furthermore neither CARM1FL nor CARM1ΔE15 expression correlated with breast cancer molecular subtypes, tumor size, or lymph node involvement.The analysis presented here lends new insights into the possible oncogenic role of CARM1ΔE15. This study also demonstrates no obvious association of CARM1 isoform expression and clinical correlates in breast cancer. Recent studies, however, have shown that CARM1 expression correlates with poor prognosis, indicating a need for further studies of both CARM1 isoforms in a large cohort of breast cancer specimens.

  12. A mouse stromal response to tumor invasion predicts prostate and breast cancer patient survival.

    Directory of Open Access Journals (Sweden)

    Marina Bacac

    Full Text Available Primary and metastatic tumor growth induces host tissue responses that are believed to support tumor progression. Understanding the molecular changes within the tumor microenvironment during tumor progression may therefore be relevant not only for discovering potential therapeutic targets, but also for identifying putative molecular signatures that may improve tumor classification and predict clinical outcome. To selectively address stromal gene expression changes during cancer progression, we performed cDNA microarray analysis of laser-microdissected stromal cells derived from prostate intraepithelial neoplasia (PIN and invasive cancer in a multistage model of prostate carcinogenesis. Human orthologs of genes identified in the stromal reaction to tumor progression in this mouse model were observed to be expressed in several human cancers, and to cluster prostate and breast cancer patients into groups with statistically different clinical outcomes. Univariate Cox analysis showed that overexpression of these genes is associated with shorter survival and recurrence-free periods. Taken together, our observations provide evidence that the expression signature of the stromal response to tumor invasion in a mouse tumor model can be used to probe human cancer, and to provide a powerful prognostic indicator for some of the most frequent human malignancies.

  13. Tumor markers in breast cancer - European Group on Tumor Markers recommendations

    OpenAIRE

    Molina, Rafael; Barak, Vivian; van Dalen, Arie; Duffy, Michael J.; Einarsson, Roland; Gion, Massimo; Goike, Helena; Lamerz, Rolf; Nap, Marius; Sölétormos, György; Stieber, Petra

    2005-01-01

    Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins ( CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of the...

  14. Surgical Management of Benign and Borderline Phyllodes Tumors of the Breast.

    Science.gov (United States)

    Moutte, Amandine; Chopin, Nicolas; Faure, Christelle; Beurrier, Frédéric; Ho Quoc, Christophe; Guinaudeau, Florence; Treilleux, Isabelle; Carrabin, Nicolas

    2016-09-01

    Phyllodes tumors (PT) are uncommon fibroepithelial breast neoplasms and there is currently no clear consensual treatment for these tumors. The aim of our study was to evaluate the surgical management and outcome of benign and borderline PT. We retrospectively assessed 76 cases of benign or borderline PT managed at the Leon Berard comprehensive cancer center in Lyon, France between July 2003 and December 2013. The mean age at diagnosis was 37.9 years and the median follow-up was 58 months. Seventy-five patients (99%), with a mean tumor size of 27 mm, underwent a breast-conserving procedure. The tumor margins were considered positive (when the tumor was present at the inked surgical section) in seven of 76 cases (9%) and negative in 65 out of 76 cases (86%). We observed the presence of small negative surgical margins <10 mm in 89% and <1 mm in 71% of the patients. Although no re-excision was performed to increase these margins, we did not see any increase in the local recurrence rate (4%) when compared to recurrence rates reported in the literature. We thus suggest that systematic revision surgery for close or positive surgical margins for benign PT should not be systematically performed. However, as recurrences occur within 2 years of initial excision, we recommend a regular clinical and imaging follow-up especially during this period for which patient's compliance is essential.

  15. Morphological heterogeneity of the simultaneous ipsilateral invasive tumor foci in breast carcinoma: a retrospective study of 418 cases of carcinomas.

    Science.gov (United States)

    Boros, Monica; Marian, Cristina; Moldovan, Cosmin; Stolnicu, Simona

    2012-10-15

    The aim of this paper was to assess whether the morphological appearance (i.e. histological tumor type and histological grade) of simultaneous invasive breast carcinoma foci is heterogeneous, since it is known that adjuvant therapy is established according to these parameters. Patients with simultaneous breast tumors in which only the features of the largest neoplastic focus are reported could thus be undertreated. A retrospective study of 418 cases of breast carcinomas was conducted over a 3-year period. The histological tumor types and histological grades of multifocal/multicentric carcinomas in each tumor focus were compared, and mismatches among foci were recorded. Ninety-one of the 418 cases reviewed had multiple carcinomas (21.77%). A comparison between multiple synchronous tumor foci revealed that their histological type was different in 12.08% of the cases. Mismatches among foci were also observed in 9.89% of the cases when evaluating the histological grade, and 5 out of 9 additional tumor foci with a different grade from the largest (index) tumor (55.55%) displayed a higher grade compared to the index tumor. Since the histological tumor type and histological grade of the individual foci may vary considerably within the same tumor and the additional foci may be of higher grade than the index tumor, we believe that reporting morphologic parameters with more unfavorable characteristics in addition to the parameters of the index tumor is imperative.

  16. Activated FXR Inhibits Leptin Signaling and Counteracts Tumor-promoting Activities of Cancer-Associated Fibroblasts in Breast Malignancy.

    Science.gov (United States)

    Giordano, Cinzia; Barone, Ines; Vircillo, Valentina; Panza, Salvatore; Malivindi, Rocco; Gelsomino, Luca; Pellegrino, Michele; Rago, Vittoria; Mauro, Loredana; Lanzino, Marilena; Panno, Maria Luisa; Bonofiglio, Daniela; Catalano, Stefania; Andò, Sebastiano

    2016-01-01

    Cancer-associated fibroblasts (CAFs), the principal components of the tumor stroma, play a central role in cancer development and progression. As an important regulator of the crosstalk between breast cancer cells and CAFs, the cytokine leptin has been associated to breast carcinogenesis. The nuclear Farnesoid X Receptor-(FXR) seems to exert an oncosuppressive role in different tumors, including breast cancer. Herein, we demonstrated, for the first time, that the synthetic FXR agonist GW4064, inhibiting leptin signaling, affects the tumor-promoting activities of CAFs in breast malignancy. GW4064 inhibited growth, motility and invasiveness induced by leptin as well as by CAF-conditioned media in different breast cancer cell lines. These effects rely on the ability of activated FXR to increase the expression of the suppressor of the cytokine signaling 3 (SOCS3) leading to inhibition of leptin-activated signaling and downregulation of leptin-target genes. In vivo xenograft studies, using MCF-7 cells alone or co-injected with CAFs, showed that GW4064 administration markedly reduced tumor growth. Interestingly, GW4064-treated tumors exhibited decreased levels of leptin-regulated proteins along with a strong staining intensity for SOCS3. Thus, FXR ligands might represent an emerging potential anti-cancer therapy able to block the tumor supportive role of activated fibroblasts within the breast microenvironment. PMID:26899873

  17. Correlation of primary tumor FDG uptake with clinicopathologic prognostic factors in invasive ductal carcinoma of the breast

    International Nuclear Information System (INIS)

    The purpose of this study was to investigate the correlation of primary tumor FDG uptake to clinicopathological prognostic factors in invasive ductal carcinoma of the breast. We retrospectively reviewed 136 of 215 female patients with pathologically proven invasive ductal breast cancer from January 2008 to December 2011 who underwent F-18 FDG PET/CT for initial staging and follow-up after curative treatment with analysis of estrogen receptor (ER), progesterone receptor (PR) and human epithelial growth factor receptor 2 (HER2). The maximum standardized uptake value (SUVmax) of the primary breast tumor was measured and compared with hormonal receptor and HER2 overexpression status. The high SUVmax of primary breast tumors is significantly correlated with the clinicopathological factors: tumor size, histologic grade, TNM stage, negativity of ER, negativity of PR, HER2 overexpression and triple negativity. The recurrent group with non-triple negative cancer had a higher SUVmax compared with the non-recurrent group, though no significant difference in FDG uptake was noted between the recurrence and non-recurrent groups in subjects with triple-negative cancer. Lymph node involvement was the independent risk factor for cancer recurrence in the multivariate analysis. In conclusion, high FDG uptake in primary breast tumors is significantly correlated with clinicopathological factors, such as tumor size, histologic grade, TNM stage, negativity of the hormonal receptor, HER2 overexpression and triple negativity. Therefore, FDG PET/CT is a helpful prognostic tool to direct the further management of patients with breast cancer

  18. Breast cancer as photodynamic therapy target: Enhanced therapeutic efficiency by overview of tumor complexity

    OpenAIRE

    Lamberti, María Julia; Vittar, Natalia Belén Rumie; RIVAROLA, VIVIANA ALICIA

    2014-01-01

    Photodynamic therapy is a minimally invasive and clinically approved procedure for eliminating selected malignant cells with specific light activation of a photosensitizer agent. Whereas interstitial and intra-operative approaches have been investigated for the ablation of a broad range of superficial or bulky solid tumors such as breast cancer, the majority of approved photodynamic therapy protocols are for the treatment of superficial lesions of skin and luminal organs. This review article ...

  19. Glucosamine-Bound Near-Infrared Fluorescent Probes with Lysosomal Specificity for Breast Tumor Imaging1

    OpenAIRE

    Li, Cong; Greenwood, Tiffany R; Glunde, Kristine

    2008-01-01

    Noninvasive imaging of lysosomes will be useful 1) to elucidate the role of lysosomal parameters in cancer, 2) to diagnose malignant lesions, and 3) to evaluate future lysosome-targeted anticancer therapies. Lysosome-specific labeling of glucosamine-bound near-infrared (NIR) fluorescent probes, IR-1 and IR-2, but not control probe IR-15 without the glucosamine moiety, was observed by fluorescence microscopy in human breast epithelial cell lines. Lysosome labeling and tumor specificity of thes...

  20. Glucosamine-Bound Near-Infrared Fluorescent Probes with Lysosomal Specificity for Breast Tumor Imaging

    OpenAIRE

    Cong Li; Greenwood, Tiffany R; Kristine Glunde

    2008-01-01

    Noninvasive imaging of lysosomes will be useful 1) to elucidate the role of lysosomal parameters in cancer, 2) to diagnose malignant lesions, and 3) to evaluate future lysosome-targeted anticancer therapies. Lysosome-specific labeling of glucosamine-bound near-infrared (NIR) fluorescent probes, IR-1 and IR-2, but not control probe IR-15 without the glucosamine moiety, was observed by fluorescence microscopy in human breast epithelial cell lines. Lysosome labeling and tumor specificity of thes...

  1. NOTCH2 in breast cancer: association of SNP rs11249433 with gene expression in ER-positive breast tumors without TP53 mutations

    Directory of Open Access Journals (Sweden)

    Ambs Stefan

    2010-05-01

    Full Text Available Abstract Background A recent genome-wide association study (GWAS has identified a single nucleotide polymorphism (SNP rs11249433 in the 1p11.2 region as a novel genetic risk factor for breast cancer, and this association was stronger in patients with estrogen receptor (ER+ versus ER- cancer. Results We found association between SNP rs11249433 and expression of the NOTCH2 gene located in the 1p11.2 region. Examined in 180 breast tumors, the expression of NOTCH2 was found to be lowest in tumors with TP53 mutations and highest in TP53 wild-type/ER+ tumors (p = 0.0059. In the latter group, the NOTCH2 expression was particularly increased in carriers of the risk genotypes (AG/GG of rs11249433 when compared to the non-risk AA genotype (p = 0.0062. Similar association between NOTCH2 expression and rs11249433 was observed in 60 samples of purified monocytes from healthy controls (p = 0.015, but not in total blood samples from 302 breast cancer patients and 76 normal breast tissue samples. We also identified the first possible dominant-negative form of NOTCH2, a truncated version of NOTCH2 consisting of only the extracellular domain. Conclusion This is the first study to show that the expression of NOTCH2 differs in subgroups of breast tumors and by genotypes of the breast cancer-associated SNP rs11249433. The NOTCH pathway has key functions in stem cell differentiation of ER+ luminal cells in the breast. Therefore, increased expression of NOTCH2 in carriers of rs11249433 may promote development of ER+ luminal tumors. Further studies are needed to investigate possible mechanisms of regulation of NOTCH2 expression by rs11249433 and the role of NOTCH2 splicing forms in breast cancer development.

  2. Targeting breast cancer stem cells by dendritic cell vaccination in humanized mice with breast tumor: preliminary results

    Science.gov (United States)

    Pham, Phuc Van; Le, Hanh Thi; Vu, Binh Thanh; Pham, Viet Quoc; Le, Phong Minh; Phan, Nhan Lu-Chinh; Trinh, Ngu Van; Nguyen, Huyen Thi-Lam; Nguyen, Sinh Truong; Nguyen, Toan Linh; Phan, Ngoc Kim

    2016-01-01

    Background Breast cancer (BC) is one of the leading cancers in women. Recent progress has enabled BC to be cured with high efficiency. However, late detection or metastatic disease often renders the disease untreatable. Additionally, relapse is the main cause of death in BC patients. Breast cancer stem cells (BCSCs) are considered to cause the development of BC and are thought to be responsible for metastasis and relapse. This study aimed to target BCSCs using dendritic cells (DCs) to treat tumor-bearing humanized mice models. Materials and methods NOD/SCID mice were used to produce the humanized mice by transplantation of human hematopoietic stem cells. Human BCSCs were injected into the mammary fat pad to produce BC humanized mice. Both hematopoietic stem cells and DCs were isolated from the human umbilical cord blood, and immature DCs were produced from cultured mononuclear cells. DCs were matured by BCSC-derived antigen incubation for 48 hours. Mature DCs were vaccinated to BC humanized mice with a dose of 106 cells/mice, and the survival percentage was monitored in both treated and untreated groups. Results The results showed that DC vaccination could target BCSCs and reduce the tumor size and prolong survival. Conclusion These results suggested that targeting BCSCs with DCs is a promising therapy for BC. PMID:27499638

  3. Expression level of novel tumor suppressor gene FATS is associated with the outcome of node positive breast cancer

    Institute of Scientific and Technical Information of China (English)

    ZHANG Jun; GU Lin; ZHAO Lu-jun; ZHANG Xi-feng; QIU Li; LI Zheng

    2011-01-01

    Background Recently, we reported the identification of a previously uncharacterized and evolutionarily conserved gene, fragile-site associated tumor suppressor (FATS), at a frequently deleted region in irradiation (IR)-induced tumors.However, the role of FATS in breast cancer development and its clinical significance has not been defined. The aim of this study was to determine the role of FA7S in breast cancer development and to evaluate its clinical significance in breast cancer.Methods The expression level of FATS mRNA was determined in 106 breast carcinomas and 23 paired normal breast tissues using quantitative real time reverse transcription-polymerase chain reaction (RT-PCR). The relationship between FATS expression and clinicopathological parameters were also analyzed.Results The mRNA level of FATS was down-regulated in breast cancer compared with paired normal tissues. Low expression of FATS was correlated with high nuclear grade. There was a tendency to a favorable outcome for patients with high expression of FATS (P=0.346). However, low expression of FATS was associated with poor outcome of breast cancer patients with node positive (P=0.011). Furthermore, the mRNA level of FATS showed an independent value in predicting the outcome of breast cancer patients with positive lymph nodes.Conclusion FATS is involved in the carcinogenesis and development of breast cancer and could be a potential biomarker and prognostic factor for breast cancer therapy.

  4. Autophagy regulates keratin 8 homeostasis in mammary epithelial cells and in breast tumors

    Science.gov (United States)

    Kongara, Sameera; Kravchuk, Olga; Teplova, Irina; Lozy, Fred; Schulte, Jennifer; Moore, Dirk; Barnard, Nicola; Neumann, Carola A.; White, Eileen; Karantza, Vassiliki

    2010-01-01

    Autophagy is activated in response to cellular stressors and mediates lysosomal degradation and recycling of cytoplasmic material and organelles as a temporary cell survival mechanism. Defective autophagy is implicated in human pathology, as disruption of protein and organelle homeostasis enables disease-promoting mechanisms such as toxic protein aggregation, oxidative stress, genomic damage and inflammation. We previously showed that autophagy-defective immortalized mouse mammary epithelial cells (iMMECs) are susceptible to metabolic stress, DNA damage and genomic instability. We now report that autophagy deficiency was associated with ER and oxidative stress, and deregulation of p62-mediated keratin homeostasis in mammary cells and allograft tumors and in mammary tissues from genetically engineered mice. In human breast tumors, high phospho(Ser73)-K8 levels inversely correlated with Beclin 1 expression. Thus, autophagy preserves cellular fitness by limiting ER and oxidative stress, a function potentially important in autophagy-mediated suppression of mammary tumorigenesis. Furthermore, autophagy regulates keratin homeostasis in the mammary gland via a p62-dependent mechanism. High phospho(Ser73)-K8 expression may be a marker of autophagy functional status in breast tumors and, as such, could have therapeutic implications for breast cancer patients. PMID:20530580

  5. Distribution of Selenium and Oxidative Stress in Breast Tumor-Bearing Mice

    Directory of Open Access Journals (Sweden)

    Pei-Chung Chen

    2013-02-01

    Full Text Available The present study investigated the effects of breast tumors on the blood and tissue distribution of essential trace mineral selenium (Se, and oxidative stress status of mice. Female 10-week-old BALB/cByJNarl mice were randomly assigned into control (CNL and breast tumor-bearing (TB groups. TB mice were injected subcutaneously into the right hind thigh with 5 × 106 EMT6 mouse mammary tumor cells. After 22 days, we measured Se concentrations, Se-dependent glutathione peroxidase (GPx activities, and malondialdehyde (MDA products (indicator of oxidative stress in plasma, various tissues, and plasma vascular endothelial growth factor (VEGF concentrations. There were no significant differences in body weights and daily intake between both groups. Compared with the CNL group, TB mice have decreases in plasma Se concentrations and GPx activities, as well as higher plasma VEGF and MDA concentrations. Plasma Se concentrations were also negatively correlated with plasma MDA and VEGF concentrations. Furthermore, tissue Se concentrations and GPx activities in TB animals were lower; whereas the MDA concentrations higher in various tissues including liver, kidney, brain, lung, spleen, and thymic tissues. In conclusion, disruption of Se homeostasis critically reflects oxidative stress in target tissues, thus may increase the risk for progression of breast cancer and metastasis.

