Prognostic Value of Triple-Negative Phenotype at the Time of Locally Recurrent, Conservatively Treated Breast Cancer

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Parikh, Rahul R.; Housman, Douglas; Yang Qifeng; Toppmeyer, Deborah; Wilson, Lynn D.; Haffty, Bruce G.

2008-01-01

Purpose: To evaluate the prognostic value of triple-negative (TN) ER, PR, Her2/neu basal-like carcinoma of the breast, at the time of ipsilateral breast tumor recurrence (IBTR) after conservative surgery and radiation treatment (RT). Methods and Materials: A tissue microarray was constructed of 47 IBTR specimens of patients who experienced an IBTR after conservative surgery and RT that were processed and stained for ER, PR, and HER2/neu. Results: At a median post-recurrence follow-up of 7.5 years, the 5-year overall survival (OS) and disease metastasis-free survival (DMFS) after IBTR were 91.4% and 83.0%, respectively. Median time to tumor recurrence (TTR) and IBTR was shorter in the TN phenotype (3.88 vs. 5.00 years; p = 0.09). The TN tumors were not associated with size of local recurrence or recurrence elsewhere in the breast. Despite administration of standard chemotherapy at the time of IBTR, the 5-year DMFS and 5-year OS for the TN cohort were 48.6% and 72.7%, respectively. The 5-year DMFS was 48.6% for TN tumors and 90.8% for non-TN tumors (p < 0.01). By univariate analysis, significant factors associated with poor 5-year DMFS and OS after IBTR included: TN phenotype (p < 0.01), TTR 3 years or less (p < 0.01), local recurrence at or near the original tumor site (p = 0.08). In multivariate analysis, TN was a significant independent predictor of poorer 5-year DMFS (relative risk, 5.91; 95% confidence interval, 1.83-19.01; p < 0.01) after IBTR. Conclusions: Although patients experiencing an IBTR have a relatively favorable prognosis, those with IBTR events of the TN phenotype had a rather poor prognosis despite receiving standard chemotherapy. Strategies with novel systemic therapies to improve outcomes in patients experiencing IBTR of the TN phenotype are warranted

Macrophage phenotypic subtypes diametrically regulate epithelial-mesenchymal plasticity in breast cancer cells

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Yang, Min; Ma, Bo; Shao, Hanshuang; Clark, Amanda M.; Wells, Alan

2016-01-01

Metastatic progression of breast cancer involves phenotypic plasticity of the carcinoma cells moving between epithelial and mesenchymal behaviors. During metastatic seeding and dormancy, even highly aggressive carcinoma cells take on an E-cadherin-positive epithelial phenotype that is absent from the emergent, lethal metastatic outgrowths. These phenotypes are linked to the metastatic microenvironment, though the specific cells and induction signals are still to be deciphered. Recent evidence suggests that macrophages impact tumor progression, and may alter the balance between cancer cell EMT and MErT in the metastatic microenvironment. Here we explore the role of M1/M2 macrophages in epithelial-mesenchymal plasticity of breast cancer cells by coculturing epithelial and mesenchymal cells lines with macrophages. We found that after polarizing the THP-1 human monocyte cell line, the M1 and M2-types were stable and maintained when co-cultured with breast cancer cells. Surprisingly, M2 macrophages may conferred a growth advantage to the epithelial MCF-7 cells, with these cells being driven to a partial mesenchymal phenotypic as indicated by spindle morphology. Notably, E-cadherin protein expression is significantly decreased in MCF-7 cells co-cultured with M2 macrophages. M0 and M1 macrophages had no effect on the MCF-7 epithelial phenotype. However, the M1 macrophages impacted the highly aggressive mesenchymal-like MDA-MB-231 breast cancer cells to take on a quiescent, epithelial phenotype with re-expression of E-cadherin. The M2 macrophages if anything exacerbated the mesenchymal phenotype of the MDA-MB-231 cells. Our findings demonstrate M2 macrophages might impart outgrowth and M1 macrophages may contribute to dormancy behaviors in metastatic breast cancer cells. Thus EMT and MErT are regulated by selected macrophage phenotype in the liver metastatic microenvironment. These results indicate macrophage could be a potential therapeutic target for limiting death due

Ewing’s sarcoma: an uncommon breast tumor

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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.

A Phenotypic Cell-Binding Screen Identifies a Novel Compound Targeting Triple-Negative Breast Cancer.

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Chen, Luxi; Long, Chao; Youn, Jonghae; Lee, Jiyong

2018-06-11

We describe a "phenotypic cell-binding screen" by which therapeutic candidate targeting cancer cells of a particular phenotype can be isolated without knowledge of drug targets. Chemical library beads are incubated with cancer cells of the phenotype of interest in the presence of cancer cells lacking the phenotype of interest, and then the beads bound to only cancer cells of the phenotype of interest are selected as hits. We have applied this screening strategy in discovering a novel compound (LC129-8) targeting triple-negative breast cancer (TNBC). LC129-8 displayed highly specific binding to TNBC in cancer cell lines and patient-derived tumor tissues. LC129-8 exerted anti-TNBC activity by inducing apoptosis, inhibiting proliferation, reversing epithelial-mesenchymal transition, downregulating cancer stem cell activity and blocking in vivo tumor growth.

Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes.

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Dobroff, Andrey S; D'Angelo, Sara; Eckhardt, Bedrich L; Ferrara, Fortunato; Staquicini, Daniela I; Cardó-Vila, Marina; Staquicini, Fernanda I; Nunes, Diana N; Kim, Kisu; Driessen, Wouter H P; Hajitou, Amin; Lomo, Lesley C; Barry, Marc; Krishnamurthy, Savitri; Sahin, Aysegul; Woodward, Wendy A; Prossnitz, Eric R; Anderson, Robin L; Dias-Neto, Emmanuel; Brown-Glaberman, Ursa A; Royce, Melanie E; Ueno, Naoto T; Cristofanilli, Massimo; Hortobagyi, Gabriel N; Marchiò, Serena; Gelovani, Juri G; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

2016-10-24

Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors.

Targeted nanodiamonds as phenotype-specific photoacoustic contrast agents for breast cancer.

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Zhang, Ti; Cui, Huizhong; Fang, Chia-Yi; Cheng, Kun; Yang, Xinmai; Chang, Huan-Cheng; Forrest, M Laird

2015-03-01

The aim is to develop irradiated nanodiamonds (INDs) as a molecularly targeted contrast agent for high-resolution and phenotype-specific detection of breast cancer with photoacoustic (PA) imaging. The surface of acid treated radiation-damaged nanodiamonds was grafted with PEG to improve its stability and circulation time in blood, followed by conjugation to an anti-HER2 peptide with a final nanoparticle size of approximately 92 nm. Immunocompetent mice bearing orthotopic HER2-positive or negative tumors were administered INDs and PA imaged using an 820-nm near-infrared laser. PA images demonstrated that INDs accumulate in tumors and completely delineated the entire tumor within 10 h. HER2 targeting significantly enhanced imaging of HER2-positive tumors. Pathological examination demonstrated INDs are nontoxic. PA technology is adaptable to low-cost bedside medicine, and with new contrast agents described herein, PA can achieve high-resolution (sub-mm) and phenotype-specific monitoring of cancer growth.

The Implications of Breast Cancer Molecular Phenotype for Radiation Oncology

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Sioshansi, Shirin [Department of Radiation Oncology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA (United States); Department of Radiation Oncology, Rhode Island Hospital, Warren Alpert School of Medicine at Brown University, Providence, RI (United States); Huber, Kathryn E. [Department of Radiation Oncology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA (United States); Wazer, David E., E-mail: dwazer@tuftsmedicalcenter.org [Department of Radiation Oncology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA (United States); Department of Radiation Oncology, Rhode Island Hospital, Warren Alpert School of Medicine at Brown University, Providence, RI (United States)

2011-06-28

The identification of distinct molecular subtypes of breast cancer has advanced the understanding and treatment of breast cancer by providing insight into prognosis, patterns of recurrence, and effectiveness of therapy. The prognostic significance of molecular phenotype with regard to distant recurrences and overall survival are well established in the literature and has been readily incorporated into systemic therapy management decisions. However, despite the accumulating data suggesting similar prognostic significance for locoregional recurrence, integration of molecular phenotype into local management decision making has lagged. Although there are some conflicting reports, collectively the literature supports a low risk of local recurrence (LR) in the hormone receptor (HR) positive luminal subtypes compared to HR negative subtypes [triple negative (TN) and HER2-enriched]. The development of targeted therapies, such as trastuzumab for the treatment of HER2-enriched subtype, has been shown to mitigate the increased risk of LR. Unfortunately, no such remedy exists to address the increased risk of LR for patients with TN tumors, making it a clinical challenge for radiation oncologists. In this review we discuss the correlation between molecular subtype and LR following either breast conservation therapy or mastectomy. We also explore the possible mechanisms for increased LR in TN breast cancer and radiotherapeutic implications for this population, such as the safety of breast conservation, consideration of dose escalation, and the appropriateness of accelerated partial breast irradiation.

The Implications of Breast Cancer Molecular Phenotype for Radiation Oncology

International Nuclear Information System (INIS)

Sioshansi, Shirin; Huber, Kathryn E.; Wazer, David E.