  6. Adipose progenitor cells increase fibronectin matrix strain and unfolding in breast tumors

    International Nuclear Information System (INIS)

    Increased stiffness represents a hallmark of breast cancer that has been attributed to the altered physicochemical properties of the extracellular matrix (ECM). However, the role of fibronectin (Fn) in modulating the composition and mechanical properties of the tumor-associated ECM remains unclear. We have utilized a combination of biochemical and physical science tools to evaluate whether paracrine signaling between breast cancer cells and adipose progenitor cells regulates Fn matrix assembly and stiffness enhancement in the tumor stroma. In particular, we utilized fluorescence resonance energy transfer imaging to map the molecular conformation and stiffness of Fn that has been assembled by 3T3-L1 preadipocytes in response to conditioned media from MDA-MB231 breast cancer cells. Our results reveal that soluble factors secreted by tumor cells promote Fn expression, unfolding, and stiffening by adipose progenitor cells and that transforming growth factor-β serves as a soluble cue underlying these changes. In vivo experiments using orthotopic co-transplantation of primary human adipose-derived stem cells and MDA-MB231 into SCID mice support the pathological relevance of our results. Insights gained by these studies advance our understanding of the role of Fn in mammary tumorigenesis and may ultimately lead to improved anti-cancer therapies

  7. Predicting local recurrence following breast-conserving treatment: parenchymal signal enhancement ratio (SER) around the tumor on preoperative MRI

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Mi Young; Cho, Nariya; Koo, Hye Ryoung; Yun, Bo La; Bae, Min Sun; Moon, Woo Kyung [Dept. of Radiology, Seoul National Univ. Coll. of Medicine, Seoul National Univ. Hospital, Seoul (Korea, Republic of)], e-mail: river7774@gmail.com; Chie, Eui Kyu [Dept. of Radiation Oncology, Seoul National Univ. Coll. of Medicine, Seoul National Univ. Hospital, Seoul (Korea, Republic of)

    2013-09-15

    Background: The level of background parenchymal enhancement around tumor is known to be associated with breast cancer risk. However, there is no study investigating predictive power of parenchymal signal enhancement ratio (SER) around tumor for ipsilateral breast tumor recurrence (IBTR). Purpose: To investigate whether the breast parenchymal SER around the tumor on preoperative dynamic contrast-enhanced magnetic resonance imaging (MRI) is associated with subsequent IBTR in breast cancer patients who had undergone breast-conserving treatment. Material and Methods: Nineteen consecutive women (mean age, 44 years; range, 34-63 years) with breast cancer who developed IBTR following breast-conserving treatment and 114 control women matched for age, as well as T and N stages were included. We compared the clinicopathologic features of the two groups including nuclear grade, histologic grade, hormonal receptor status, human epidermal growth factor receptor-2 (HER-2) status, lymphovascular invasion, negative margin width, use of adjuvant therapy, and parenchymal SER around the tumor on preoperative DCE-MRI. The SER was measured on a slice showing the largest dimension of the tumor. Multivariate conditional logistic regression analysis was used to identify independent factors associated with IBTR. Results: In univariate analysis, ER negativity (odds ratio [OR] = 4.7; P = 0.040), PR negativity (OR = 4.0; P = 0.013), HER-2 positivity (OR = 3.6; P = 0.026), and a parenchymal SER greater than 0.53 (OR = 23.3; P = 0.011) were associated with IBTR. In multivariate analysis, ER negativity (OR = 3.8; P = 0.015) and a parenchymal SER greater than 0.53 (OR = 13.2; P = 0.040) on preoperative MRI were independent factors associated with IBTR. Conclusion: In addition to ER negativity, a higher parenchymal SER on preoperative MRI was an independent factor associated with subsequent IBTR in patients with breast cancer who had undergone breast-conserving treatment.

  8. Autoantibodies to Tailor-Made Panels of Tumor-Associated Antigens in Breast Carcinoma

    Directory of Open Access Journals (Sweden)

    Ettie Piura

    2011-01-01

    Full Text Available Autoantibodies (AAbs to tumor-associated antigens (TAAs have been identified in the sera of cancer patients. In a previous review published in this journal, we have focused on recent knowledge related to circulating AAbs to individual TAAs in breast carcinoma. This review will focus on recent knowledge related to AAb assays to tailor-made panels of TAAs in breast carcinoma. So far, AAb assays to the following tailor-made panels of TAAs have been assessed in breast carcinoma: (1 p53, c-myc, HER2, NY-ESO-1, BRCA2, and MUC1, (2 IMP1, p62, Koc, p53, c-MYC, cyclin B1, and survivin, (3 PPIA, PRDX2, FKBP52, HSP-60, and MUC1, (4 MUC1, HER2, p53, and IGFBP2, (5 p53, HER2, IGFBP-2, and TOPO2α, (6 survivin and livin, (7 ASB-9, SERAC1, and RELT, and (8 p16, p53, and c-myc. Assessment of serum AAbs to a tailor-made panel of TAAs provides better sensitivity to diagnosis of breast carcinoma than measuring serum AAbs to a single TAA. Nevertheless, measurement of serum AAbs to a panel of TAAs for screening and early diagnosis of breast carcinoma is still investigational and should be carried out along with traditional diagnostic studies.

  9. Malignant breast tumors among Atomic Bomb Survivors, Hirsoshima and Nagasaki, 1950 to 1974

    Energy Technology Data Exchange (ETDEWEB)

    Tokunaga, M. (Radiation Effects Research Foundation, Hiroshima, Japan); Norman, J.E. Jr.; Asano, M.; Tokuoka, S.; Ezaki, H.; Nishimori, I.; Tsuji, Y.

    1979-06-01

    From 1950 to 1974, 360 cases of malignant breast tumors were identified among the 63,000 females of the Radiation Effects Research Foundation's (Hiroshima and Nagasaki) Extended Life-Span Study sample of survivors of the 1945 atomic bombings of Hiroshima and Nagasaki; 288 of these females were residing in one of these two cities at the time of bombing (ATB). Two-thirds of all cases were classified as breast cancers on the basis of microscopic review of slides, and 108 cases received an estimated breast tissue dose of at least 10 rads. The number of cases of radiogenic breast cancer could be well estimated by a linear function of radiation dose for tissue doses below 200 rads. Excess risk estimates, based on this function, for women 10 to 19, 20 to 29, 30 to 39, and 50 years old or older ATB were 7.3, 4.2, 2.6, and 4.7 cases per million women per year per rad, respectively. Women irradiated in their forties showed no dose effect. Among all women who received at least 10 rads, those irradiated before age 20 years will have experienced the highest rates of breast cancer throughout their lifetimes. Separate excess risk estimates for Hiroshima and Nagasaki did not differ significantly, which indicates that for radiogenic breast cancer the effects of neutrons (emitted only in the Hiroshima explosion) and gamma radiation were about equal. Radiation did not reduce the latency period for the development of breast cancer, which was at least 10 years. The distribution of histologic types of cancers did not vary significantly with radiation dose. The data suggested that irradiation prior to menarche conferred a greater risk than irradiation after menarche.

  10. Infrared imaging of MDA-MB-231 breast cancer cell line phenotypes in 2D and 3D cultures.

    Science.gov (United States)

    Smolina, Margarita; Goormaghtigh, Erik

    2015-04-01

    One current challenge in the field of breast cancer infrared imaging is the identification of carcinoma cell subtypes in the tissue. Neither sequencing nor immunochemistry is currently able to provide a cell by cell thorough classification. The latter is needed to build accurate statistical models capable of recognizing the diversity of breast cancer cell lines that may be present in a tissue section. One possible approach for overcoming this problem is to obtain the IR spectral signature of well-characterized tumor cell lines in culture. Cultures in three-dimensional matrices appear to generate an environment that mimics better the in vivo environment. There are, at present, series of breast cancer cell lines that have been thoroughly characterized in two- and three-dimensional (2D and 3D) cultures by full transcriptomics analyses. In this work, we describe the methods used to grow, to process, and to characterize a triple-negative breast cancer cell line, MDA-MB-231, in 3D laminin-rich extracellular matrix (lrECM) culture and compare it with traditional monolayer cultures and tissue sections. While unsupervised analyses did not completely separate spectra of cells grown in 2D from 3D lrECM cultures, a supervised statistical analysis resulted in an almost perfect separation. When IR spectral responses of epithelial tumor cells from clinical triple-negative breast carcinoma samples were added to these data, a principal component analysis indicated that they cluster closer to the spectra of 3D culture cells than to the spectra of cells grown on a flat plastic substrata. This result is encouraging because of correlating well-characterized cell line features with clinical biopsies. PMID:25568895

  11. Downregulation of Smurf2, a tumor-suppressive ubiquitin ligase, in triple-negative breast cancers: Involvement of the RB-microRNA axis

    International Nuclear Information System (INIS)

    The HECT family ubiquitin ligase Smurf2 regulates cell polarity, migration, division, differentiation and death, by targeting diverse substrates that are critical for receptor signaling, cytoskeleton, chromatin remodeling and transcription. Recent studies suggest that Smurf2 functions as a tumor suppressor in mice. However, no inactivating mutation of SMURF2 has been reported in human, and information about Smurf2 expression in human cancer remains limited or complicated. Here we demonstrate that Smurf2 expression is downregulated in human breast cancer tissues, especially of the triple-negative subtype, and address the mechanism of Smurf2 downregulation in triple-negative breast cancer cells. Human breast cancer tissues (47 samples expressing estrogen receptor (ER) and 43 samples with triple-negative status) were examined by immunohistochemistry for the expression of Smurf2. Ten widely-studied human breast cancer cell lines were examined for the expression of Smurf2. Furthermore, microRNA-mediated regulation of Smurf2 was investigated in triple-negative cancer cell lines. Immunohistochemical analysis showed that benign mammary epithelial cells expressed high levels of Smurf2, so did cells in ductal carcinomas in situ. In contrast, invasive ductal carcinomas showed focal or diffuse decrease in Smurf2 expression, which was observed more frequently in triple-negative tumors than in ER-positive tumors. Consistently, human triple-negative breast cancer cell lines such as BT549, MDA-MB-436, DU-4475 and MDA-MB-468 cells showed significantly lower expression of Smurf2 protein, compared to ER + or HER2+ cell lines. Studies using quantitative PCR and specific microRNA inhibitors indicated that increased expression of miR-15a, miR-15b, miR-16 and miR-128 was involved in Smurf2 downregulation in those triple-negative cancer cell lines, which have mutations in the retinoblastoma (RB) gene. Forced expression of RB increased levels of Smurf2 protein with concomitant decreases in

  12. Pleomorphic Adenoma of Breast: A Radiological and Pathological Study of a Common Tumor in an Uncommon Location

    Directory of Open Access Journals (Sweden)

    Paula S. Ginter

    2015-01-01

    Full Text Available Pleomorphic adenoma occurs commonly in the major salivary glands but is uncommonly encountered in the breast. In both of these locations, the tumor is typically grossly circumscribed and has a “mixed” histological appearance, being composed of myoepithelial and epithelial components amid a myxochondroid matrix. Herein, we report a case of pleomorphic adenoma of the breast which was preoperatively thought to represent a fibroadenoma on clinical and radiological grounds. It is the rarity of the tumor in the breast, rather than its histological appearance, that causes diagnostic difficulty.

  13. Serum‐derived exosomes from mice with highly metastatic breast cancer transfer increased metastatic capacity to a poorly metastatic tumor

    OpenAIRE

    Gorczynski, Reginald M.; Erin, Nuray; Zhu, Fang

    2016-01-01

    Abstract Altered interaction between CD200 and CD200R represents an example of “checkpoint blockade” disrupting an effective, tumor‐directed, host response in murine breast cancer cells. In CD200R1KO mice, long‐term cure of EMT6 breast cancer, including metastatic spread to lung and liver, was achieved in BALB/c mice. The reverse was observed with 4THM tumors, an aggressive, inflammatory breast cancer, with increased tumor metastasis in CD200R1KO. We explored possible explanations for this di...

  14. Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Wei [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Li, Ying; Zhao, Haixia; Xie, Xianfei; Zheng, Hao; Wang, Chenlong; Wang, Xue [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Yang, Guifang [Department of Pathology, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Cai, Xiaojun [Department of Ophthalmology, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Falck, John R. [Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 (United States); Yang, Jing, E-mail: yangjingliu@yahoo.com.cn [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China)

    2012-10-01

    Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressing cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1-expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9-fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation. -- Highlights: ► CYP4Z1 overexpression promotes human breast cancer growth and angiogenesis. ► The pro-angiogenic effects of CYP4Z1 have

  15. Identifying metastatic breast tumors using textural kinetic features of a contrast based habitat in DCE-MRI

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    Chaudhury, Baishali; Zhou, Mu; Goldgof, Dmitry B.; Hall, Lawrence O.; Gatenby, Robert A.; Gillies, Robert J.; Drukteinis, Jennifer S.

    2015-03-01

    The ability to identify aggressive tumors from indolent tumors using quantitative analysis on dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) would dramatically change the breast cancer treatment paradigm. With this prognostic information, patients with aggressive tumors that have the ability to spread to distant sites outside of the breast could be selected for more aggressive treatment and surveillance regimens. Conversely, patients with tumors that do not have the propensity to metastasize could be treated less aggressively, avoiding some of the morbidity associated with surgery, radiation and chemotherapy. We propose a computer aided detection framework to determine which breast cancers will metastasize to the loco-regional lymph nodes as well as which tumors will eventually go on to develop distant metastses using quantitative image analysis and radiomics. We defined a new contrast based tumor habitat and analyzed textural kinetic features from this habitat for classification purposes. The proposed tumor habitat, which we call combined-habitat, is derived from the intersection of two individual tumor sub-regions: one that exhibits rapid initial contrast uptake and the other that exhibits rapid delayed contrast washout. Hence the combined-habitat represents the tumor sub-region within which the pixels undergo both rapid initial uptake and rapid delayed washout. We analyzed a dataset of twenty-seven representative two dimensional (2D) images from volumetric DCE-MRI of breast tumors, for classification of tumors with no lymph nodes from tumors with positive number of axillary lymph nodes. For this classification an accuracy of 88.9% was achieved. Twenty of the twenty-seven patients were analyzed for classification of distant metastatic tumors from indolent cancers (tumors with no lymph nodes), for which the accuracy was 84.3%.

  16. Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer.

    Directory of Open Access Journals (Sweden)

    Bruna Victorasso Jardim-Perassi

    Full Text Available As neovascularization is essential for tumor growth and metastasis, controlling angiogenesis is a promising tactic in limiting cancer progression. Melatonin has been studied for their inhibitory properties on angiogenesis in cancer. We performed an in vivo study to evaluate the effects of melatonin treatment on angiogenesis in breast cancer. Cell viability was measured by MTT assay after melatonin treatment in triple-negative breast cancer cells (MDA-MB-231. After, cells were implanted in athymic nude mice and treated with melatonin or vehicle daily, administered intraperitoneally 1 hour before turning the room light off. Volume of the tumors was measured weekly with a digital caliper and at the end of treatments animals underwent single photon emission computed tomography (SPECT with Technetium-99m tagged vascular endothelial growth factor (VEGF C to detect in vivo angiogenesis. In addition, expression of pro-angiogenic/growth factors in the tumor extracts was evaluated by membrane antibody array and collected tumor tissues were analyzed with histochemical staining. Melatonin in vitro treatment (1 mM decreased cell viability (p0.05 images. In addition, there was a decrease of micro-vessel density (Von Willebrand Factor in melatonin treated mice (p<0.05. However, semiquantitative densitometry analysis of membrane array indicated increased expression of epidermal growth factor receptor and insulin-like growth factor 1 in treated tumors compared to vehicle treated tumors (p<0.05. In conclusion, melatonin treatment showed effectiveness in reducing tumor growth and cell proliferation, as well as in the inhibition of angiogenesis.

  17. Circulating Tumor Cells: A Review of Present Methods and the Need to Identify Heterogeneous Phenotypes

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    Millner, Lori M.; Linder, Mark W.; Valdes, Roland

    2016-01-01

    The measurement and characterization of circulating tumor cells (CTCs) hold promise for advancing personalized therapeutics. CTCs are the precursor to metastatic cancer and thus have the potential to radically alter patient treatment and outcome. Currently, clinical information provided by the enumeration of CTCs is limited to predicting clinical outcome. Other areas of interest in advancing the practice of pathology include: using CTCs for early detection of potential metastasis, determining and monitoring the efficacy of individualized treatment regimens, and predicting site-specific metastasis. Important hurdles to overcome in obtaining this type of clinical information involve present limitations in defining, detecting, and isolating CTCs. Currently, CTCs are detected using epithelial markers. The definition of what distinguishes a CTC should be expanded to include CTCs with heterogeneous phenotypes, and markers should be identified to enable a more comprehensive capture. Additionally, most methods available for detecting CTCs do not capture functionally viable CTCs. Retaining functional viability would provide a significant advantage in characterizing CTC-subtypes that may predict the site of metastatic invasion and thus assist in selecting effective treatment regimens. In this review we describe areas of clinical interest followed by a summary of current circulating cell-separation technologies and present limitations. Lastly, we provide insight into what is required to overcome these limitations as they relate to applications in advancing the practice of pathology and laboratory medicine. PMID:23884225

  18. Multi-modality imaging of tumor phenotype and response to therapy

    Science.gov (United States)

    Nyflot, Matthew J.