2011-01-01

The identification of distinct molecular subtypes of breast cancer has advanced the understanding and treatment of breast cancer by providing insight into prognosis, patterns of recurrence, and effectiveness of therapy. The prognostic significance of molecular phenotype with regard to distant recurrences and overall survival are well established in the literature and has been readily incorporated into systemic therapy management decisions. However, despite the accumulating data suggesting similar prognostic significance for locoregional recurrence, integration of molecular phenotype into local management decision making has lagged. Although there are some conflicting reports, collectively the literature supports a low risk of local recurrence (LR) in the hormone receptor (HR) positive luminal subtypes compared to HR negative subtypes [triple negative (TN) and HER2-enriched]. The development of targeted therapies, such as trastuzumab for the treatment of HER2-enriched subtype, has been shown to mitigate the increased risk of LR. Unfortunately, no such remedy exists to address the increased risk of LR for patients with TN tumors, making it a clinical challenge for radiation oncologists. In this review we discuss the correlation between molecular subtype and LR following either breast conservation therapy or mastectomy. We also explore the possible mechanisms for increased LR in TN breast cancer and radiotherapeutic implications for this population, such as the safety of breast conservation, consideration of dose escalation, and the appropriateness of accelerated partial breast irradiation.

Adenoid cystic carcinoma of the breast, high grade with basal phenotype, literature review

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Enaam Junainah

Full Text Available Adenoid cystic carcinoma (ACC is a rare type of breast carcinoma resembling adenoid cystic carcinoma of other sites. this type of tumors usually characterized by the exhibiting dual cell population of luminal and basaloid with specific growth pattern Most of these sub types are triple-negative with basal-like breast features (tumors that are devoid of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, and express basal cell markers, they are usually low-grade but can be high grade, clinical behavior is indolent despite the nuclear grade, lymph node involvement or distant metastases which is rarely occur. Treatment is either simple mastectomy or lumpectomy. Chemotherapy, radiation and hormonal treatment have limited used in those cases. Keywords: Adenoid cystic carcinoma, Breast, Triple-negative and basal-like phenotype

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

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

2017-09-01

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

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

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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.

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

International Nuclear Information System (INIS)

Flemban, Arwa; Qualtrough, David

2015-01-01

The epithelium of the lactiferous ducts in the breast is comprised of luminal epithelial cells and underlying basal myoepithelial cells. The regulation of cell fate and transit of cells between these two cell types remains poorly understood. This relationship becomes of greater importance when studying the subtypes of epithelial breast carcinoma, which are categorized according to their expression of luminal or basal markers. The epithelial mesenchymal transition (EMT) is a pivotal event in tumor invasion. It is important to understand mechanisms that regulate this process, which bears relation to the normal dynamic of epithelial/basal phenotype regulation in the mammary gland. Understanding this process could provide answers for the regulation of EMT in breast cancer, and thereby identify potential targets for therapy. Evidence points towards a role for hedgehog signaling in breast tissue homeostasis and also in mammary neoplasia. This review examines our current understanding of role of the hedgehog-signaling (Hh) pathway in breast epithelial cells both during breast development and homeostasis and to assess the potential misappropriation of Hh signals in breast neoplasia, cancer stem cells and tumor metastasis via EMT

The implications of breast cancer molecular phenotype for radiation oncology

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Shirin eSioshansi

2011-06-01

Full Text Available The identification of distinct molecular subtypes of breast cancer has advanced the understanding and treatment of breast cancer by providing insight into prognosis, patterns of recurrence and effectiveness of therapy. The prognostic significance of molecular phenotype with regard to distant recurrences and overall survival are well established in the literature and has been readily incorporated into systemic therapy management decisions. However, despite the accumulating data suggesting similar prognostic significance for locoregional recurrence, integration of molecular phenotype into local management decision making has lagged. Although there are some conflicting reports, collectively the literature supports a low risk of local recurrence in the hormone receptor positive luminal subtypes compared to hormone receptor negative subtypes (triple negative and HER2-enriched. The development of targeted therapies, such as trastuzumab for the treatment of HER2-enriched subtype, has been shown to mitigate the increased risk of local recurrence. Unfortunately, no such remedy exists to address the increased risk of local recurrence for patients with triple negative tumors, making it a clinical challenge for radiation oncologists. In this review we discuss the correlation between molecular subtype and local recurrence following either breast conservation therapy or mastectomy. We also explore the possible mechanisms for increased local recurrence in triple negative breast cancer and radiotherapeutic implications for this population, such as the safety of breast conservation, consideration of dose escalation and the appropriateness of accelerated partial breast irradiation.

Inference of Tumor Evolution during Chemotherapy by Computational Modeling and In Situ Analysis of Genetic and Phenotypic Cellular Diversity

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Vanessa Almendro

2014-02-01

Full Text Available 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 posttreatment 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.

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

International Nuclear Information System (INIS)

Almendro, Vanessa; Cheng, Yu-Kang; Randles, Amanda; Itzkovitz, Shalev; Marusyk, Andriy; Ametller, Elisabet; Gonzalez-Farre, Xavier; Muñoz, Montse; Russnes, Hege G.; Helland, Åslaug; 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-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

Targeted Nanodiamonds as Phenotype Specific Photoacoustic Contrast Agents for Breast Cancer

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Zhang, Ti; Cui, Huizhong; Fang, Chia-Yi; Cheng, Kun; Yang, Xinmai; Chang, Huan-Cheng; Forrest, M. Laird

2015-01-01

Aim The aim is to develop irradiated nanodiamonds (INDs) as a molecularly-targeted contrast agent for high resolution and phenotype-specific detection of breast cancer with photoacoustic (PA) imaging. Materials & Methods The surface of acid treated radiation-damaged nanodiamonds was grafted with polyethylene glycol (PEG) to improve its stability and circulation time in blood, followed by conjugation to an anti-Human epidermal growth factor receptor-2 (HER2) peptide (KCCYSL) with a final nanoparticle size of ca. 92 nm. Immunocompetent mice bearing orthotopic HER2 positive or negative tumors were administered INDs and PA imaged using an 820-nm near infrared laser. Results PA images demonstrated that INDs accumulate in tumors and completely delineated the entire tumor within 10 hours. HER2 targeting significantly enhanced imaging of HER2-positive tumors. Pathological examination demonstrated INDs are non-toxic. Conclusions PA technology is adaptable to low-cost bedside medicine, and with new contrast agents described herein, PA can achieve high resolution (sub-mm) and phenotype specific monitoring of cancer growth. PMID:25723091

Molecular subtypes and imaging phenotypes of breast cancer

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Nariya Cho

2016-10-01

Full Text Available During the last 15 years, traditional breast cancer classifications based on histopathology have been reorganized into the luminal A, luminal B, human epidermal growth factor receptor 2 (HER2, and basal-like subtypes based on gene expression profiling. Each molecular subtype has shown varying risk for progression, response to treatment, and survival outcomes. Research linking the imaging phenotype with the molecular subtype has revealed that non-calcified, relatively circumscribed masses with posterior acoustic enhancement are common in the basal-like subtype, spiculated masses with a poorly circumscribed margin and posterior acoustic shadowing in the luminal subtype, and pleomorphic calcifications in the HER2-enriched subtype. Understanding the clinical implications of the molecular subtypes and imaging phenotypes could help radiologists guide precision medicine, tailoring medical treatment to patients and their tumor characteristics.

Molecular subtypes and imaging phenotypes of breast cancer

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Cho, Nariya [Dept. of Radiology, Seoul National University Hospital, Seoul (Korea, Republic of)

2016-08-15

During the last 15 years, traditional breast cancer classifications based on histopathology have been reorganized into the luminal A, luminal B, human epidermal growth factor receptor 2 (HER2), and basal-like subtypes based on gene expression profiling. Each molecular subtype has shown varying risk for progression, response to treatment, and survival outcomes. Research linking the imaging phenotype with the molecular subtype has revealed that non-calcified, relatively circumscribed masses with posterior acoustic enhancement are common in the basal-like subtype, spiculated masses with a poorly circumscribed margin and posterior acoustic shadowing in the luminal subtype, and pleomorphic calcifications in the HER2-enriched subtype. Understanding the clinical implications of the molecular subtypes and imaging phenotypes could help radiologists guide precision medicine, tailoring medical treatment to patients and their tumor characteristics.

Molecular subtypes and imaging phenotypes of breast cancer

International Nuclear Information System (INIS)

Cho, Nariya

2016-01-01

During the last 15 years, traditional breast cancer classifications based on histopathology have been reorganized into the luminal A, luminal B, human epidermal growth factor receptor 2 (HER2), and basal-like subtypes based on gene expression profiling. Each molecular subtype has shown varying risk for progression, response to treatment, and survival outcomes. Research linking the imaging phenotype with the molecular subtype has revealed that non-calcified, relatively circumscribed masses with posterior acoustic enhancement are common in the basal-like subtype, spiculated masses with a poorly circumscribed margin and posterior acoustic shadowing in the luminal subtype, and pleomorphic calcifications in the HER2-enriched subtype. Understanding the clinical implications of the molecular subtypes and imaging phenotypes could help radiologists guide precision medicine, tailoring medical treatment to patients and their tumor characteristics

Morphological and immuno phenotypic characterization of mammary carcinomas in relation to family history of breast cancer

International Nuclear Information System (INIS)

Gualco, G.; Ortega, V.; Musto, M.; Delgado, L.