    2011-12-01

    Imaging and radiation oncology have historically been closely linked. However, the vast majority of techniques used in the clinic involve anatomical imaging. Biological imaging offers the potential for innovation in the areas of cancer diagnosis and staging, radiotherapy target definition, and treatment response assessment. Some relevant imaging techniques are FDG PET (for imaging cellular metabolism), FLT PET (proliferation), CuATSM PET (hypoxia), and contrast-enhanced CT (vasculature and perfusion). Here, a technique for quantitative spatial correlation of tumor phenotype is presented for FDG PET, FLT PET, and CuATSM PET images. Additionally, multimodality imaging of treatment response with FLT PET, CuATSM, and dynamic contrast-enhanced CT is presented, in a trial of patients receiving an antiangiogenic agent (Avastin) combined with cisplatin and radiotherapy. Results are also presented for translational applications in animal models, including quantitative assessment of proliferative response to cetuximab with FLT PET and quantification of vascular volume with a blood-pool contrast agent (Fenestra). These techniques have clear applications to radiobiological research and optimized treatment strategies, and may eventually be used for personalized therapy for patients.

  19. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters.

    Science.gov (United States)

    Cheung, Kevin J; Padmanaban, Veena; Silvestri, Vanesa; Schipper, Koen; Cohen, Joshua D; Fairchild, Amanda N; Gorin, Michael A; Verdone, James E; Pienta, Kenneth J; Bader, Joel S; Ewald, Andrew J

    2016-02-16

    Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases. We directly observed multicolored tumor cell clusters across major stages of metastasis, including collective invasion, local dissemination, intravascular emboli, circulating tumor cell clusters, and micrometastases. Experimentally aggregating tumor cells into clusters induced a >15-fold increase in colony formation ex vivo and a >100-fold increase in metastasis formation in vivo. Intriguingly, locally disseminated clusters, circulating tumor cell clusters, and lung micrometastases frequently expressed the epithelial cytoskeletal protein, keratin 14 (K14). RNA-seq analysis revealed that K14(+) cells were enriched for desmosome and hemidesmosome adhesion complex genes, and were depleted for MHC class II genes. Depletion of K14 expression abrogated distant metastases and disrupted expression of multiple metastasis effectors, including Tenascin C (Tnc), Jagged1 (Jag1), and Epiregulin (Ereg). Taken together, our findings reveal K14 as a key regulator of metastasis and establish the concept that K14(+) epithelial tumor cell clusters disseminate collectively to colonize distant organs. PMID:26831077

  20. Biomarker and Phenotypic Risk Factors for Breast Cancer Lymphedema | Division of Cancer Prevention

    Science.gov (United States)

     DESCRIPTION (provided by applicant): Lymphedema (LE) following treatment for breast cancer is the most common form of secondary LE in the industrialized world. It occurs in 20% to 87% of patients following treatment for breast cancer and results in significant disability. At the |

  1. LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ong, Danny C.T.; Rudduck, Christina; Chin, Koei; Kuo, Wen-Lin; Lie, Daniel K.H.; Chua, Constance L.M.; Wong, Chow Yin; Hong, Ga Sze; Gray, Joe; Lee, Ann S.G.

    2008-05-06

    Deletion of 11q23-q24 is frequent in a diverse variety of malignancies, including breast and colorectal carcinoma, implicating the presence of a tumor suppressor gene at that chromosomal region. We show here that LARG, from 11q23, has functional characteristics of a tumor suppressor. We examined a 6-Mb region on 11q23 by high-resolution deletion mapping, utilizing both loss of heterozygosity (LOH) analysis and microarray comparative genomic hybridization (CGH). LARG (also called ARHGEF12), identified from the analyzed region, was underexpressed in 34% of primary breast carcinomas and 80% of breast cancer cell lines including the MCF-7 line. Multiplex ligation-dependent probe amplification on 30 primary breast cancers and six breast cancer cell lines showed that LARG had the highest frequency of deletion compared to the BCSC-1 and TSLC1 genes, two known candidate tumor suppressor genes from 11q. In vitro analysis of breast cancer cell lines that underexpress LARG showed that LARG could be reactivated by trichostatin A, a histone deacetylase inhibitor, but not by 5-Aza-2{prime}-deoxycytidine, a demethylating agent. Bisulfite sequencing and quantitative high-throughput analysis of DNA methylation confirmed the lack of CpG island methylation in LARG in breast cancer. Restoration of LARG expression in MCF-7 cells by stable transfection resulted in reduced proliferation and colony formation, suggesting that LARG has functional characteristics of a tumor suppressor gene.

  2. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4⁺ T cells to T-regulatory cells.

    Science.gov (United States)

    Olkhanud, Purevdorj B; Damdinsuren, Bazarragchaa; Bodogai, Monica; Gress, Ronald E; Sen, Ranjan; Wejksza, Katarzyna; Malchinkhuu, Enkhzol; Wersto, Robert P; Biragyn, Arya

    2011-05-15

    Pulmonary metastasis of breast cancer requires recruitment and expansion of T-regulatory cells (Treg) that promote escape from host protective immune cells. However, it remains unclear precisely how tumors recruit Tregs to support metastatic growth. Here we report the mechanistic involvement of a unique and previously undescribed subset of regulatory B cells. These cells, designated tumor-evoked Bregs (tBreg), phenotypically resemble activated but poorly proliferative mature B2 cells (CD19(+) CD25(High) CD69(High)) that express constitutively active Stat3 and B7-H1(High) CD81(High) CD86(High) CD62L(Low) IgM(Int). Our studies with the mouse 4T1 model of breast cancer indicate that the primary role of tBregs in lung metastases is to induce TGF-β-dependent conversion of FoxP3(+) Tregs from resting CD4(+) T cells. In the absence of tBregs, 4T1 tumors cannot metastasize into the lungs efficiently due to poor Treg conversion. Our findings have important clinical implications, as they suggest that tBregs must be controlled to interrupt the initiation of a key cancer-induced immunosuppressive event that is critical to support cancer metastasis. PMID:21444674

  3. Clinical Outcome of Breast Conservation Therapy for Breast Cancer in Hong Kong: Prognostic Impact of Ipsilateral Breast Tumor Recurrence and 2005 St. Gallen Risk Categories

    International Nuclear Information System (INIS)

    Purpose: The aim of this study was to evaluate the clinical outcome of breast conservation therapy (BCT) for invasive breast cancers in our predominantly Chinese population. Methods and Materials: Clinical outcomes of 412 T1-2 invasive breast cancers treated by wide local excision and external radiotherapy from 1994 to 2003 were retrospectively analyzed. Only 7% lesions were first detected by mammograms. Adjuvant tamoxifen and chemotherapy were added in 74% and 45% patients, respectively. Results: The median follow-up was 5.4 years. The 5-year actuarial ipsilateral breast tumor recurrence (IBTR) rate, distant failure-free survival, cause-specific survival, and overall survival were 4%, 92%, 96%, and 98%, respectively. The 5-year distant failure-free survival for the low-risk, intermediate-risk, and high-risk categories (2005 St. Gallen) were 98%, 91%, and 80%, respectively (p 0.0003). Cosmetic results were good to excellent in more than 90% of the assessable patients. Grade 3 histology (hazard ratio [HR], 4.461; 95% CI, 1.216-16.360; p = 0.024), age (HR, 0.915; 95% CI, 0.846-0.990; p = 0.027), and close/positive final margins (HR, 3.499; 95% CI, 1.141-10.729; p = 0.028) were significant independent risk factors for IBTR. Both St. Gallen risk categories (p = 0.003) and IBTR (HR, 5.885; 95% CI, 2.494-13.889; p < 0.0005) were independent prognostic factors for distant failure-free survival. Conclusions: Despite the low percentage of mammographically detected lesions, the overall clinical outcome of BCT for invasive breast cancers in the Chinese population is comparable to the Western series. The 2005 St. Gallen risk category is a promising clinical tool, but further validation by large studies is warranted

  4. Minimal elastographic modeling of breast cancer for model based tumor detection in a digital image elasto tomography (DIET) system

    Science.gov (United States)

    Lotz, Thomas F.; Muller, Natalie; Hann, Christopher E.; Chase, J. Geoffrey

    2011-03-01

    Digital Image Elasto Tomography (DIET) is a non-invasive breast cancer screening technology that images the surface motion of a breast under harmonic mechanical actuation. A new approach capturing the dynamics and characteristics of tumor behavior is presented. A simple mechanical model of the breast is used to identify a transfer function relating the input harmonic actuation to the output surface displacements using imaging data of a silicone phantom. Areas of higher stiffness cause significant changes of damping and resonant frequencies as seen in the resulting Bode plots. A case study on a healthy and tumor silicone breast phantom shows the potential for this model-based method to clearly distinguish cancerous and healthy tissue as well as correctly predicting the tumor position.

  5. Chemotherapeutic (cyclophosphamide) effects on rat breast tumor hemodynamics monitored by multi-channel NIRS

    Science.gov (United States)

    Kim, Jae G.; Zhao, Dawen; Mason, Ralph P.; Liu, Hanli

    2005-04-01

    We previously suggested that the two time constants quantified from the increase of tumor oxyhemoglobin concentration, ▵ [HbO2], during hyperoxic gas intervention are associated with two blood flow/perfusion rates in well perfused and poorly perfused regions of tumors. In this study, our hypothesis is that when cancer therapy is applied to a tumor, changes in blood perfusion will occur and be detected by the NIRS. For experiments, systemic chemotherapy, cyclophosphamide (CTX), was applied to two groups of rats bearing syngeneic 13762NF mammary adenocarcinomas: one group received a single high dose i. p. (200 mg/kg CTX) and the other group continuous low doses (20 mg/kg CTX i. p. for 10 days). Time courses of changes in tumor ▵ [HbO2] were measured at four different locations on the breast tumors non-invasively with an inhaled gas sequence of air-oxygen-air before and after CTX administration. Both rat body weight and tumor volume decreased after administration of high dose CTX, but continuous low doses showed decrease of tumor volume only. Baselines (without any therapy) intra- and inter-tumor heterogeneity of vascular oxygenation during oxygen inhalation were similar to our previous observations. After CTX treatment, significant changes in vascular hemodynamic response to oxygen inhalation were observed from both groups. By fitting the increase of ▵ [HbO2] during oxygen inhalation, we have obtained changes of vascular structure ratio and also of perfusion rate ratio before and after chemotherapy. The preliminary results suggest that cyclophosphamide has greatest effect on the well perfused tumor vasculature. Overall, our study supports our earlier hypothesis, proving that the effects of chemotherapy in tumor may be monitored non-invasively by using NIRS to detect changes of hemodynamics induced with respiratory challenges.

  6. Patched Targeting Peptides for Imaging and Treatment of Hedgehog Positive Breast Tumors

    Directory of Open Access Journals (Sweden)

    Daniel Smith

    2014-01-01

    Full Text Available High tumor hedgehog expression is correlated with poor prognosis in invasive ductal carcinoma. Peptides which bind the patched receptor have recently been reported to have a growth inhibitory effect in tumors with activated hedgehog signaling. We sought to examine growth inhibition with these peptides in breast cancer cells and use these peptides as molecular imaging probes to follow changes in hedgehog expression after chemotherapy. Significant growth inhibition was observed in breast cancer cell lines treated with PTCH-blocking peptides. Significant in vitro uptake was observed with both FITC- and 99mTc-EC-peptide conjugates. In vivo imaging studies displayed greater accumulation of 99mTc-labeled peptides within tumors as compared to adjacent muscle tissue. Patched receptor expression increased after treatment and this correlated with an increase in tumor radiotracer uptake. These studies suggest that peptides which bind the sonic hedgehog docking site in patched receptor correlate with patched expression and can be used to image patched in vivo. Further, our data suggest that radiolabeled peptides may enable us to examine the activity of the hedgehog signaling pathway and to evaluate response to anti-cancer therapies.

  7. Patched Targeting Peptides for Imaging and Treatment of Hedgehog Positive Breast Tumors

    Science.gov (United States)

    Smith, Daniel; Kong, Fanlin; Yang, David; Woodward, Wendy A.

    2014-01-01

    High tumor hedgehog expression is correlated with poor prognosis in invasive ductal carcinoma. Peptides which bind the patched receptor have recently been reported to have a growth inhibitory effect in tumors with activated hedgehog signaling. We sought to examine growth inhibition with these peptides in breast cancer cells and use these peptides as molecular imaging probes to follow changes in hedgehog expression after chemotherapy. Significant growth inhibition was observed in breast cancer cell lines treated with PTCH-blocking peptides. Significant in vitro uptake was observed with both FITC- and 99mTc-EC-peptide conjugates. In vivo imaging studies displayed greater accumulation of 99mTc-labeled peptides within tumors as compared to adjacent muscle tissue. Patched receptor expression increased after treatment and this correlated with an increase in tumor radiotracer uptake. These studies suggest that peptides which bind the sonic hedgehog docking site in patched receptor correlate with patched expression and can be used to image patched in vivo. Further, our data suggest that radiolabeled peptides may enable us to examine the activity of the hedgehog signaling pathway and to evaluate response to anti-cancer therapies. PMID:25276795

  8. Chloroquine Engages the Immune System to Eradicate Irradiated Breast Tumors in Mice

    International Nuclear Information System (INIS)

    Purpose: This study used chloroquine to direct radiation-induced tumor cell death pathways to harness the antitumor activity of the immune system. Methods and Materials: Chloroquine given immediately after tumor irradiation increased the cure rate of MCaK breast cancer in C3H mice. Chloroquine blocked radiation-induced autophagy and drove MCaK cells into a more rapid apoptotic and more immunogenic form of cell death. Results: Chloroquine treatment made irradiated tumor vaccines superior at inducing strong interferon gamma-associated immune responses in vivo and protecting mice from further tumor challenge. In vitro, chloroquine slowed antigen uptake and degradation by dendritic cells, although T-cell stimulation was unaffected. Conclusions: This study illustrates a novel approach to improve the efficacy of breast cancer radiation therapy by blocking endosomal pathways, which enhances radiation-induced cell death within the field and drives antitumor immunity to assist therapeutic cure. The study illuminates and merges seemingly disparate concepts regarding the importance of autophagy in cancer therapy

  9. Chloroquine Engages the Immune System to Eradicate Irradiated Breast Tumors in Mice

    Energy Technology Data Exchange (ETDEWEB)

    Ratikan, Josephine Anna [Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California (United States); Sayre, James William [Public Health Biostatistics/Radiology at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, California (United States); Schaue, Dörthe, E-mail: dschaue@mednet.ucla.edu [Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California (United States)

    2013-11-15

    Purpose: This study used chloroquine to direct radiation-induced tumor cell death pathways to harness the antitumor activity of the immune system. Methods and Materials: Chloroquine given immediately after tumor irradiation increased the cure rate of MCaK breast cancer in C3H mice. Chloroquine blocked radiation-induced autophagy and drove MCaK cells into a more rapid apoptotic and more immunogenic form of cell death. Results: Chloroquine treatment made irradiated tumor vaccines superior at inducing strong interferon gamma-associated immune responses in vivo and protecting mice from further tumor challenge. In vitro, chloroquine slowed antigen uptake and degradation by dendritic cells, although T-cell stimulation was unaffected. Conclusions: This study illustrates a novel approach to improve the efficacy of breast cancer radiation therapy by blocking endosomal pathways, which enhances radiation-induced cell death within the field and drives antitumor immunity to assist therapeutic cure. The study illuminates and merges seemingly disparate concepts regarding the importance of autophagy in cancer therapy.

  10. Functional EpoR pathway utilization is not detected in primary tumor cells isolated from human breast, non-small cell lung, colorectal, and ovarian tumor tissues.

    Directory of Open Access Journals (Sweden)

    Scott D Patterson

    Full Text Available Several clinical trials in oncology have reported increased mortality or disease progression associated with erythropoiesis-stimulating agents. One hypothesis proposes that erythropoiesis-stimulating agents directly stimulate tumor proliferation and/or survival through cell-surface receptors. To test this hypothesis and examine if human tumors utilize the erythropoietin receptor pathway, the response of tumor cells to human recombinant erythropoietin was investigated in disaggregated tumor cells obtained from 186 patients with colorectal, breast, lung, ovarian, head and neck, and other tumors. A cocktail of well characterized tumor growth factors (EGF, HGF, and IGF-1 were analyzed in parallel as a positive control to determine whether freshly-isolated tumor cells were able to respond to growth factor activation ex vivo. Exposing tumor cells to the growth factor cocktail resulted in stimulation of survival and proliferation pathways as measured by an increase in phosphorylation of the downstream signaling proteins AKT and ERK. In contrast, no activation by human recombinant erythropoietin was observed in isolated tumor cells. Though tumor samples exhibited a broad range of cell-surface expression of EGFR, c-Met, and IGF-1R, no cell-surface erythropoietin receptor was detected in tumor cells from the 186 tumors examined (by flow cytometry or Western blot. Erythropoiesis-stimulating agents did not act directly upon isolated tumor cells to stimulate pathways known to promote proliferation or survival of human tumor cells isolated from primary and metastatic tumor tissues.