2004-01-01

Objective: To investigate histopathological and immuno phenotypic differences between breast carcinomas sporadic (CM E) and developed in the context of breast cancer (B C) Family (CM F). Methodology: The study included in the CME group (n = 34) patients (pts) with unilateral CM diagnosed after age 30 without family history of CM. In CM F group (n = 26) family members were included pts with 3 or more cases of CM (at least one diagnosed before age 50) or two cases with any of the following sub-criteria: at least one case diagnosed before age 35, paternal transmission, bilateral breast cancer, cancer ovary. Each group was subdivided into 2 subgroups according to age at diagnosis of CM: age equal to or greater than 40 years (subgroup 1) and age under 40 years (subgroup 2). It recorded the clinical characteristics and conventional anatomical and pathological parameters. By immunohistochemistry (IHC) expression of estrogen receptors was studied and progesterone (E R, P R), HER2, p3, bcl-2 and Ki67. Appropriate statistical tests were applied to Univariate and multivariate analyzes. Results: Mean age at diagnosis (45 vs 58, p <0.001) and tumor size (p <0.05) were lower in the CMF group than in the group with CME. In both groups predominant histological type was infiltrating ductal carcinoma NOS. He documented a tendency to higher histological grade and lower E R expression in CMF regarding CME. There were no differences in the expression of Pr, HER2, Ki67, bcl2 and p53. while in the CMF group no differences in tumor characteristics were observed by age diagnosis, in the CME, subgroup 2 showed a predominance of edges expansive growth, lower tubular differentiation, histological grade end stores III, minor component in situ, and low expression of RE. Discussion: Morphologic and immune phenotypic features are similar to the CMF studies documented in the United States and Europe, which agrees with the ancestral origin predominant in our population. Overall, the group presented

Intra-tumor heterogeneity in breast cancer has limited impact on transcriptomic-based molecular profiling.

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Karthik, Govindasamy-Muralidharan; Rantalainen, Mattias; Stålhammar, Gustav; Lövrot, John; Ullah, Ikram; Alkodsi, Amjad; Ma, Ran; Wedlund, Lena; Lindberg, Johan; Frisell, Jan; Bergh, Jonas; Hartman, Johan

2017-11-29

Transcriptomic profiling of breast tumors provides opportunity for subtyping and molecular-based patient stratification. In diagnostic applications the specimen profiled should be representative of the expression profile of the whole tumor and ideally capture properties of the most aggressive part of the tumor. However, breast cancers commonly exhibit intra-tumor heterogeneity at molecular, genomic and in phenotypic level, which can arise during tumor evolution. Currently it is not established to what extent a random sampling approach may influence molecular breast cancer diagnostics. In this study we applied RNA-sequencing to quantify gene expression in 43 pieces (2-5 pieces per tumor) from 12 breast tumors (Cohort 1). We determined molecular subtype and transcriptomic grade for all tumor pieces and analysed to what extent pieces originating from the same tumors are concordant or discordant with each other. Additionally, we validated our finding in an independent cohort consisting of 19 pieces (2-6 pieces per tumor) from 6 breast tumors (Cohort 2) profiled using microarray technique. Exome sequencing was also performed on this cohort, to investigate the extent of intra-tumor genomic heterogeneity versus the intra-tumor molecular subtype classifications. Molecular subtyping was consistent in 11 out of 12 tumors and transcriptomic grade assignments were consistent in 11 out of 12 tumors as well. Molecular subtype predictions revealed consistent subtypes in four out of six patients in this cohort 2. Interestingly, we observed extensive intra-tumor genomic heterogeneity in these tumor pieces but not in their molecular subtype classifications. Our results suggest that macroscopic intra-tumoral transcriptomic heterogeneity is limited and unlikely to have an impact on molecular diagnostics for most patients.

Tumor-derived Matrix Metalloproteinase-13 (MMP-13) correlates with poor prognoses of invasive breast cancer

International Nuclear Information System (INIS)

Zhang, Bin; Niu, Yun; Niu, Ruifang; Sun, Baocun; Hao, Xishan; Cao, Xuchen; Liu, Yanxue; Cao, Wenfeng; Zhang, Fei; Zhang, Shiwu; Li, Hongtao; Ning, Liansheng; Fu, Li

2008-01-01

Experimental evidence suggests that matrix metalloproteinase-13 (MMP-13) protein may promote breast tumor progression. However, its relevance to the progression of human breast cancer is yet to be established. Furthermore, it is not clear whether MMP-13 can be used as an independent breast cancer biomarker. This study was conducted to assess the expression profile of MMP-13 protein in invasive breast carcinomas to determine its diagnostic and prognostic significance, as well as its correlation with other biomarkers including estrogen receptor (ER), progesterone receptor (PR), Her-2/neu, MMP-2, MMP-9, tissue inhibitor of MMP-1 and -2 (TIMP-1 and TIMP-2). Immunohistochemistry (IHC) was performed on paraffin-embedded tissue microarray containing specimens from 263 breast carcinomas. The intensity and the extent of IHC were scored by pathologists in blind fashion. The correlation of the gene expression profiles with patients' clinicopathological features and clinical outcomes were analyzed for statistical significance. MMP-13 protein was detected in the cytoplasm of the malignant cells and the peritumoral stromal cells. MMP-13 expression by tumor cells (p < 0.001) and stromal fibroblasts (p <0.001) both correlated with carcinoma infiltration of lymph nodes. MMP-13 also correlated with the expression of Her-2/neu (p = 0.015) and TIMP-1 (p < 0.010), respectively in tumor cells. Tumor-derived, but not stromal fibroblast-derived, MMP-13 correlated with aggressive tumor phenotypes. Moreover, high levels of MMP-13 expression were associated with decreased overall survival. In parallel, the prognostic value of MMP-13 expressed by peritumoral fibroblasts seems less significant. Our data suggest that lymph node status, tumor size, Her-2/neu expression, TIMP-1 and MMP-13 expression in cancer cells are independent prognostic factors. Tumor-derived, but not stromal fibroblast-derived, MMP-13 correlated with aggressive tumor phenotypes, and inversely correlated with the