  11. Radio-photothermal therapy mediated by a single compartment nanoplatform depletes tumor initiating cells and reduces lung metastasis in the orthotopic 4T1 breast tumor model

    Science.gov (United States)

    Zhou, Min; Zhao, Jun; Tian, Mei; Song, Shaoli; Zhang, Rui; Gupta, Sanjay; Tan, Dongfeng; Shen, Haifa; Ferrari, Mauro; Li, Chun

    2015-11-01

    Tumor Initiating Cells (TICs) are resistant to radiotherapy and chemotherapy, and are believed to be responsible for tumor recurrence and metastasis. Combination therapies can overcome the limitation of conventional cancer treatments, and have demonstrated promising application in the clinic. Here, we show that dual modality radiotherapy (RT) and photothermal therapy (PTT) mediated by a single compartment nanosystem copper-64-labeled copper sulfide nanoparticles ([64Cu]CuS NPs) could suppress breast tumor metastasis through eradication of TICs. Positron electron tomography (PET) imaging and biodistribution studies showed that more than 90% of [64Cu]CuS NPs was retained in subcutaneously grown BT474 breast tumor 24 h after intratumoral (i.t.) injection, indicating the NPs are suitable for the combination therapy. Combined RT/PTT therapy resulted in significant tumor growth delay in the subcutaneous BT474 breast cancer model. Moreover, RT/PTT treatment significantly prolonged the survival of mice bearing orthotopic 4T1 breast tumors compared to no treatment, RT alone, or PTT alone. The RT/PTT combination therapy significantly reduced the number of tumor nodules in the lung and the formation of tumor mammospheres from treated 4T1 tumors. No obvious side effects of the CuS NPs were noted in the treated mice in a pilot toxicity study. Taken together, our data support the feasibility of a therapeutic approach for the suppression of tumor metastasis through localized RT/PTT therapy.Tumor Initiating Cells (TICs) are resistant to radiotherapy and chemotherapy, and are believed to be responsible for tumor recurrence and metastasis. Combination therapies can overcome the limitation of conventional cancer treatments, and have demonstrated promising application in the clinic. Here, we show that dual modality radiotherapy (RT) and photothermal therapy (PTT) mediated by a single compartment nanosystem copper-64-labeled copper sulfide nanoparticles ([64Cu]CuS NPs) could suppress

  12. Tiling array-CGH for the assessment of genomic similarities among synchronous unilateral and bilateral invasive breast cancer tumor pairs

    Directory of Open Access Journals (Sweden)

    Ringnér Markus

    2008-07-01

    Full Text Available Abstract Background Today, no objective criteria exist to differentiate between individual primary tumors and intra- or intermammary dissemination respectively, in patients diagnosed with two or more synchronous breast cancers. To elucidate whether these tumors most likely arise through clonal expansion, or whether they represent individual primary tumors is of tumor biological interest and may have clinical implications. In this respect, high resolution genomic profiling may provide a more reliable approach than conventional histopathological and tumor biological factors. Methods 32 K tiling microarray-based comparative genomic hybridization (aCGH was used to explore the genomic similarities among synchronous unilateral and bilateral invasive breast cancer tumor pairs, and was compared with histopathological and tumor biological parameters. Results Based on global copy number profiles and unsupervised hierarchical clustering, five of ten (p = 1.9 × 10-5 unilateral tumor pairs displayed similar genomic profiles within the pair, while only one of eight bilateral tumor pairs (p = 0.29 displayed pair-wise genomic similarities. DNA index, histological type and presence of vessel invasion correlated with the genomic analyses. Conclusion Synchronous unilateral tumor pairs are often genomically similar, while synchronous bilateral tumors most often represent individual primary tumors. However, two independent unilateral primary tumors can develop synchronously and contralateral tumor spread can occur. The presence of an intraductal component is not informative when establishing the independence of two tumors, while vessel invasion, the presence of which was found in clustering tumor pairs but not in tumor pairs that did not cluster together, supports the clustering outcome. Our data suggest that genomically similar unilateral tumor pairs may represent a more aggressive disease that requires the addition of more severe treatment modalities, and

  13. Postmenopausal obesity promotes tumor angiogenesis and breast cancer progression in mice.

    Science.gov (United States)

    Gu, Jian-Wei; Young, Emily; Patterson, Sharla G; Makey, Kristina L; Wells, Jeremy; Huang, Min; Tucker, Kevan B; Miele, Lucio

    2011-05-15

    Obese postmenopausal women have a 50% higher risk of breast cancer than non-obese women. There is not an animal model that mimics postmenopausal obesity related to breast cancer progression. Using age-relevant C57BL/6 mice, this study determined whether postmenopausal obesity increases VEGF expression, tumor angiogenesis, and breast tumor growth. Ovariectomy (OVX) was performed in 12 sixty week-old female mice, then followed by a low-fat (5%, LF, n=6) or a high-fat (60%, HF, n=6) diet for 12 weeks. In the eighth week of the dietary program, 10(6) E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland. Tumor size was monitored for 4 weeks. Body weights were monitored weekly. At the end of the experiment, blood samples, visceral fat and tumors were collected for measuring VEGF expression using ELISA and intratumoral microvessel density (IMD) using CD31 immunochemistry. Body weight was significantly increased in OVX/HF mice, compared to OVX/LF group (55.3±1.7 vs. 41.5±1.5 g; p < 0.01). There was a two-fold increase in the ratio of visceral fat/BW in OVX/HF mice, compared to those in OVX/LF group (0.062±0.005 vs. 0.032±0.003; p < 0.01). Postmenopausal obesity significantly increased breast tumor weight over the control (4.62±0.63 vs. 1.98±0.27 g; p < 0.01) and IMD (173±3.7 vs. 139±4.3 IM#/mm^2; p < 0.01). Tumor VEGF levels were higher in OVX/HF mice, compared to OVX/LF group (73.3±3.8 vs. 49.5±4.3 pg/mg protein; p < 0.01). Plasma VEGF levels (69±7.1 vs. 48±3.5 pg/ml) and visceral fat VEGF levels (424.4±39.5 vs. 208.5±22.4 pg/mg protein) were significantly increased in OVX/HF mice, compared to OVX/LF group, respectively (n=6; p < 0.01). Interestingly, adipose tissue primary culture showed that subcutaneous fat released more VEGF, compared to visceral fat (6.77±1.14 vs. 0.94±0.16 pg/mg tissue; n=6; p < 0.01). These findings support the hypothesis that postmenopausal obesity promotes tumor angiogenesis and breast cancer

  14. Chemotherapy triggers HIF-1-dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype.

    Science.gov (United States)

    Lu, Haiquan; Samanta, Debangshu; Xiang, Lisha; Zhang, Huimin; Hu, Hongxia; Chen, Ivan; Bullen, John W; Semenza, Gregg L

    2015-08-18

    Triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancer but is responsible for a disproportionate share of morbidity and mortality because of its aggressive characteristics and lack of targeted therapies. Chemotherapy induces enrichment of breast cancer stem cells (BCSCs), which are responsible for tumor recurrence and metastasis. Here, we demonstrate that chemotherapy induces the expression of the cystine transporter xCT and the regulatory subunit of glutamate-cysteine ligase (GCLM) in a hypoxia-inducible factor (HIF)-1-dependent manner, leading to increased intracellular glutathione levels, which inhibit mitogen-activated protein kinase kinase (MEK) activity through copper chelation. Loss of MEK-ERK signaling causes FoxO3 nuclear translocation and transcriptional activation of the gene encoding the pluripotency factor Nanog, which is required for enrichment of BCSCs. Inhibition of xCT, GCLM, FoxO3, or Nanog blocks chemotherapy-induced enrichment of BCSCs and impairs tumor initiation. These results suggest that, in combination with chemotherapy, targeting BCSCs by inhibiting HIF-1-regulated glutathione synthesis may improve outcome in TNBC.

  15. Basal-Like Phenotype in a Breast Carcinoma Case Series from Sudan: Prevalence and Clinical/Pathological Correlations

    Directory of Open Access Journals (Sweden)

    Khalid Dafaallah Awadelkarim

    2011-01-01

    Full Text Available Basal-like breast cancer, an aggressive subtype associated with high grade, poor prognosis, and younger age, is reported frequently in Africa. We analyzed the expression of the basal cytokeratins (CKs 5/6 and 17 in a case series from Central Sudan and investigated correlations among basal CK status, ER, PgR, and Her-2/neu, and individual/clinicopathological data. Of 113 primary breast cancers 26 (23%, 38 (34%, and 46 (41% were, respectively, positive for CK5/6, CK17, and combined basal CKs (CK5/6 and/or CK17. Combined basal CK+ status was associated with higher grade (P<.03 and inversely correlated with ER (P<.002, PgR (P=.004 and combined ER and/or PgR (P<.0002. Two clusters based on all tested markers were generated by hierarchical cluster analysis and k-mean clustering: I: designated ``hormone receptors positive/luminal-like’’ and II: designated ``hormone receptors negative’’, including both basal-like and Her-2/neu+ tumors. The most important factors for dataset variance were ER status, followed by PgR, CK17, and CK5/6 statuses. Overall basal CKs were expressed in a fraction of cases comparable to that reported for East and West African case series. Lack of associations with age and tumor size may represent a special feature of basal-like breast cancer in Sudan.

  16. Using diffuse optical tomograpy to monitor tumor response to neoadjuvant chemotherapy in breast cancer patients

    Science.gov (United States)

    Gunther, Jacqueline E.; Lim, Emerson; Kim, Hyun Keol; Flexman, Molly; Brown, Mindy; Refrice, Susan; Kalinsky, Kevin; Hershman, Dawn; Hielscher, Andreas H.

    2013-03-01

    Breast cancer patients often undergo neoadjuvant chemotherapy to reduce the size of the tumor before surgery. Tumors which demonstrate a pathologic complete response associate with improved disease-free survival; however, as low as 10% of patients may achieve this status. The goal is to predict response to anti-cancer therapy early, so as to develop personalized treatments and optimize the patient's results. Previous studies have shown that tumor response can be predicted within a few days of treatment initiation. We have developed a diffuse optical tomography (DOT) imaging system for monitoring the response of breast cancer patients to neoadjuvant chemotherapy. Our breast imaging system is a continuous wave system that uses four wavelengths in the near-infrared spectrum (765 nm, 808 nm, 827 nm, and 905 nm). Both breasts are imaged simultaneously with a total of 64 sources and 128 detectors. Three dimensional reconstructions for oxy-hemoglobin concentration ([HbO2]), deoxy-hemoglobin ([Hb]) concentrations, and water are performed using a PDE-constrained multispectral imaging method that uses the diffusion approximation as a model for light propagation. Each patient receives twelve weekly treatments of Taxane followed by four cycles of Doxorubicin and Cyclophosphamide (AC) given every other week. There are six DOT imaging time points: baseline, week 3 and 5 of Paclitaxel, before cycle 1 and 2 of AC, and before surgery. Preliminary results show that there is statistical significance for the percent change of [HbO2], [Hb], [HbT], and percent water at week 2 from the baseline between patients with a pathologic response to chemotherapy.

  17. Which patients don't need a tumor-bed boost after whole-breast radiotherapy?

    International Nuclear Information System (INIS)

    Background: Retrospective dose-response data suggest that a boost of about 15 Gy to the tumor bed following whole-breast radiotherapy reduces the risk of local recurrence (IBTR) by as much as 2-fold. Even if this benefit is confirmed by prospective trials, boost irradiation may not be considered cost-effective in patients having an IBTR risk of less than 1% per annum. Methods: Published prospective trials of invasive breast cancers (National Surgical Adjuvant Breast and Bowel Project; Stockholm Adjuvant Tamoxifen Trial) in which patients received 50 Gy whole-breast irradiation, without a boost, were analyzed to identify subgroups with IBTR risk less than 1% per year. All studies were based on lumpectomy (rather than segmental or quadrant excision) and eligibility required the absence of cancer cells at the margins. It was assumed that clinical and pathological factors, other than those defining trial eligibility, were of negligible importance regarding IBTR risk, with the exception of young age. Results: All patients not receiving adjuvant systemic therapy, including tumors<1 cm, have IBTR risk justifying boost irradiation. Of patients receiving systemic therapy, only patients with node-negative, estrogen receptor-positive tumors have low IBTR risk (3% at 10 years), provided that tamoxifen is administered. Of patients receiving only adjuvant chemotherapy, low IBTR risk seems to be associated with administration concomitantly with radiotherapy. IBTR risk in patients receiving chemotherapy sequentially with respect to radiotherapy probably is high enough to justify a boost. A boost is probably indicated in all patients younger than 40 years, regardless of other factors. (orig.)

  18. Magnetic resonance characterization of tumor microvessels in experimental breast tumors using a slow clearance blood pool contrast agent (carboxymethyldextran-A2-Gd-DOTA) with histopathological correlation

    International Nuclear Information System (INIS)

    Carboxymethyldextran (CMD)-A2-Gd-DOTA, a slow clearance blood pool contrast agent with a molecular weight of 52.1 kDa, designed to have intravascular residence for more than 1 h, was evaluated for its potential to characterize and differentiate the microvessels of malignant and benign breast tumors. Precontrast single-slice inversion-recovery snapshot FLASH and dynamic contrast-enhanced MRI using an axial T1-weighted three-dimensional spoiled gradient recalled sequence was performed in 30 Sprague-Dawley rats with chemically induced breast tumors. Endothelial transfer coefficient and fractional plasma volume of the breast tumors were estimated from MRI data acquired with CMD-A2-Gd-DOTA enhancement injected at a dose of 0.1 mmol Gd/kg body weight using a two-compartment bidirectional model of the tumor tissue. The correlation between MRI microvessel characteristics and histopathological tumor grade was determined using the Scarff-Bloom-Richardson method. Using CMD-A2-Gd-DOTA, no significant correlations were found between the MR-estimated endothelial transfer coefficient or plasma volumes with histological tumor grade. Analysis of CMD-A2-Gd-DOTA-enhanced MR kinetic data failed to demonstrate feasibility for the differentiation of benign from malignant tumors or for image-based tumor grading. (orig.)

  19. Luminal breast cancer metastasis is dependent on estrogen signaling

    OpenAIRE

    Ganapathy, Vidya; Banach-Petrosky, Whitney; Xie, Wen; Kareddula, Aparna; Nienhuis, Hilde; Miles, Gregory; Reiss, Michael

    2012-01-01

    Luminal breast cancer is the most frequently encountered type of human breast cancer and accounts for half of all breast cancer deaths due to metastatic disease. We have developed new in vivo models of disseminated human luminal breast cancer that closely mimic the human disease. From initial lesions in the tibia, locoregional metastases develop predictably along the iliac and retroperitoneal lymph node chains. Tumors cells retain their epithelioid phenotype throughout the process of dissemin...

  20. Brain tumor stem cells maintain overall phenotype and tumorigenicity after in vitro culturing in serum-free conditions

    Science.gov (United States)

    Vik-Mo, Einar Osland; Sandberg, Cecilie; Olstorn, Havard; Varghese, Mercy; Brandal, Petter; Ramm-Pettersen, Jon; Murrell, Wayne; Langmoen, Iver Arne

    2010-01-01

    Traditional in vitro culturing of tumor cells has been shown to induce changes so that cultures no longer represent the tumor of origin. Serum-free culturing conditions are used in a variety of cancers to propagate stem-like cells in vitro. Limited reports, however, exist on the effects of such propagation. We have compared cells from brain tumor biopsies cultivated under serum-free conditions at passages 2 and 10 to describe the effects of in vitro culturing. We were able to establish cell lines from 7 of 10 biopsies from patients with glioblastoma. The cell lines adapted to conditions and had 2.2 times increased population doubling rate at later passages. Karyotyping and comparative genomic hybridization analysis revealed that all examined cell lines had cytogenetic aberrations commonly found in glioblastomas, and there were only minor differences between tumor and early and late passages in the same culture. Whole-transcriptome analysis shows that tumors had interindividual differences. Changes in the overall expression patterns through passaging were modest, with a significant change in only 14 genes; the variation among cultures was, however, reduced through passages. The ability to differentiate differed among tumors but was maintained throughout passaging. The cells initiated tumors upon transplantation to immunodeficient mice with differing phenotypes, but a given cell culture maintained tumor phenotype after serial cultivation. The cultures established maintained individual characteristics specific to culture identity. Thus, each cell culture reflects an image of the tumor—or a personalized model—from which it was derived and remains representative after moderate expansion. PMID:20843775

  1. Bioenergy and Breast Cancer: A Report on Tumor Growth and Metastasis.

    Science.gov (United States)

    Running, Alice; Greenwood, Mark; Hildreth, Laura; Schmidt, Jade

    2016-01-01

    As many as 80% of the 296,000 women and 2,240 men diagnosed with breast cancer in the United States will seek out complementary and alternative medicine (CAM) treatments. One such therapy is Healing Touch (HT), recognized by the National Center for Complementary and Integrative Health (NCCIH) as a treatment modality. Using a multiple experimental groups design, fifty-six six- to eight-week-old Balb/c mice were injected with 4T1 breast cancer tumor cells and randomly divided into intervention and positive control groups. Five days after tumor cell injection, mice in the intervention groups received HT either daily or every other day for 10 minutes by one HT practitioner. At 15 days after tumor cell injection, tumor size was measured, and metastasis was evaluated by a medical pathologist after necropsy. Tumor size did not differ significantly among the groups (F(3,52) = 0.75, p value = 0.53). The presence of metastasis did not differ across groups (chi-square(3) = 3.902, p = 0.272) or when compared within an organ (liver: chi-square(3) = 2.507, p = 0.474; lungs: chi-square(3) = 3.804, p = 0.283; spleen: chi-square(3) = 0.595, p = 0.898). However, these results did indicate a moderate, though insignificant, positive impact of HT and highlight the need for continued research into dose, length of treatment, and measurable outcomes (tumor size, metastasis) to provide evidence to suggest application for nursing care.

  2. Levels of plasma circulating cell free nuclear and mitochondrial DNA as potential biomarkers for breast tumors

    Directory of Open Access Journals (Sweden)

    Diesch Claude

    2009-11-01

    Full Text Available Abstract Background With the aim to simplify cancer management, cancer research lately dedicated itself more and more to discover and develop non-invasive biomarkers. In this connection, circulating cell-free DNA (ccf DNA seems to be a promising candidate. Altered levels of ccf nuclear DNA (nDNA and mitochondrial DNA (mtDNA have been found in several cancer types and might have a diagnostic value. Methods Using multiplex real-time PCR we investigated the levels of ccf nDNA and mtDNA in plasma samples from patients with malignant and benign breast tumors, and from healthy controls. To evaluate the applicability of plasma ccf nDNA and mtDNA as a biomarker for distinguishing between the three study-groups we performed ROC (Receiver Operating Characteristic curve analysis. We also compared the levels of both species in the cancer group with clinicopathological parameters. Results While the levels of ccf nDNA in the cancer group were significantly higher in comparison with the benign tumor group (P P P P = 0.022. The level of ccf nDNA was also associated with tumor-size (2 cmP = 0.034. Using ROC curve analysis, we were able to distinguish between the breast cancer cases and the healthy controls using ccf nDNA as marker (cut-off: 1866 GE/ml; sensitivity: 81%; specificity: 69%; P P Conclusion Our data suggests that nuclear and mitochondrial ccf DNA have potential as biomarkers in breast tumor management. However, ccf nDNA shows greater promise regarding sensitivity and specificity.