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

International Nuclear Information System (INIS)

Hage-Sleiman, Rouba; Herveau, Stéphanie; Matera, Eva-Laure; Laurier, Jean-Fabien; Dumontet, Charles

2010-01-01

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. 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. 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 antimicrotubule agents both in vitro and in xenografts. These

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.

Glycolytic activity in breast cancer using 18F-FDG PET/CT as prognostic predictor: A molecular phenotype approach.

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Garcia Vicente, A M; Soriano Castrejón, A; Amo-Salas, M; Lopez Fidalgo, J F; Muñoz Sanchez, M M; Alvarez Cabellos, R; Espinosa Aunion, R; Muñoz Madero, V

2016-01-01

To explore the relationship between basal (18)F-FDG uptake in breast tumors and survival in patients with breast cancer (BC) using a molecular phenotype approach. This prospective and multicentre study included 193 women diagnosed with BC. All patients underwent an (18)F-FDG PET/CT prior to treatment. Maximum standardized uptake value (SUVmax) in tumor (T), lymph nodes (N), and the N/T index was obtained in all the cases. Metabolic stage was established. As regards biological prognostic parameters, tumors were classified into molecular sub-types and risk categories. Overall survival (OS) and disease free survival (DFS) were obtained. An analysis was performed on the relationship between semi-quantitative metabolic parameters with molecular phenotypes and risk categories. The effect of molecular sub-type and risk categories in prognosis was analyzed using Kaplan-Meier and univariate and multivariate tests. Statistical differences were found in both SUVT and SUVN, according to the molecular sub-types and risk classifications, with higher semi-quantitative values in more biologically aggressive tumors. No statistical differences were observed with respect to the N/T index. Kaplan-Meier analysis revealed that risk categories were significantly related to DFS and OS. In the multivariate analysis, metabolic stage and risk phenotype showed a significant association with DFS. High-risk phenotype category showed a worst prognosis with respect to the other categories with higher SUVmax in primary tumor and lymph nodes. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

Genetic susceptibility markers for a breast-colorectal cancer phenotype: Exploratory results from genome-wide association studies

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Joon, Aron; Brewster, Abenaa M.; Chen, Wei V.; Eng, Cathy; Shete, Sanjay; Casey, Graham; Schumacher, Fredrick; Lin, Yi; Harrison, Tabitha A.; White, Emily; Ahsan, Habibul; Andrulis, Irene L.; Whittemore, Alice S.; Ko Win, Aung; Schmidt, Daniel F.; Kapuscinski, Miroslaw K.; Ochs-Balcom, Heather M.; Gallinger, Steven; Jenkins, Mark A.; Newcomb, Polly A.; Lindor, Noralane M.; Peters, Ulrike; Amos, Christopher I.; Lynch, Patrick M.

2018-01-01

Background Clustering of breast and colorectal cancer has been observed within some families and cannot be explained by chance or known high-risk mutations in major susceptibility genes. Potential shared genetic susceptibility between breast and colorectal cancer, not explained by high-penetrance genes, has been postulated. We hypothesized that yet undiscovered genetic variants predispose to a breast-colorectal cancer phenotype. Methods To identify variants associated with a breast-colorectal cancer phenotype, we analyzed genome-wide association study (GWAS) data from cases and controls that met the following criteria: cases (n = 985) were women with breast cancer who had one or more first- or second-degree relatives with colorectal cancer, men/women with colorectal cancer who had one or more first- or second-degree relatives with breast cancer, and women diagnosed with both breast and colorectal cancer. Controls (n = 1769), were unrelated, breast and colorectal cancer-free, and age- and sex- frequency-matched to cases. After imputation, 6,220,060 variants were analyzed using the discovery set and variants associated with the breast-colorectal cancer phenotype at Pcolorectal cancer phenotype in the discovery and replication data (most significant; rs7430339, Pdiscovery = 1.2E-04; rs7429100, Preplication = 2.8E-03). In meta-analysis of the discovery and replication data, the most significant association remained at rs7429100 (P = 1.84E-06). Conclusion The results of this exploratory analysis did not find clear evidence for a susceptibility locus with a pleiotropic effect on hereditary breast and colorectal cancer risk, although the suggestive association of genetic variation in the region of ROBO1, a potential tumor suppressor gene, merits further investigation. PMID:29698419

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

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Santander, Ana M.; Lopez-Ocejo, Omar; Casas, Olivia; Agostini, Thais; Sanchez, Lidia; Lamas-Basulto, Eduardo; Carrio, Roberto; Cleary, Margot P.; Gonzalez-Perez, Ruben R.; Torroella-Kouri, Marta

2015-01-01

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

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

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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.