  3. Household income is associated with the p53 mutation frequency in human breast tumors.

    Directory of Open Access Journals (Sweden)

    Adrienne M Starks

    Full Text Available BACKGROUND: A study from Scotland reported that the p53 mutation frequency in breast tumors is associated with socio-economic deprivation. METHODS: We analyzed the association of the tumor p53 mutational status with tumor characteristics, education, and self-reported annual household income (HI among 173 breast cancer patients from the greater Baltimore area, United States. RESULTS: p53 mutational frequency was significantly associated with HI. Patients with < $15,000 HI had the highest p53 mutation frequency (21%, followed by the income group between $15,000 and $60,000 (18%, while those above $60,000 HI had the fewest mutations (5%. When dichotomized at $60,000, 26 out of 135 patients in the low income category had acquired a p53 mutation, while only 2 out of 38 with a high income carried a mutation (P < 0.05. In the adjusted logistic regression analysis with 3 income categories (trend test, the association between HI and p53 mutational status was independent of tumor characteristics, age, race/ethnicity, tobacco smoking and body mass. Further analyses revealed that HI may impact the p53 mutational frequency preferentially in patients who develop an estrogen receptor (ER-negative disease. Within this group, 42% of the low income patients (< $15,000 HI carried a mutation, followed by the middle income group (21%, while those above $60,000 HI did not carry mutations (Ptrend < 0.05. CONCLUSIONS: HI is associated with the p53 mutational frequency in patients who develop an ER-negative disease. Furthermore, high income patients may acquire fewer p53 mutations than other patients, suggesting that lifetime exposures associated with socio-economic status may impact breast cancer biology.

  4. Small interfering RNA targeted to secretory clusterin blocks tumor growth, motility, and invasion in breast cancer

    Institute of Scientific and Technical Information of China (English)

    Zhaohe Niu; Xinhui Li; Bin Hu; Rong Li; Ligang Wang; Lilin Wu; Xingang Wang

    2012-01-01

    Clusterin/apolipoprotein J (Clu) is a ubiquitously expressed secreted heterodimeric glycoprotein that is implicated in several physiological processes.It has been reported that the elevated level of secreted clusterin (sClu) protein is associated with poor survival in breast cancer patients and can induce metastasis in rodent models.In this study,we investigated the effects of sClu inhibition with small interfering RNAs (siRNAs) on cell motility,invasion,and growth in vitro and in vivo.MDA-MB-231 cells were transfected with pSuper-siRNA/sClu.Cell survival and proliferation were examined by 3-(4,5-dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and clonogenic survival assay.The results showed that sClu silencing significantly inhibited the proliferation of MDA-MB-231 cells.The invasion and migration ability were also dramatically decreased,which was detected by matrigel assays.TUNEL staining and caspase-3 activity assay demonstrated that sClu silencing also could increase the apoptosis rate of cells,resulting in the inhibition of cell growth.We also determined the effects of sClu silencing on tumor growth and metastatic progression in an orthotopic breast cancer model.The results showed that orthotopic primary tumors derived from MDA-MB-231/pSuper sClu siRNA cells grew significantly slower than tumors derived from parental MDA-MB-231 or MDA-MB-231/pSuper scramble siRNA cells,and metastasize less to the lungs.These data suggest that secretory clusterin plays a significant role in tumor growth and metastatic progression.Knocking-down sClu gene expression may provide a valuable method for breast cancer therapy.

  5. Early-Stage Breast Cancer in the Octogenarian: Tumor Characteristics, Treatment Choices, and Clinical Outcomes

    Science.gov (United States)

    Mamtani, Anita; Gonzalez, Julie J.; Neo, Dayna; Slanetz, Priscilla J.; Houlihan, Mary Jane; Herold, Christina I.; Recht, Abram; Hacker, Michele R.; Sharma, Ranjna

    2016-01-01

    Background Nodal staging with sentinel node biopsy (SLNB), post-lumpectomy radiotherapy (RT), and endocrine therapy (ET) for estrogen receptor-positive (ER+) tumors is valuable in the treatment of early-stage (stages 1 or 2) breast cancer but used less often for elderly women. Methods This retrospective study investigated women referred for surgical evaluation of biopsy-proven primary early-stage invasive breast cancer from January 2001 to December 2010. Clinicopathologic features, treatment course, and outcomes for women ages 80–89 years and 50–59 years were compared. Results The study identified 178 eligible women ages 80–89 years and 169 women ages 50–59 years. The elderly women more often had grade 1 or 2 disease (p = 0.003) and ER+ tumors (p = 0.007) and less frequently had undergone adjuvant therapies (all p ≤ 0.001). Lumpectomy was performed more commonly for the elderly (92 vs. 83 %, p = 0.02), and axillary surgery was less commonly performed (46 vs. 96 %; p < 0.001). Fewer elderly women had undergone post-lumpectomy RT (42 vs. 89 %; p < 0.001) and ET for ER+ tumors (72 vs. 95 %; p < 0.001). During the median follow-up period of 56 months for the 80- to 89-year old group and 98 months for the 50- to 59-year-old group, death from breast cancer was similar (4 vs. 5 %; p = 0.5). The two groups respectively experienced 7 versus 6 locoregional recurrences and 11 versus 13 distant recurrences. Conclusions The octogenarians had disease survivorship similar to that of the younger women despite less frequent use of adjuvant therapies, likely reflecting lower-risk disease features. Whether increased use of axillary surgery, post-lumpectomy RT, and/or ET for ER+ tumors would further improve outcomes is an important area for further study, but treatment should not be deferred solely on the basis of age. PMID:27364507

  6. Function of immunoadjuvants in laser immunotherapy for treatment of metastatic breast tumors in rats

    Science.gov (United States)

    Chen, Wei R.; Liu, Hong; Wolf, Roman F.; Lucroy, Michael D.; Nordquist, Robert E.

    2002-06-01

    Tumor cell destruction usually induces host immune responses, such as local inflammation and increased activities of macrophages and neutrophils. Use of immunoadjuvant can usually enhance such immune activities. Laser immunotherapy is designed to use the combination of laser photothermal and immunological interactions to induce long-term antitumor immunity with the help of immunoadjuvant. It uses a selective hyperthermia for acute tumor destruction through an intratumor administration of indocyanine green and a noninvasive irradiation by an 805-nm laser. The concurrent in situ administration of immunoadjuvant helped achieve the desired effect: tumor eradication and antitumor immunity. The current study further explores the function of immunoadjuvants in laser immunotherapy by testing four different adjuvants: glycated chitosan, complete Freund's adjuvant, incomplete Freund's adjuvant, and c-parvum. Each adjuvant provided long-term tumor cure in the treatment of a metastatic mammary tumor model in rats. However, glycated chitosan and complete Freund's adjuvant were most effective with 25% and 18% long- term cure rates, respectively. Different concentrations of glycated chitosan were also used in treatment of rats bearing metastatic breast tumors.

  7. Hereditary breast and gynecological tumors: Italian legal issues.

    Science.gov (United States)

    DI Vella, Giancarlo

    2016-10-01

    The availability of diagnostic and therapeutic procedures that lower the risk for developing hereditary family-related tumors is weighed against Italian ethical and legal provisions. The healthcare environment in which a professional works should require that he possess specific technical, relational and medical competencies based upon legal orientation in addition to scientific evidence. Particular emphasis is attributed to the doctor-patient relationship, with explicit reference to the following: 1) all of the information at hand that is required to achieve a "therapeutic alliance" that combines the best interests of the patient with treatment options; 2) the completeness and intelligibility of health records, as they are likely to explain the background logic and the following of scientific clinical procedure; 3) the observance of guidelines and protocols, and their relevance to the legal responsibility of the individual and health care companies; 4) the need of a multidisciplinary approach in the treatment of these patients and the obligation of the team to have malpractice insurance. Advances on "provisions concerning liability of health personnel", which is currently awaiting approval, allows the professional to protect the patient's health without the fear of being unnecessarily censured, and unjustified from a penal or civil point of view which can deteriorate the relationship of trust and cooperation established. PMID:26924172

  8. Hereditary breast and gynecological tumors: Italian legal issues.

    Science.gov (United States)

    DI Vella, Giancarlo

    2016-10-01

    The availability of diagnostic and therapeutic procedures that lower the risk for developing hereditary family-related tumors is weighed against Italian ethical and legal provisions. The healthcare environment in which a professional works should require that he possess specific technical, relational and medical competencies based upon legal orientation in addition to scientific evidence. Particular emphasis is attributed to the doctor-patient relationship, with explicit reference to the following: 1) all of the information at hand that is required to achieve a "therapeutic alliance" that combines the best interests of the patient with treatment options; 2) the completeness and intelligibility of health records, as they are likely to explain the background logic and the following of scientific clinical procedure; 3) the observance of guidelines and protocols, and their relevance to the legal responsibility of the individual and health care companies; 4) the need of a multidisciplinary approach in the treatment of these patients and the obligation of the team to have malpractice insurance. Advances on "provisions concerning liability of health personnel", which is currently awaiting approval, allows the professional to protect the patient's health without the fear of being unnecessarily censured, and unjustified from a penal or civil point of view which can deteriorate the relationship of trust and cooperation established.

  9. Radiotherapy alone in breast cancer. I. Analysis of tumor parameters, tumor dose and local control: the experience of the Gustave-Roussy Institute and the Princess Margaret Hospital

    International Nuclear Information System (INIS)

    This retrospective study involved 463 breast cancer patients treated by radiotherapy alone at the Princess Margaret Hospital and at the Institut Gustave-Roussy. These patients either had operable tumors, but were unfit for general anesthesia, or had inoperable tumors due to local contraindications to surgery. Results were analyzed according to tumor response, local recurrence rate, tumor size, tumor fixation, nodal fixation and tumor dose. Conventional statistical analysis of local control showed two significant factors: tumor dose and tumor size. Multivariate analysis permitted to define an ''individual risk'' (IR) of local recurrence according to three independent factors: tumor size, tumor fixation, and nodal fixation. It was shown that the IR was a good prognostic factor for local control. Increase in tumor dose gave a similar effect in the local recurrence relative risk for all the IR groups. According to the slope of the dose-effect curve, it was deduced that a dose increase of 15 Gy can decrease the relative risk of local recurrence 2-fold. In fact, it was shown that tumor dose was the most significant independent factor on local control, able to produce up to a 10-fold increase compared to 2-fold decrease for tumor size. If the IR of local recurrence is known, a theoretical predictive value on local control, taking into account the tumor dose, can be determined according to the present data

  10. Novel Therapeutic Strategies for Malignant Salivary Gland Tumors: Lessons Learned from Breast Cancer

    Directory of Open Access Journals (Sweden)

    Ryuichi Murase

    2011-01-01

    Full Text Available Malignant salivary gland tumors (MSGTs account for 2–6% of all head and neck cancers. Despite the rarity, MSGTs have been of great interest due to a wide variety of pathological features and high metastasis rates resulting in poor prognosis. Surgical resection followed by radiation therapy represents the main treatment of this malignancy. Adjuvant therapy is reserved for the management of local recurrence, no longer amenable to additional local therapy, and for metastasis. Based on the studies from other types of tumors, particularly breast cancer, the expression and function of sex steroid hormone receptors in cancer have been extensively studied and applied to diagnosis and treatment. Although a number of studies in MSGTs have been published, the rationale for hormone therapy is still controversial due to the disparate results and insufficient number of cases. However, some recent reports have demonstrated that certain salivary gland neoplasms are similar to breast cancer, not only in terms of the pathological features, but also at the molecular level. Here, we shed light on the biological similarity between MSGTs and certain types of breast cancer, and describe the potential use of hormone and additional therapies for MSGTs.

  11. Can Biomarker Assessment on Circulating Tumor Cells Help Direct Therapy in Metastatic Breast Cancer?

    Energy Technology Data Exchange (ETDEWEB)

    Turner, Natalie [Sandro Pitigliani Medical Oncology Department, Prato Hospital, Istituto Toscano Tumori, Via Ugo Foscolo, Prato, PO 59100 (Italy); Pestrin, Marta [Sandro Pitigliani Medical Oncology Department, Prato Hospital, Istituto Toscano Tumori, Via Ugo Foscolo, Prato, PO 59100 (Italy); Translational Research Laboratory, Prato Hospital, Via Ugo Foscolo, Prato, PO 59100 (Italy); Galardi, Francesca; De Luca, Francesca [Translational Research Laboratory, Prato Hospital, Via Ugo Foscolo, Prato, PO 59100 (Italy); Malorni, Luca [Sandro Pitigliani Medical Oncology Department, Prato Hospital, Istituto Toscano Tumori, Via Ugo Foscolo, Prato, PO 59100 (Italy); Translational Research Laboratory, Prato Hospital, Via Ugo Foscolo, Prato, PO 59100 (Italy); Di Leo, Angelo, E-mail: adileo@usl4.toscana.it [Sandro Pitigliani Medical Oncology Department, Prato Hospital, Istituto Toscano Tumori, Via Ugo Foscolo, Prato, PO 59100 (Italy)

    2014-03-25

    Circulating tumor cell (CTC) count has prognostic significance in metastatic breast cancer, but the predictive utility of CTCs is uncertain. Molecular studies on CTCs have often been limited by a low number of CTCs isolated from a high background of leukocytes. Improved enrichment techniques are now allowing molecular characterisation of single CTCs, whereby molecular markers on single CTCs may provide a real-time assessment of tumor biomarker status from a blood test or “liquid biopsy”, potentially negating the need for a more invasive tissue biopsy. The predictive ability of CTC biomarker analysis has predominantly been assessed in relation to HER2, with variable and inconclusive results. Limited data exist for other biomarkers, such as the estrogen receptor. In addition to the need to define and validate the most accurate and reproducible method for CTC molecular analysis, the clinical relevance of biomarkers, including gain of HER2 on CTC after HER2 negative primary breast cancer, remains uncertain. This review summarises the currently available data relating to biomarker evaluation on CTCs and its role in directing management in metastatic breast cancer, discusses limitations, and outlines measures that may enable future development of this approach.

  12. Can Biomarker Assessment on Circulating Tumor Cells Help Direct Therapy in Metastatic Breast Cancer?

    Directory of Open Access Journals (Sweden)

    Natalie Turner

    2014-03-01

    Full Text Available Circulating tumor cell (CTC count has prognostic significance in metastatic breast cancer, but the predictive utility of CTCs is uncertain. Molecular studies on CTCs have often been limited by a low number of CTCs isolated from a high background of leukocytes. Improved enrichment techniques are now allowing molecular characterisation of single CTCs, whereby molecular markers on single CTCs may provide a real-time assessment of tumor biomarker status from a blood test or “liquid biopsy”, potentially negating the need for a more invasive tissue biopsy. The predictive ability of CTC biomarker analysis has predominantly been assessed in relation to HER2, with variable and inconclusive results. Limited data exist for other biomarkers, such as the estrogen receptor. In addition to the need to define and validate the most accurate and reproducible method for CTC molecular analysis, the clinical relevance of biomarkers, including gain of HER2 on CTC after HER2 negative primary breast cancer, remains uncertain. This review summarises the currently available data relating to biomarker evaluation on CTCs and its role in directing management in metastatic breast cancer, discusses limitations, and outlines measures that may enable future development of this approach.

  13. [MRI-guided breast microbiospy or macrobiopsy: which is the best option for a small tumor?].

    Science.gov (United States)

    Morin, B; Bretz-Grenier, M-F; Foessel, L; Guillaume, A; Gangi, A; Mathelin, C

    2014-06-01

    The choice of the optimum therapeutic strategy for breast cancer depends on the histological diagnosis of the sample obtained by biopsy. The microbiopsy is the preferred method as it provides an accurate diagnosis of the histological type as well as the main prognostic factors, whilst being simple, fast and inexepensive. However, some infraclinic breast tumors are not accessible by conventional guidance due to excessive depth inside the breast, their small size or technical inability to image them by mammography or ultrasonography. In those cases, the MRI guidance may help to perform the biopsy. Most MRI biopsies are made by large-core needle that are known to alter the histological structure of the tumor and to disturb the anatomopatholgical analysis (size and surgical margin). Those are very important elements to know before treatment. Our case report details an original technique of MRI microbiopsy of a deep 4mm opacity found on the occasion of a patient's mammography. The operative specimen revealed an invasive ductal carcinoma of 4mm diameter which scored III on the Elston and Ellis scale (oestrogen and progesterone receptors tested negative and HER-2 was over-expressed). It was associated with a high grade in situ ductal carcinoma. No systemic treatment was prescribed due to the small size of the carcinoma. The development of partially or totally amagnetic microbiopsy pistols would help perform microbiopses guided by MRI. PMID:24852912

  14. Phase- and GVF-Based Level Set Segmentation of Ultrasonic Breast Tumors

    Directory of Open Access Journals (Sweden)

    Liang Gao

    2012-01-01

    Full Text Available Automatically extracting breast tumor boundaries in ultrasound images is a difficult task due to the speckle noise, the low image contrast, the variance in shapes, and the local changes of image intensity. In this paper, an improved edge-based active contour model in a variational level set formulation is proposed for semi-automatically capturing ultrasonic breast tumor boundaries. First, we apply the phase asymmetry approach to enhance the edges, and then we define a new edge stopping function, which can increase the robustness to the intensity inhomogeneities. To extend the capture range of the method and provide good convergence to boundary concavities, we use the phase information to obtain an improved edge map, which can be used to calculate the gradient vector flow (GVF. Combining the edge stopping term and the improved GVF in the level set framework, the proposed method can robustly cope with noise, and it can extract the low contrast and/or concave boundaries well. Experiments on breast ultrasound images show that the proposed method outperforms the state-of-art methods.

  15. Expression of Stem Cell and Epithelial-Mesenchymal Transition Markers in Circulating Tumor Cells of Breast Cancer Patients

    OpenAIRE

    Natalia Krawczyk; Franziska Meier-Stiegen; Malgorzata Banys; Hans Neubauer; Eugen Ruckhaeberle; Tanja Fehm

    2014-01-01

    Evaluation and characterization of circulating tumor cells (CTCs) have become a major focus of translational cancer research. Presence of CTCs predicts worse clinical outcome in early and metastatic breast cancer. Whether all cells from the primary tumor have potential to disseminate and form subsequent metastasis remains unclear. As part of the metastatic cascade, tumor cells lose their cell-to-cell adhesion and undergo epithelial-mesenchymal transition (EMT) in order to enter blood circulat...

  16. Molecular biology of breast tumors and prognosis [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Gustavo Baldassarre

    2016-04-01

    Full Text Available Breast cancer is the most common cancer among women worldwide. Great scientific, economical, and organizational efforts are in place to understand the causes of onset, identify the critical molecular players of progression, and define new lines of intervention providing more benefits and less toxicity. These efforts have certainly not been vain, since overall survival, especially in specific subsets of breast cancer, has greatly improved during the last decades. At present, breast cancer patients’ treatment and care have reached a high standard of quality, and currently one of the most urgent needs resides in the necessity to better distinguish the tumors that need to be more aggressively treated and identify the best therapeutic option tailored to each patient. This objective will be achievable only if the information clarifying the biology of breast cancer can be successfully transferred to the clinic. A common effort by scientists and clinicians toward this integration and toward the use of multidisciplinary approaches will be necessary to reach this important goal.

  17. VGLL1 expression is associated with a triple-negative basal-like phenotype in breast cancer.

    Science.gov (United States)

    Castilla, María Ángeles; López-García, María Ángeles; Atienza, María Reina; Rosa-Rosa, Juan Manuel; Díaz-Martín, Juan; Pecero, María Luisa; Vieites, Begoña; Romero-Pérez, Laura; Benítez, Javier; Calcabrini, Annarica; Palacios, José

    2014-08-01

    Vestigial-like 1 (VGLL1) is a poorly characterized gene encoding a transcriptional co-activator structurally homologous to TAZ and YAP that modulates the Hippo pathway in Drosophila. In this study, we examined the expression of VGLL1 and its intronic miRNA, miR-934, in breast cancer. VGLL1 and miR-934 expression miRNA profiling was carried out on frozen samples of grade 3 invasive ductal carcinomas. VGLL1 protein was also examined in 433 sporadic and BRCA1-associated breast carcinomas on tissue microarrays. RNA-seq data from The Cancer Genome Atlas (TCGA) was used to confirm differences in VGLL1 and miR-934 expression in different breast cancer subtypes, and to correlate their expression with that of other genes and miRNAs. Of 28 miRNAs differentially expressed in estrogen receptor (ER)-positive and ER-negative grade 3 breast carcinomas, miR-934 was most strongly upregulated in ER-negative carcinomas, and its expression was correlated with that of VGLL1. Nuclear VGLL1 expression was observed in 13% of sporadic breast carcinomas, and while VGLL1 was only occasionally found in luminal A (0.70%) and B (5.60%) carcinomas, it was often expressed in HER2-positive (17%), triple-negative (TN) breast carcinomas (>40%) and BRCA1-associated TN carcinomas (>50%). These findings were confirmed in the TCGA dataset, which revealed positive associations with luminal progenitor genes (GABRP, SLC6A14, FOXC1, PROM1, and BBOX1) and strong negative correlations with ER-associated genes (ESR1, C6ORF211, GATA3, and FOXA1). Moreover, VGLL1 expression was associated with reduced overall survival. In conclusion, VGLL1 and miR-934 are mainly expressed in sporadic and BRCA1-associated TN basal-like breast carcinomas, and their coordinated expression, at least partially mediated by the direct modulation of ESR1, might be involved in the maintenance of a luminal progenitor phenotype.

  18. An Investigation on the Phenotype of Cultured Dendritic Cells from the Peripheral Blood of Patients with Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    范萍; 武正炎; 王水

    2002-01-01

    Objective To induce and culture the derenditic cells in the peripheral blood of breast cancer patients and research on their phenotypc. Methods Mononuclear cells were isolated by Ficoll Hypaque centrifutation from 32 breast cancer patients' peripheral blood. These cells were plaed in six-well culture plates ( 106 /ml, 2 ml/well) in RPMI 1640 medium supplemented with 10 % heat-in activated fetal bovine serum, 1 00 ng/ml GM-CSF, 20 ng/ml IL-4,and/or 20 ng/ml TNF-a. Two hours later, nonadherent cells were gently removed and fresh medium was added. Cultured cells were ana lyzed by flow cytometry with fluorescence labeled monoclonal antibodies. Pictures of cultured and fluores cence staidned cells were taken by confocal scanning miroscope. Results The diameter of the cells was between 10 and 20 micron. Cells displayed a characteristic CD1a+ ,CD40+ ,CD80+ , CD86+ and CD83+ phenotypes. All of the se molecules were not specific for dendritic cells. CD1a and CD83 molecules could also be expressed on the surface of CD3+ T lymphocyte and CD 19+ B lymphocytes, es pecially on activated lymphocytes. Conclusion The molecules of CD1a and CD83 are not specific phenotypes for dendritic cells. Currently, we still need to apply both cell morphology and costimulatory molecules such as CD40, CD 80, and CD86 to the identificatwn of dendritic cells.

  19. Exosomal Proteome Profiling: A Potential Multi-Marker Cellular Phenotyping Tool to Characterize Hypoxia-Induced Radiation Resistance in Breast Cancer

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    Stefani N. Thomas

    2013-08-01

    Full Text Available Radiation and drug resistance are significant challenges in the treatment of locally advanced, recurrent and metastatic breast cancer that contribute to mortality. Clinically, radiotherapy requires oxygen to generate cytotoxic free radicals that cause DNA damage and allow that damage to become fixed in the genome rather than repaired. However, approximately 40% of all breast cancers have hypoxic tumor microenvironments that render cancer cells significantly more resistant to irradiation. Hypoxic stimuli trigger changes in the cell death/survival pathway that lead to increased cellular radiation resistance. As a result, the development of noninvasive strategies to assess tumor hypoxia in breast cancer has recently received considerable attention. Exosomes are secreted nanovesicles that have roles in paracrine signaling during breast tumor progression, including tumor-stromal interactions, activation of proliferative pathways and immunosuppression. The recent development of protocols to isolate and purify exosomes, as well as advances in mass spectrometry-based proteomics have facilitated the comprehensive analysis of exosome content and function. Using these tools, studies have demonstrated that the proteome profiles of tumor-derived exosomes are indicative of the oxygenation status of patient tumors. They have also demonstrated that exosome signaling pathways are potentially targetable drivers of hypoxia-dependent intercellular signaling during tumorigenesis. This article provides an overview of how proteomic tools can be effectively used to characterize exosomes and elucidate fundamental signaling pathways and survival mechanisms underlying hypoxia-mediated radiation resistance in breast cancer.

  20. Effects of ulinastatin and docataxel on breast tumor growth and expression of IL-6, IL-8, and TNF-α

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    Luo Jie

    2011-02-01

    Full Text Available Abstract Objective This study investigated the effects of Ulinastatin (UTI and docataxel (Taxotere, TAX on tumor growth and expression of interleukin-6 (IL-6, interleukin-8 (IL-8, and tumor necrosis factor-α (TNF-α in breast cancer. Methods MDA-MB-231 human breast carcinoma cells were cultured in vitro and injected into nude mice to establish breast tumor xenografts in vivo. Cultured cells and mice with tumors were randomly divided into four groups for treatment with TAX, UTI, and TAX+UTI. The effects of these drug treatments on cell proliferation and apoptosis was measured using the MTT assay and the Annexin V/propidium iodide (PI double-staining method, respectively. IL-6, IL-8, and TNF-α expression levels were determined by measuring mRNA transcripts in cultured cells by RT-PCR and cytokine proteins in solid tumors using immunohistochemistry. Results UTI, TAX, and UTI+TAX inhibited the growth of MDA-MB-231 cells in vitro and tumors in vivo. These two drugs, particularly when used in combination, promote tumor cell apoptosis and down-regulate the expression IL-6, IL-8, and TNF-α cytokines. Conclusion Both UTI and TAX inhibited the growth of MDA-MB-231 breast carcinoma cells. UTI enhanced the inhibitory effect of TAX by a mechanism consistent with the down-regulated expression of IL-6, IL-8, and TNF-α.

  1. Sulfatase 1 and sulfatase 2 in hepatocellular carcinoma: associated signaling pathways, tumor phenotypes, and survival.

    Science.gov (United States)

    Yang, Ju Dong; Sun, Zhifu; Hu, Chunling; Lai, Jinping; Dove, Rebecca; Nakamura, Ikuo; Lee, Ju-Seog; Thorgeirsson, Snorri S; Kang, Koo Jeong; Chu, In-Sun; Roberts, Lewis R

    2011-02-01

    The heparin-degrading endosulfatases sulfatase 1 (SULF1) and sulfatase 2 (SULF2) have opposing effects in hepatocarcinogenesis despite structural similarity. Using mRNA expression arrays, we analyzed the correlations of SULF expression with signaling networks in human hepatocellular carcinomas (HCCs) and the associations of SULF expression with tumor phenotype and patient survival. Data from two mRNA microarray analyses of 139 and 36 HCCs and adjacent tissues were used as training and validation sets. Partek and Metacore software were used to identify SULF correlated genes and their associated signaling pathways. Associations between SULF expression, the hepatoblast subtype of HCC, and survival were examined. Both SULF1 and 2 had strong positive correlations with periostin, IQGAP1, TGFB1, and vimentin and inverse correlations with HNF4A and IQGAP2. Genes correlated with both SULFs were highly associated with the cell adhesion, cytoskeletal remodeling, blood coagulation, TGFB, and Wnt/β-catenin and epithelial mesenchymal transition signaling pathways. Genes uniquely correlated with SULF2 were more associated with neoplastic processes than genes uniquely correlated with SULF1. High SULF expression was associated with the hepatoblast subtype of HCC. There was a bimodal effect of SULF1 expression on prognosis, with patients in the lowest or highest tertile having a worse prognosis than those in the middle tertile. SULFs have complex effects on HCC signaling and patient survival. There are functionally similar associations with cell adhesion, ECM remodeling, TGFB, and WNT pathways, but also unique associations of SULF1 and SULF2. The roles and targeting of the SULFs in cancer require further investigation. PMID:21104785

  2. An MMP13-selective inhibitor delays primary tumor growth and the onset of tumor-associated osteolytic lesions in experimental models of breast cancer.

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    Manisha Shah

    Full Text Available We investigated the effects of the matrix metalloproteinase 13 (MMP13-selective inhibitor, 5-(4-{4-[4-(4-fluorophenyl-1,3-oxazol-2-yl]phenoxy}phenoxy-5-(2-methoxyethyl pyrimidine-2,4,6(1H,3H,5H-trione (Cmpd-1, on the primary tumor growth and breast cancer-associated bone remodeling using xenograft and syngeneic mouse models. We used human breast cancer MDA-MB-231 cells inoculated into the mammary fat pad and left ventricle of BALB/c Nu/Nu mice, respectively, and spontaneously metastasizing 4T1.2-Luc mouse mammary cells inoculated into mammary fat pad of BALB/c mice. In a prevention setting, treatment with Cmpd-1 markedly delayed the growth of primary tumors in both models, and reduced the onset and severity of osteolytic lesions in the MDA-MB-231 intracardiac model. Intervention treatment with Cmpd-1 on established MDA-MB-231 primary tumors also significantly inhibited subsequent growth. In contrast, no effects of Cmpd-1 were observed on soft organ metastatic burden following intracardiac or mammary fat pad inoculations of MDA-MB-231 and 4T1.2-Luc cells respectively. MMP13 immunostaining of clinical primary breast tumors and experimental mice tumors revealed intra-tumoral and stromal expression in most tumors, and vasculature expression in all. MMP13 was also detected in osteoblasts in clinical samples of breast-to-bone metastases. The data suggest that MMP13-selective inhibitors, which lack musculoskeletal side effects, may have therapeutic potential both in primary breast cancer and cancer-induced bone osteolysis.

  3. MicroRNA Profiling of Laser-Microdissected Hepatocellular Carcinoma Reveals an Oncogenic Phenotype of the Tumor Capsule

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    Jan Peveling-Oberhag

    2014-12-01

    Full Text Available Several microRNAs (miRNAs are associated with the molecular pathogenesis of hepatocellular carcinoma (HCC. However, previous studies analyzing the dysregulation of miRNAs in HCC show heterogeneous results. We hypothesized that part of this heterogeneity might be attributable to variations of miRNA expression deriving from the HCC capsule or the fibrotic septa within the peritumoral tissue used as controls. Tissue from surgically resected hepatitis C–associated HCC from six well-matched patients was microdissected using laser microdissection and pressure catapulting technique. Four distinct histologic compartments were isolated: tumor parenchyma (TP, fibrous capsule of the tumor (TC, tumor-adjacent liver parenchyma (LP, and cirrhotic septa of the tumor-adjacent liver (LC. MiRNA expression profiling analysis of 1105 mature miRNAs and precursors was performed using miRNA microarray. Principal component analysis and consecutive pairwise supervised comparisons demonstrated distinct patterns of expressed miRNAs not only for TP versus LP (e.g., intratumoral down-regulation of miR-214, miR-199a, miR-146a, and miR-125a; P< .05 but also for TC versus LC (including down-regulation within TC of miR-126, miR-99a/100, miR-26a, and miR-125b; P< .05. The tumor capsule therefore demonstrates a tumor-like phenotype with down-regulation of well-known tumor-suppressive miRNAs. Variations of co-analyzed fibrotic tissue within the tumor or in controls may have profound influence on miRNA expression analyses in HCC. Several miRNAs, which are proposed to be HCC specific, may indeed be rather associated to the tumor capsule. As miRNAs evolve to be important biomarkers in liver tumors, the presented data have important translational implications on diagnostics and treatment in patients with HCC.

  4. MicroRNA Profiling of Laser-Microdissected Hepatocellular Carcinoma Reveals an Oncogenic Phenotype of the Tumor Capsule123

    Science.gov (United States)

    Peveling-Oberhag, Jan; Seiz, Anna; Döring, Claudia; Hartmann, Sylvia; Köberle, Verena; Liese, Juliane; Zeuzem, Stefan; Hansmann, Martin-Leo; Piiper, Albrecht

    2014-01-01

    Several microRNAs (miRNAs) are associated with the molecular pathogenesis of hepatocellular carcinoma (HCC). However, previous studies analyzing the dysregulation of miRNAs in HCC show heterogeneous results. We hypothesized that part of this heterogeneity might be attributable to variations of miRNA expression deriving from the HCC capsule or the fibrotic septa within the peritumoral tissue used as controls. Tissue from surgically resected hepatitis C–associated HCC from six well-matched patients was microdissected using laser microdissection and pressure catapulting technique. Four distinct histologic compartments were isolated: tumor parenchyma (TP), fibrous capsule of the tumor (TC), tumor-adjacent liver parenchyma (LP), and cirrhotic septa of the tumor-adjacent liver (LC). MiRNA expression profiling analysis of 1105 mature miRNAs and precursors was performed using miRNA microarray. Principal component analysis and consecutive pairwise supervised comparisons demonstrated distinct patterns of expressed miRNAs not only for TP versus LP (e.g., intratumoral down-regulation of miR-214, miR-199a, miR-146a, and miR-125a; P< .05) but also for TC versus LC (including down-regulation within TC of miR-126, miR-99a/100, miR-26a, and miR-125b; P< .05). The tumor capsule therefore demonstrates a tumor-like phenotype with down-regulation of well-known tumor-suppressive miRNAs. Variations of co-analyzed fibrotic tissue within the tumor or in controls may have profound influence on miRNA expression analyses in HCC. Several miRNAs, which are proposed to be HCC specific, may indeed be rather associated to the tumor capsule. As miRNAs evolve to be important biomarkers in liver tumors, the presented data have important translational implications on diagnostics and treatment in patients with HCC. PMID:25500075

  5. Improvement in the drug delivery and anti-tumor efficacy of PEGylated liposomal doxorubicin by targeting RNA aptamers in mice bearing breast tumor model.

    Science.gov (United States)

    Moosavian, Seyedeh Alia; Abnous, Khalil; Badiee, Ali; Jaafari, Mahmoud Reza

    2016-03-01

    Targeted delivery by ligands such as aptamers, is a promising method to increase the efficiency of PEGylated-liposomal doxorubicin (PL-Dox). In this study, we have successfully conjugated our recently developed anti-breast cancer RNA aptamer (TSA14) to the surface of PL-Dox and characterized for their size, zeta potential, Dox percent encapsulation and release properties in the presence of fetal bovine serum. In vitro experiments showed that aptamer could improve cellular uptake and cytotoxicity of PL-Dox in TUBO breast cell line. In mice bearing TUBO breast tumor, although, the doxorubicin plasma level of liposomal doxorubicin did not significantly change after modification of nanoparticles with aptamer, however, much higher tumor accumulation of Dox as compared with non-targeted liposomes proved the tumor-targeting capability of aptamers. In the same way, aptamer-PL-Dox improved anti-tumor efficiency of liposomes in TUBO breast tumor in mice compared to non-targeted liposomes. Overall, the results showed that aptamer decoration of PL-Dox could significantly improve selectivity and the therapeutic efficacy of liposomal DOX and merits further investigation. PMID:26722819

  6. Characterization of metabolic profile of intact non-tumor and tumor breast cells by high-resolution magic angle spinning nuclear magnetic resonance spectroscopy.