Tumor cell expression of CD163 is associated to postoperative radiotherapy and poor prognosis in patients with breast cancer treated with breast-conserving surgery.

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Garvin, Stina; Oda, Husam; Arnesson, Lars-Gunnar; Lindström, Annelie; Shabo, Ivan

2018-05-03

Cancer cell fusion with macrophages results in highly tumorigenic hybrids that acquire genetic and phenotypic characteristics from both maternal cells. Macrophage traits, exemplified by CD163 expression, in tumor cells are associated with advanced stages and poor prognosis in breast cancer (BC). In vitro data suggest that cancer cells expressing CD163 acquire radioresistance. Tissue microarray was constructed from primary BC obtained from 83 patients treated with breast-conserving surgery, 50% having received postoperative radiotherapy (RT) and none of the patients had lymph node or distant metastasis. Immunostaining of CD163 in cancer cells and macrophage infiltration (MI) in tumor stroma were evaluated. Macrophage:MCF-7 hybrids were generated by spontaneous in vitro cell fusion. After irradiation (0, 2.5 and 5 Gy γ-radiation), both hybrids and their maternal MCF-7 cells were examined by clonogenic survival. CD163-expression by cancer cells was significantly associated with MI and clinicopathological data. Patients with CD163-positive tumors had significantly shorter disease-free survival (DFS) after RT. In vitro generated macrophage:MCF-7 hybrids developed radioresistance and exhibited better survival and colony forming ability after radiation compared to maternal MCF-7 cancer cells. Our results suggest that macrophage phenotype in tumor cells results in radioresistance in breast cancer and shorter DFS after radiotherapy.

TIE-2 and VEGFR kinase activities drive immunosuppressive function of TIE-2-expressing monocytes in human breast tumors.

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Ibberson, Mark; Bron, Sylvian; Guex, Nicolas; Faes-van't Hull, Eveline; Ifticene-Treboux, Assia; Henry, Luc; Lehr, Hans-Anton; Delaloye, Jean-François; Coukos, George; Xenarios, Ioannis; Doucey, Marie-Agnès

2013-07-01

Tumor-associated TIE-2-expressing monocytes (TEM) are highly proangiogenic cells critical for tumor vascularization. We previously showed that, in human breast cancer, TIE-2 and VEGFR pathways control proangiogenic activity of TEMs. Here, we examine the contribution of these pathways to immunosuppressive activity of TEMs. We investigated the changes in immunosuppressive activity of TEMs and gene expression in response to specific kinase inhibitors of TIE-2 and VEGFR. The ability of tumor TEMs to suppress tumor-specific T-cell response mediated by tumor dendritic cells (DC) was measured in vitro. Characterization of TEM and DC phenotype in addition to their interaction with T cells was done using confocal microscopic images analysis of breast carcinomas. TEMs from breast tumors are able to suppress tumor-specific immune responses. Importantly, proangiogenic and suppressive functions of TEMs are similarly driven by TIE-2 and VEGFR kinase activity. Furthermore, we show that tumor TEMs can function as antigen-presenting cells and elicit a weak proliferation of T cells. Blocking TIE-2 and VEGFR kinase activity induced TEMs to change their phenotype into cells with features of myeloid dendritic cells. We show that immunosuppressive activity of TEMs is associated with high CD86 surface expression and extensive engagement of T regulatory cells in breast tumors. TIE-2 and VEGFR kinase activity was also necessary to maintain high CD86 surface expression levels and to convert T cells into regulatory cells. These results suggest that TEMs are plastic cells that can be reverted from suppressive, proangiogenic cells into cells that are able to mediate an antitumoral immune response. ©2013 AACR.

Primary Neuroendocrine Tumor of the Breast: Imaging Features

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Chang, Eun Deok; Kim, Min Kyun; Kim, Jeong Soo; Whang, In Yong

2013-01-01

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

Chemotherapy and radiation therapy elicits tumor specific T cell responses in a breast cancer patient

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Bernal-Estévez, David; Sánchez, Ramiro; Tejada, Rafael E.; Parra-López, Carlos