    Science.gov (United States)

    Maria, Roberta M; Altei, Wanessa F; Andricopulo, Adriano D; Becceneri, Amanda B; Cominetti, Márcia R; Venâncio, Tiago; Colnago, Luiz A

    2015-11-01

    (1)H high-resolution magic angle spinning nuclear magnetic resonance ((1)H HR-MAS NMR) spectroscopy was used to analyze the metabolic profile of an intact non-tumor breast cell line (MCF-10A) and intact breast tumor cell lines (MCF-7 and MDA-MB-231). In the spectra of MCF-10A cells, six metabolites were assigned, with glucose and ethanol in higher concentrations. Fifteen metabolites were assigned in MCF-7 and MDA-MB-231 (1)H HR-MAS NMR spectra. They did not show glucose and ethanol, and the major component in both tumor cells was phosphocholine (higher in MDA-MB-231 than in MCF-7), which can be considered as a tumor biomarker of breast cancer malignant transformation. These tumor cells also show acetone signal that was higher in MDA-MB-231 cells than in MCF-7 cells. The high acetone level may be an indication of high demand for energy in MDA-MB-231 to maintain cell proliferation. The higher acetone and phosphocholine levels in MDA-MB-231 cells indicate the higher malignance of the cell line. Therefore, HR-MAS is a rapid reproducible method to study the metabolic profile of intact breast cells, with minimal sample preparation and contamination, which are critical in the analyses of slow-growth cells.

  7. Deep learning based classification of breast tumors with shear-wave elastography.

    Science.gov (United States)

    Zhang, Qi; Xiao, Yang; Dai, Wei; Suo, Jingfeng; Wang, Congzhi; Shi, Jun; Zheng, Hairong

    2016-12-01

    This study aims to build a deep learning (DL) architecture for automated extraction of learned-from-data image features from the shear-wave elastography (SWE), and to evaluate the DL architecture in differentiation between benign and malignant breast tumors. We construct a two-layer DL architecture for SWE feature extraction, comprised of the point-wise gated Boltzmann machine (PGBM) and the restricted Boltzmann machine (RBM). The PGBM contains task-relevant and task-irrelevant hidden units, and the task-relevant units are connected to the RBM. Experimental evaluation was performed with five-fold cross validation on a set of 227 SWE images, 135 of benign tumors and 92 of malignant tumors, from 121 patients. The features learned with our DL architecture were compared with the statistical features quantifying image intensity and texture. Results showed that the DL features achieved better classification performance with an accuracy of 93.4%, a sensitivity of 88.6%, a specificity of 97.1%, and an area under the receiver operating characteristic curve of 0.947. The DL-based method integrates feature learning with feature selection on SWE. It may be potentially used in clinical computer-aided diagnosis of breast cancer.

  8. Deep learning based classification of breast tumors with shear-wave elastography.

    Science.gov (United States)

    Zhang, Qi; Xiao, Yang; Dai, Wei; Suo, Jingfeng; Wang, Congzhi; Shi, Jun; Zheng, Hairong

    2016-12-01

    This study aims to build a deep learning (DL) architecture for automated extraction of learned-from-data image features from the shear-wave elastography (SWE), and to evaluate the DL architecture in differentiation between benign and malignant breast tumors. We construct a two-layer DL architecture for SWE feature extraction, comprised of the point-wise gated Boltzmann machine (PGBM) and the restricted Boltzmann machine (RBM). The PGBM contains task-relevant and task-irrelevant hidden units, and the task-relevant units are connected to the RBM. Experimental evaluation was performed with five-fold cross validation on a set of 227 SWE images, 135 of benign tumors and 92 of malignant tumors, from 121 patients. The features learned with our DL architecture were compared with the statistical features quantifying image intensity and texture. Results showed that the DL features achieved better classification performance with an accuracy of 93.4%, a sensitivity of 88.6%, a specificity of 97.1%, and an area under the receiver operating characteristic curve of 0.947. The DL-based method integrates feature learning with feature selection on SWE. It may be potentially used in clinical computer-aided diagnosis of breast cancer. PMID:27529139

  9. Small cell neuroendocrine tumor of the breast in a 40 year-old woman: a case report

    Directory of Open Access Journals (Sweden)

    Pasquini Enzo

    2010-06-01

    Full Text Available Abstract Introduction Small cell neuroendocrine cancer of the breast is a rare tumor with less than 30 cases reported in the literature. The morphological and immunohistochemical patterns of this tumor are similar to small cell neuroendocrine cancer of the lung. For this reason, it is often difficult to distinguish a primary small cell neuroendocrine cancer of the breast from a metastatic lesion from other sites. Case presentation We report and characterize with immunohistochemical techniques a case of primary small cell neuroendocrine cancer of the breast occurring in a 40-year-old Caucasian woman. A palpable and mobile 3.0 cm tumor was located in the upper-outer quadrant of her right breast. Lumpectomy and subsequent radical mastectomy with axillary lymph node resection were performed. Microscopically, the tumor consisted predominantly of a diffuse proliferation of small oat cells. The tumor cells were positive for neuroendocrine markers chromogranin A and synaptophysin. One of 16 lymph nodes was metastatic. A correct treatment needs to be chosen. Conclusions It has recently been demonstrated that early small cell neuroendocrine cancer of the breast shows a good prognosis with adjuvant treatments with high disease free survival. Our patient is alive and well without disease eight years after treatment. We performed an adjuvant therapy with the classic scheme doxorubicin and cyclophosphamide, followed by carboplatin and etoposide. A more extensive review is required to define a standard treatment protocol for this rare neoplasm.

  10. The number of tumor-free axillary lymph nodes removed as a prognostic parameter for node-negative breast cancer

    Institute of Scientific and Technical Information of China (English)

    Fei Gao; Ni He; Pei-Hong Wu

    2014-01-01

    Recently, there has been controversy about the relationship between the number of lymph nodes removed and survival of patients diagnosed with lymph node-negative breast cancer. To assess this relationship, 603 cases of lymph node-negative breast cancer with a median of 126 months of follow-up data were studied. Patients were stratified into two groups (Group A, 10 or fewer tumor-free lymph nodes removed; Group B, more than 10 tumor-free lymph nodes removed). The number of tumor-free lymph nodes in ipsilateral axilary resections as wel as 5 other disease parameters were analyzed for prognostic value. Our results revealed that the risk of death from breast cancer was significantly associated with patient age, marital status, histologic grade, tumor size, and adjuvant therapy. The 5- and 10-year survival rates for patients with 10 or fewer tumor-free lymph nodes removed was 88.0% and 66.4%, respectively, compared with 69.2% and 51.1%, respectively, for patients with more than 10 tumor-free lymph nodes removed. For patients with 10 or fewer tumor-free lymph nodes removed, the adjusted hazard ratio (HR) for risk of death from breast cancer was 0.579 (95% confidence interval, 0.492-0.687,P < 0.001), independent of patient age, marital status, histologic grade, tumor size, and adjuvant therapy. Our study suggests that the number of tumor-free lymph nodes removed is an independent predictor in cases of lymph node-negative breast cancer.

  11. The impact of breast cancer biological subtyping on tumor size assessment by ultrasound and mammography - a retrospective multicenter cohort study of 6543 primary breast cancer patients

    OpenAIRE

    Stein, Roland Gregor; Wollschläger, Daniel; Kreienberg, Rolf; Janni, Wolfgang; Wischnewsky, Manfred; Diessner, Joachim; Stüber, Tanja; Bartmann, Catharina; Krockenberger, Mathias; Wischhusen, Jörg; Wöckel, Achim; Blettner, Maria; Schwentner, Lukas; ,

    2016-01-01

    Background Mammography and ultrasound are the gold standard imaging techniques for preoperative assessment and for monitoring the efficacy of neoadjuvant chemotherapy in breast cancer. Maximum accuracy in predicting pathological tumor size non-invasively is critical for individualized therapy and surgical planning. We therefore aimed to assess the accuracy of tumor size measurement by ultrasound and mammography in a multicentered health services research study. Methods We retrospectively anal...

  12. Phenotype diversity in familial cylindromatosis: a frameshift mutation in the tumor suppressor gene CYLD underlies different tumors of skin appendages.

    Science.gov (United States)

    Poblete Gutiérrez, Pamela; Eggermann, Thomas; Höller, Daniela; Jugert, Frank K; Beermann, Torsten; Grussendorf-Conen, Elke-Ingrid; Zerres, Klaus; Merk, Hans F; Frank, Jorge

    2002-08-01

    Familial cylindromatosis (turban tumor syndrome; Brooke-Spiegler syndrome) (OMIM numbers 123850, 132700, 313100, and 605041) is a rare autosomal dominantly inherited tumor syndrome. The disorder can present with cutaneous adnexal tumors such as cylindromas, trichoepitheliomas, and spiradenomas, and tumors preferably develop in hairy areas of the body such as head and neck. In affected families, mutations have been demonstrated in the CYLD gene located on chromosome 16q12-13 and reveal the characteristic attributes of a tumor suppressor. Here, we studied familial cylindromatosis in a multigeneration family of German origin. Clinically, some individuals only revealed discrete small skin-colored tumors localized in the nasolabial region whereas one family member showed expansion of multiple big tumors on the trunk and in a turban-like fashion on the scalp. Histologically, cylindromas as well as epithelioma adenoides cysticum were found. We detected a frameshift mutation in the CYLD gene, designated 2253delG, underlying the disorder and were able to show that a single mutation can result in distinct clinical and histologic expression in familial cylindromatosis. The reasons for different expression patterns of the same genetic defect in this disease remain elusive, however. Identification of mutations in the CYLD gene enable us to rapidly confirm putative diagnoses on the genetic level and to provide affected families with genetic counseling.

  13. Differential expression of growth factor receptors and membrane-bound tumor markers for imaging in male and female breast cancer.

    Directory of Open Access Journals (Sweden)

    Jeroen F Vermeulen

    Full Text Available INTRODUCTION: Male breast cancer accounts for 0.5-1% of all breast cancers and is generally diagnosed at higher stage than female breast cancers and therefore might benefit from earlier detection and targeted therapy. Except for HER2 and EGFR, little is known about expression of growth factor receptors in male breast cancer. We therefore investigated expression profiles of growth factor receptors and membrane-bound tumor markers in male breast cancer and gynecomastia, in comparison with female breast cancer. METHODS: Tissue microarrays containing 133 male breast cancer and 32 gynecomastia cases were stained by immunohistochemistry for a panel of membrane-bound targets and compared with data on 266 female breast cancers. RESULTS: Growth factor receptors were variably expressed in 4.5% (MET up to 38.5% (IGF1-R of male breast cancers. Compared to female breast cancer, IGF1-R and carbonic anhydrase 12 (CAXII were more frequently and CD44v6, MET and FGFR2 less frequently expressed in male breast cancer. Expression of EGFR, HER2, CAIX, and GLUT1 was not significantly different between male and female breast cancer. Further, 48.1% of male breast cancers expressed at least one and 18.0% expressed multiple growth factor receptors. Since individual membrane receptors are expressed in only half of male breast cancers, a panel of membrane markers will be required for molecular imaging strategies to reach sensitivity. A potential panel of markers for molecular imaging, consisting of EGFR, IGF1-R, FGFR2, CD44v6, CAXII, GLUT1, and CD44v6 was positive in 77% of male breast cancers, comparable to female breast cancers. CONCLUSIONS: Expression patterns of growth factor receptors and hypoxia membrane proteins in male breast cancer are different from female breast cancer. For molecular imaging strategies, a putative panel consisting of markers for EGFR, IGF1-R, FGFR2, GLUT1, CAXII, CD44v6 was positive in 77% of cases and might be considered for development of

  14. Dysfunctional telomeres in human BRCA2 mutated breast tumors and cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Bodvarsdottir, Sigridur K., E-mail: skb@hi.is [Cancer Research Laboratory, BioMedical Centre, Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavik (Iceland); Steinarsdottir, Margret [Chromosome Laboratory, Department of Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik (Iceland); Bjarnason, Hordur; Eyfjord, Jorunn E. [Cancer Research Laboratory, BioMedical Centre, Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavik (Iceland)

    2012-01-03

    In the present study the possible involvement of telomeres in chromosomal instability of breast tumors and cell lines from BRCA2 mutation carriers was examined. Breast tumors from BRCA2 mutation carriers showed significantly higher frequency of chromosome end-to-end fusions (CEFs) than tumors from non-carriers despite normal telomere DNA content. Frequent CEFs were also found in four different BRCA2 heterozygous breast epithelial cell lines, occasionally with telomere signal at the fusion point, indicating telomere capping defects. Extrachromosomal telomeric repeat (ECTR) DNA was frequently found scattered around metaphase chromosomes and interstitial telomere sequences (ITSs) were also common. Telomere sister chromatid exchanges (T-SCEs), characteristic of cells using alternative lengthening of telomeres (ALT), were frequently detected in all heterozygous BRCA2 cell lines as well as the two ALT positive cell lines tested. Even though T-SCE frequency was similar in BRCA2 heterozygous and ALT positive cell lines they differed in single telomere signal loss and ITSs. Chromatid type alterations were more prominent in the BRCA2 heterozygous cell lines that may have propensity for telomere based chromosome healing. Telomere dysfunction-induced foci (TIFs) formation, identified by co-localization of telomeres and {gamma}-H2AX, supported telomere associated DNA damage response in BRCA2 heterozygous cell lines. TIFs were found in interphase nuclei, at chromosome ends, ITSs and ECTR DNA. In conclusion, our results suggest that BRCA2 has an important role in telomere stabilization by repressing CEFs through telomere capping and the prevention of telomere loss by replication stabilization.

  15. Reproducibility of Digital PCR Assays for Circulating Tumor DNA Analysis in Advanced Breast Cancer

    Science.gov (United States)

    Hrebien, Sarah; O’Leary, Ben; Beaney, Matthew; Schiavon, Gaia; Fribbens, Charlotte; Bhambra, Amarjit; Johnson, Richard; Turner, Nicholas

    2016-01-01

    Circulating tumor DNA (ctDNA) analysis has the potential to allow non-invasive analysis of tumor mutations in advanced cancer. In this study we assessed the reproducibility of digital PCR (dPCR) assays of circulating tumor DNA in a cohort of patients with advanced breast cancer and assessed delayed plasma processing using cell free DNA preservative tubes. We recruited a cohort of 96 paired samples from 71 women with advanced breast cancer who had paired blood samples processed either immediately or delayed in preservative tubes with processing 48–72 hours after collection. Plasma DNA was analysed with multiplex digital PCR (mdPCR) assays for hotspot mutations in PIK3CA, ESR1 and ERBB2, and for AKT1 E17K. There was 94.8% (91/96) agreement in mutation calling between immediate and delayed processed tubes, kappa 0.88 95% CI 0.77–0.98). Discordance in mutation calling resulted from low allele frequency and likely stochastic effects. In concordant samples there was high correlation in mutant copies per ml plasma (r2 = 0.98; pprocessed tubes, although overall quantification of total cell free plasma DNA had similar prognostic effects in immediate (HR 3.6) and delayed (HR 3.0) tubes. There was moderate agreement in changes in allele fraction between sequential samples in quantitative mutation tracking (r = 0.84, p = 0.0002). Delayed processing of samples using preservative tubes allows for centralized ctDNA digital PCR mutation screening in advanced breast cancer. The potential of preservative tubes in quantitative mutation tracking requires further research. PMID:27760227

  16. Tumor-derived microvesicles mediate human breast cancer invasion through differentially glycosylated EMMPRIN

    Science.gov (United States)

    Menck, Kerstin; Scharf, Christian; Bleckmann, Annalen; Dyck, Lydia; Rost, Ulrike; Wenzel, Dirk; Dhople, Vishnu M.; Siam, Laila; Pukrop, Tobias; Binder, Claudia; Klemm, Florian

    2015-01-01

    Tumor cells secrete not only a variety of soluble factors, but also extracellular vesicles that are known to support the establishment of a favorable tumor niche by influencing the surrounding stroma cells. Here we show that tumor-derived microvesicles (T-MV) also directly influence the tumor cells by enhancing their invasion in a both autologous and heterologous manner. Neither the respective vesicle-free supernatant nor MV from benign mammary cells mediate invasion. Uptake of T-MV is essential for the proinvasive effect. We further identify the highly glycosylated form of the extracellular matrix metalloproteinase inducer (EMMPRIN) as a marker for proinvasive MV. EMMPRIN is also present at high levels on MV from metastatic breast cancer patients in vivo. Anti-EMMPRIN strategies, such as MV deglycosylation, gene knockdown, and specific blocking peptides, inhibit MV-induced invasion. Interestingly, the effect of EMMPRIN-bearing MV is not mediated by matrix metalloproteinases but by activation of the p38/MAPK signaling pathway in the tumor cells. In conclusion, T-MV stimulate cancer cell invasion via a direct feedback mechanism dependent on highly glycosylated EMMPRIN. PMID:25503107

  17. STEP: spatiotemporal enhancement pattern for MR-based breast tumor diagnosis.

    Science.gov (United States)

    Zheng, Yuanjie; Englander, Sarah; Baloch, Sajjad; Zacharaki, Evangelia I; Fan, Yong; Schnall, Mitchell D; Shen, Dinggang

    2009-07-01

    The authors propose a spatiotemporal enhancement pattern (STEP) for comprehensive characterization of breast tumors in contrast-enhanced MR images. By viewing serial contrast-enhanced MR images as a single spatiotemporal image, they formulate the STEP as a combination of (1) dynamic enhancement and architectural features of a tumor, and (2) the spatial variations of pixelwise temporal enhancements. Although the latter has been widely used by radiologists for diagnostic purposes, it has rarely been employed for computer-aided diagnosis. This article presents two major contributions. First, the STEP features are introduced to capture temporal enhancement and its spatial variations. This is essentially carried out through the Fourier transformation and pharmacokinetic modeling of various temporal enhancement features, followed by the calculation of moment invariants and Gabor texture features. Second, for effectively extracting the STEP features from tumors, we develop a graph-cut based segmentation algorithm that aims at refining coarse manual segmentations of tumors. The STEP features are assessed through their diagnostic performance for differentiating between benign and malignant tumors using a linear classifier (along with a simple ranking-based feature selection) in a leave-one-out cross-validation setting. The experimental results for the proposed features exhibit superior performance, when compared to the existing approaches, with the area under the ROC curve approaching 0.97.

  18. Tocotrienol-adjuvanted dendritic cells inhibit tumor growth and metastasis: a murine model of breast cancer.

    Directory of Open Access Journals (Sweden)

    Sitti Rahma Abdul Hafid

    Full Text Available Tocotrienol-rich fraction (TRF from palm oil is reported to possess anti-cancer and immune-enhancing effects. In this study, TRF supplementation was used as an adjuvant to enhance the anti-cancer effects of dendritic cells (DC-based cancer vaccine in a syngeneic mouse model of breast cancer. Female BALB/c mice were inoculated with 4T1 cells in mammary pad to induce tumor. When the tumor was palpable, the mice in the experimental groups were injected subcutaneously with DC-pulsed with tumor lysate (TL from 4T1 cells (DC+TL once a week for three weeks and fed daily with 1 mg TRF or vehicle. Control mice received unpulsed DC and were fed with vehicle. The combined therapy of using DC+TL injections and TRF supplementation (DC+TL+TRF inhibited (p<0.05 tumor growth and metastasis. Splenocytes from the DC+TL+TRF group cultured with mitomycin-C (MMC-treated 4T1 cells produced higher (p<0.05 levels of IFN-γ and IL-12. The cytotoxic T-lymphocyte (CTL assay also showed enhanced tumor-specific killing (p<0.05 by CD8(+ T-lymphocytes isolated from mice in the DC+TL+TRF group. This study shows that TRF has the potential to be used as an adjuvant to enhance effectiveness of DC-based vaccines.

  19. Amine-modified hyaluronic acid-functionalized porous silicon nanoparticles for targeting breast cancer tumors

    Science.gov (United States)

    Almeida, Patrick V.; Shahbazi, Mohammad-Ali; Mäkilä, Ermei; Kaasalainen, Martti; Salonen, Jarno; Hirvonen, Jouni; Santos, Hélder A.

    2014-08-01

    Active targeting of nanoparticles to receptor-overexpressing cancer cells has great potential for enhancing the cellular uptake of nanoparticles and for reducing fast clearance of the nanoparticles from the body. Herein, we present a preparation method of a porous silicon (PSi)-based nanodelivery system for breast cancer targeting, by covalently conjugating a synthesized amide-modified hyaluronic acid (HA+) derived polymer on the surface of undecylenic acid-modified thermally hydrocarbonized PSi (UnTHCPSi) nanoparticles. The resulting UnTHCPSi-HA+ nanoparticles showed relatively small size, reduced polydispersibility, high biocompatibility, improved colloidal and human plasma stability, as well as enhanced cellular interactions and internalization. Moreover, we demonstrated that the enhanced cellular association of UnTHCPSi-HA+ relies on the capability of the conjugated HA+ to bind and consequently target CD44 receptors expressed on the surface of breast cancer cells, thus making the HA+-functionalized UnTHCPSi nanoparticles a suitable and promising nanoplatform for the targeting of CD44-overexpressing breast tumors and for drug delivery.Active targeting of nanoparticles to receptor-overexpressing cancer cells has great potential for enhancing the cellular uptake of nanoparticles and for reducing fast clearance of the nanoparticles from the body. Herein, we present a preparation method of a porous silicon (PSi)-based nanodelivery system for breast cancer targeting, by covalently conjugating a synthesized amide-modified hyaluronic acid (HA+) derived polymer on the surface of undecylenic acid-modified thermally hydrocarbonized PSi (UnTHCPSi) nanoparticles. The resulting UnTHCPSi-HA+ nanoparticles showed relatively small size, reduced polydispersibility, high biocompatibility, improved colloidal and human plasma stability, as well as enhanced cellular interactions and internalization. Moreover, we demonstrated that the enhanced cellular association of Un

  20. Mitochondrial DNA Mutations Regulate Metastasis of Human Breast Cancer Cells

    OpenAIRE

    Hirotake Imanishi; Keisuke Hattori; Reiko Wada; Kaori Ishikawa; Sayaka Fukuda; Keizo Takenaga; Kazuto Nakada; Jun-ichi Hayashi

    2011-01-01

    Mutations in mitochondrial DNA (mtDNA) might contribute to expression of the tumor phenotypes, such as metastatic potential, as well as to aging phenotypes and to clinical phenotypes of mitochondrial diseases by induction of mitochondrial respiration defects and the resultant overproduction of reactive oxygen species (ROS). To test whether mtDNA mutations mediate metastatic pathways in highly metastatic human tumor cells, we used human breast carcinoma MDA-MB-231 cells, which simultaneously e...

  1. Functional Characterization and Drug Response of Freshly Established Patient-Derived Tumor Models with CpG Island Methylator Phenotype.

    Directory of Open Access Journals (Sweden)

    Claudia Maletzki

    Full Text Available Patient-individual tumor models constitute a powerful platform for basic and translational analyses both in vitro and in vivo. However, due to the labor-intensive and highly time-consuming process, only few well-characterized patient-derived cell lines and/or corresponding xenografts exist. In this study, we describe successful generation and functional analysis of novel tumor models from patients with sporadic primary colorectal carcinomas (CRC showing CpG island methylator phenotype (CIMP. Initial DNA fingerprint analysis confirmed identity with the patient in all four cases. These freshly established cells showed characteristic features associated with the CIMP-phenotype (HROC40: APCwt, TP53 mut, KRAS mut; 3/8 marker methylated; HROC43: APC mut, TP53 mut, KRAS mut; 4/8 marker methylated; HROC60: APCwt, TP53 mut, KRASwt; 4/8 marker methylated; HROC183: APC mut, TP53 mut, KRAS mut; 6/8 marker methylated. Cell lines were of epithelial origin (EpCAM+ with distinct morphology and growth kinetics. Response to chemotherapeutics was quite individual between cells, with stage I-derived cell line HROC60 being most susceptible towards standard clinically approved chemotherapeutics (e.g. 5-FU, Irinotecan. Of note, most cell lines were sensitive towards "non-classical" CRC standard drugs (sensitivity: Gemcitabin > Rapamycin > Nilotinib. This comprehensive analysis of tumor biology, genetic alterations and assessment of chemosensitivity towards a broad range of (chemo- therapeutics helps bringing forward the concept of personalized tumor therapy.

  2. Aldehyde Dehydrogenase1 Immunohistochemical Staining in Primary Breast Cancer Cells Independently Predicted Overall Survival But Did Not Correlate with the Presence of Circulating or Disseminated Tumors Cells

    OpenAIRE

    Woodward, Wendy A.; Krishnamurthy, Savitri; Lodhi, Ashutosh; Xiao, Lianchun; Gong, Yun; Cristofanilli, Massimo; Buchholz, Thomas A.; Lucci, Anthony

    2014-01-01

    Purpose: We hypothesized that aldehyde dehydrogenase 1 (ALDH1) staining in breast cancer tumor cells might be a simple surrogate for the presence of circulating tumor cells (CTCs) or disseminated tumor cells (DTCs). Experimental Design: Whole tissue primary tumor sections from 121 patients enrolled in a clinical trial assessing CTCs and DTCs at the time of surgery were stained for ALDH1 and scored by a dedicated breast pathologist blinded to outcome. Clinical data was extracted and staining w...

  3. Human in-vivo 31P MR spectroscopy of benign and malignant breast tumors

    International Nuclear Information System (INIS)

    To assess the potential clinical utility of in-vivo 31P magnetic resonance spectroscopy (MRS) in patients with various malignant and benign breast lesions. Seventeen patients with untreated primary malignant breast lesions (group I), eight patients with untreated benign breast lesions (group II) and seven normal breasts (group III) were included in this study. In-vivo 31P MRS was performed using a 1.5 Tesla MR scanner. Because of the characteristics of the coil, the volume of the tumor had to exceed 12 cc (3x2x2 cm), with a superoinferior diameter at least 3 cm. Mean and standard deviations of each metabolite were calculated and metabolite ratios, such as PME/PCr, PDE/PCr, T-ATP/PCr and PCr/T-ATP were calculated and statistically analyzed. Significant differences in PME were noted between groups I and III (p=0.0213), and between groups II and III (p=0.0213). The metabolite ratios which showed significant differences were PME/PCr (between groups II and III) (p=0.0201), PDE/PCr (between groups I and III, and between groups II and III) (p=0.0172), T-ATP/PCr (between groups II and III) (p=0.0287), and PCr/T-ATP (between groups II and III) (p=0.0287). There were no significant parameters between groups I and II. In-vivo 31P MRS is not helpful for establishing a differential diagnosis between benign and malignant breast lesions, at least with relatively large lesions greater than 3 cm in one or more dimensions

  4. Riluzole mediates anti-tumor properties in breast cancer cells independent of metabotropic glutamate receptor-1.

    Science.gov (United States)

    Speyer, Cecilia L; Nassar, Mahdy A; Hachem, Ali H; Bukhsh, Miriam A; Jafry, Waris S; Khansa, Rafa M; Gorski, David H

    2016-06-01

    Riluzole, the only drug approved by the FDA for treating amyotrophic lateral sclerosis, inhibits melanoma proliferation through its inhibitory effect on glutamatergic signaling. We demonstrated that riluzole also inhibits the growth of triple-negative breast cancer (TNBC) and described a role for metabotropic glutamate receptor-1 (GRM1) in regulating TNBC cell growth and progression. However, the role of GRM1 in mediating riluzole's effects in breast cancer has not been fully elucidated. In this study, we seek to determine how much of riluzole's action in breast cancer is mediated through GRM1. We investigated anti-tumor properties of riluzole in TNBC and ER+ cells using cell growth, invasion, and soft-agar assays and compared riluzole activity with GRM1 levels. Using Lentiviral vectors expressing GRM1 or shGRM1, these studies were repeated in cells expressing high or low GRM1 levels where the gene was either silenced or overexpressed. Riluzole inhibited proliferation, invasion, and colony formation in both TNBC and ER+ cells. There was a trend between GRM1 expression in TNBC cells and their response to riluzole in both cell proliferation and invasion assays. However, silencing and overexpression studies had no effect on cell sensitivity to riluzole. Our results clearly suggest a GRM1-independent mechanism through which riluzole mediates its effects on breast cancer cells. Understanding the mechanism by which riluzole mediates breast cancer progression will be useful in identifying new therapeutic targets for treating TNBC and in facilitating stratification of patients in clinical trials using riluzole in conjunction with conventional therapy. PMID:27146584

  5. Mesenchymal Tumors Can Derive from Ng2/Cspg4-Expressing Pericytes with β-Catenin Modulating the Neoplastic Phenotype

    Directory of Open Access Journals (Sweden)

    Shingo Sato

    2016-07-01

    Full Text Available The cell of origin for most mesenchymal tumors is unclear. One cell type that contributes to this lineages is the pericyte, a cell expressing Ng2/Cspg4. Using lineage tracing, we demonstrated that bone and soft tissue sarcomas driven by the deletion of the Trp53 tumor suppressor, or desmoid tumors driven by a mutation in Apc, can derive from cells expressing Ng2/Cspg4. Deletion of the Trp53 tumor suppressor gene in these cells resulted in the bone and soft tissue sarcomas that closely resemble human sarcomas, while stabilizing β-catenin in this same cell type caused desmoid tumors. Comparing expression between Ng2/Cspg4-expressing pericytes lacking Trp53 and sarcomas that arose from deletion of Trp53 showed inhibition of β-catenin signaling in the sarcomas. Activation of β-catenin inhibited the formation and growth of sarcomas. Thus, pericytes can be a cell of origin for mesenchymal tumors, and β-catenin dysregulation plays an important role in the neoplastic phenotype.

  6. Liquid biopsy in breast cancer:serum biomarker and circulating tumor cell detection%乳腺癌“液体活检”:血清标志物与循环肿瘤细胞的检测

    Institute of Scientific and Technical Information of China (English)

    陈小松; 沈坤炜

    2012-01-01

      Detection of efficacy and prognosis predictive factors in breast cancer can help us with individualized treatment. Circulating tumor cells (CTCs) test provides us a real-time "liquid biopsy" in breast cancer, which can predict the prognosis of breast cancer patients, monitor the CTCs number changes before and after chemotherapy or endocrine therapy, and predict the treatment efficacy. The further study of CTCs gene phenotype and its biological behavior can improve the therapeutic effect of breast cancer, thereby reducing the breast cancer mortality.%  乳腺癌疗效和预后指标的检测可以帮助我们进行个体化治疗。循环肿瘤细胞(Circulating tumor cells, CTCs)的检测为我们提供了乳腺癌的实时“液体活检”,可以预测乳腺癌患者的预后;进行乳腺癌化疗、内分泌等治疗前后CTCs变化情况的监测,预测治疗的疗效;进一步研究CTCs的基因表型,明确其生物学行为,从而提高乳腺癌的治疗效果,降低其死亡率。

  7. Context dependent reversion of tumor phenotype by connexin-43 expression in MDA-MB231 cells and MCF-7 cells: Role of β-catenin/connexin43 association

    Energy Technology Data Exchange (ETDEWEB)

    Talhouk, Rabih S., E-mail: rtalhouk@aub.edu.lb [Department of Biology, Faculty of Arts and Sciences, American University of Beirut, P.O. Box 11-0236, Beirut (Lebanon); Fares, Mohamed-Bilal; Rahme, Gilbert J.; Hariri, Hanaa H.; Rayess, Tina; Dbouk, Hashem A.; Bazzoun, Dana; Al-Labban, Dania [Department of Biology, Faculty of Arts and Sciences, American University of Beirut, P.O. Box 11-0236, Beirut (Lebanon); El-Sabban, Marwan E., E-mail: me00@aub.edu.lb [Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, P.O. Box 11-0236, Beirut (Lebanon)

    2013-12-10

    Connexins (Cx), gap junction (GJ) proteins, are regarded as tumor suppressors, and Cx43 expression is often down regulated in breast tumors. We assessed the effect of Cx43 over-expression in 2D and 3D cultures of two breast adenocarcinoma cell lines: MCF-7 and MDA-MB-231. While Cx43 over-expression decreased proliferation of 2D and 3D cultures of MCF-7 by 56% and 80% respectively, MDA-MB-231 growth was not altered in 2D cultures, but exhibited 35% reduction in 3D cultures. C-terminus truncated Cx43 did not alter proliferation. Untransfected MCF-7 cells formed spherical aggregates in 3D cultures, and MDA-MB-231 cells formed stellar aggregates. However, MCF-7 cells over-expressing Cx43 formed smaller sized clusters and Cx43 expressing MDA-MB-231 cells lost their stellar morphology. Extravasation ability of both MCF-7 and MDA-MB-231 cells was reduced by 60% and 30% respectively. On the other hand, silencing Cx43 in MCF10A cells, nonneoplastic human mammary cell line, increased proliferation in both 2D and 3D cultures, and disrupted acinar morphology. Although Cx43 over-expression did not affect total levels of β-catenin, α-catenin and ZO-2, it decreased nuclear levels of β-catenin in 2D and 3D cultures of MCF-7 cells, and in 3D cultures of MDA-MB-231 cells. Cx43 associated at the membrane with α-catenin, β-catenin and ZO-2 in 2D and 3D cultures of MCF-7 cells, and only in 3D conditions in MDA-MB-231 cells. This study suggests that Cx43 exerts tumor suppressive effects in a context-dependent manner where GJ assembly with α-catenin, β-catenin and ZO-2 may be implicated in reducing growth rate, invasiveness, and, malignant phenotype of 2D and 3D cultures of MCF-7 cells, and 3D cultures of MDA-MB-231 cells, by sequestering β-catenin away from nucleus. - Highlights: • Cx43 over-expressing MCF-7 and MDA-MB-231 were grown in 2D and 3D cultures. • Proliferation and growth morphology were affected in a context dependent manner. • Extravasation ability of both MCF

  8. Pathological predictive factors for tumor response in locally advanced breast carcinomas treated with anthracyclin-based neoadjuvant chemotherapy

    OpenAIRE

    Trupti Patel; Anuja Gupta; Manoj Shah

    2013-01-01

    Aim: Neoadjuvant chemotherapy (NACT) is used as a primary treatment for locally advanced breast carcinoma (LABC) and also extended to operable breast cancer. The aim of this study was to evaluate the predictive value of different histological parameters in core biopsy of LABC patients treated with anthracycline-based chemotherapy regimen. Pathological assessment of the excised tumor bed is the gold standard and is essential for identifying the group of patients with pathologic complete respon...

  9. Tumor Initiating Cells and FZD8 play a major role in drug resistance in Triple-Negative Breast Cancer

    OpenAIRE

    Yin, Shuping; Xu, Liping; Bonfil, R. Daniel; Banerjee, Sanjeev; Sarkar, Fazlul H; Sethi, Seema; Reddy, Kaladhar B.

    2013-01-01

    Triple-negative breast cancer (TNBC) studies have shown that neoadjuvant chemotherapy before surgery was effective in the minority of women, whereas the majority who had residual tumor had a relatively poor outcome. To identify the mechanism by which residual cancer cells survive chemotherapy, we initially performed gene expression profiling using the CRL2335 TNBC cell line derived from a squamous breast carcinoma before and after treatment with cisplatin plus TRAIL. We found a significant in...

  10. Pleomorphic Adenoma of Breast: A Radiological and Pathological Study of a Common Tumor in an Uncommon Location

    OpenAIRE

    Ginter, Paula S.; Theresa Scognamiglio; Pamela Tauchi-Nishi; Antonio, Lilian B.; Hoda, Syed A.

    2015-01-01

    Pleomorphic adenoma occurs commonly in the major salivary glands but is uncommonly encountered in the breast. In both of these locations, the tumor is typically grossly circumscribed and has a “mixed” histological appearance, being composed of myoepithelial and epithelial components amid a myxochondroid matrix. Herein, we report a case of pleomorphic adenoma of the breast which was preoperatively thought to represent a fibroadenoma on clinical and radiological grounds. It is the rarity of the...

  11. Breast Cancer Mortality among Asian-American Women in California: Variation according to Ethnicity and Tumor Subtype

    OpenAIRE

    Parise, Carol; Caggiano, Vincent

    2016-01-01

    Purpose Asian-American women have equal or better breast cancer survival rates than non-Hispanic white women, but many studies use the aggregate term "Asian/Pacific Islander" (API) or consider breast cancer as a single disease. The purpose of this study was to assess the risk of mortality in seven subgroups of Asian-Americans expressing the estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) tumor marker subtypes and determine whether the ris...

  12. MRI monitoring of tumor response following angiogenesis inhibition in an experimental human