2016-01-01

Experimental evidence and clinical studies in breast cancer suggest that some anti-tumor therapy regimens generate stimulation of the immune system that accounts for tumor clinical responses, however, demonstration of the immunostimulatory power of these therapies on cancer patients continues to be a formidable challenge. Here we present experimental evidence from a breast cancer patient with complete clinical response after 7 years, associated with responsiveness of tumor specific T cells. T cells were obtained before and after anti-tumor therapy from peripheral blood of a 63-years old woman diagnosed with ductal breast cancer (HER2/neu+++, ER-, PR-, HLA-A*02:01) treated with surgery, followed by paclitaxel, trastuzumab (suspended due to cardiac toxicity), and radiotherapy. We obtained a leukapheresis before surgery and after 8 months of treatment. Using in vitro cell cultures stimulated with autologous monocyte-derived dendritic cells (DCs) that produce high levels of IL-12, we characterize by flow cytometry the phenotype of tumor associated antigens (TAAs) HER2/neu and NY-ESO 1 specific T cells. The ex vivo analysis of the TCR-Vβ repertoire of TAA specific T cells in blood and Tumor Infiltrating Lymphocytes (TILs) were performed in order to correlate both repertoires prior and after therapy. We evidence a functional recovery of T cell responsiveness to polyclonal stimuli and expansion of TAAs specific CD8+ T cells using peptide pulsed DCs, with an increase of CTLA-4 and memory effector phenotype after anti-tumor therapy. The ex vivo analysis of the TCR-Vβ repertoire of TAA specific T cells in blood and TILs showed that whereas the TCR-Vβ04-02 clonotype is highly expressed in TILs the HER2/neu specific T cells are expressed mainly in blood after therapy, suggesting that this particular TCR was selectively enriched in blood after anti-tumor therapy. Our results show the benefits of anti-tumor therapy in a breast cancer patient with clinical complete response in

The Human Cell Surfaceome of Breast Tumors

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

2013-01-01

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

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

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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.

2016-01-01

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 ...

Phyllodes tumor of the breast

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Cubells, M.; Uixera, I.; Miranda, V.; Gil de Ramales, V.; Bulto, J. A.; Mendez, M.; Morcillo, E.

1999-01-01

To study the phyllodes tumors of the breast diagnosed in our hospital, assessing the clinical, mammographic, ultrasonographic and color Doppler ultrasound findings. A retrospective study was carried out of 20 histologically diagnosed cases of phyllodes tumor of the breast over a 20-year period, taking into account patient age, clinical signs, mammographic and ultrasonographic findings, surgical treatment and recurrences. The clinical presentation was that of a palpable, usually painless, mass with a firm, elastic consistency. Mammographic images showed a lesion of homogeneous density and well-defined, round or lobulated margins. Two tumors contained large calcifications associated with previous fibroadenoma. Ultrasound revealed a slightly enhanced solid nodule of homogeneous echogenicity. Color Doppler ultrasound disclosed the presence of hypervascularization. The lesions were treated by surgical enucleation with follow-up examination every 6 months. Recurrences were treated by radical mastectomy. The phyllodes tumor of the breast is difficult to diagnose because of its similarity to the fibroadenoma. However, it should be suspected in the presence of a late-developing, rapidly growing mass. Mammography and breast ultrasound are of diagnostic utility, but the definitive diagnosis requires biopsy. (Author) 12 refs

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.

Ethanol exposure induces the cancer-associated fibroblast phenotype and lethal tumor metabolism: implications for breast cancer prevention.

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

2013-01-15

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 also show that

RAC1 GTP-ase signals Wnt-beta-catenin pathway mediated integrin-directed metastasis-associated tumor cell phenotypes in triple negative breast cancers.

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De, Pradip; Carlson, Jennifer H; Jepperson, Tyler; Willis, Scooter; Leyland-Jones, Brian; Dey, Nandini

2017-01-10

The acquisition of integrin-directed metastasis-associated (ID-MA) phenotypes by Triple-Negative Breast Cancer (TNBC) cells is caused by an upregulation of the Wnt-beta-catenin pathway (WP). We reported that WP is one of the salient genetic features of TNBC. RAC-GTPases, small G-proteins which transduce signals from cell surface proteins including integrins, have been implicated in tumorigenesis and metastasis by their role in essential cellular functions like motility. The collective percentage of alteration(s) in RAC1 in ER+ve BC was lower as compared to ER-ve BC (35% vs 57%) (brca/tcga/pub2015). High expression of RAC1 was associated with poor outcome for RFS with HR=1.48 [CI: 1.15-1.9] p=0.0019 in the Hungarian ER-veBC cohort. Here we examined how WP signals are transduced via RAC1 in the context of ID-MA phenotypes in TNBC. Using pharmacological agents (sulindac sulfide), genetic tools (beta-catenin siRNA), WP modulators (Wnt-C59, XAV939), RAC1 inhibitors (NSC23766, W56) and WP stimulations (LWnt3ACM, Wnt3A recombinant) in a panel of 6-7 TNBC cell lines, we studied fibronectin-directed (1) migration, (2) matrigel invasion, (3) RAC1 and Cdc42 activation, (4) actin dynamics (confocal microscopy) and (5) podia-parameters. An attenuation of WP, which (a) decreased cellular levels of beta-catenin, as well as its nuclear active-form, (b) decreased fibronectin-induced migration, (c) decreased invasion, (d) altered actin dynamics and (e) decreased podia-parameters was successful in blocking fibronectin-mediated RAC1/Cdc42 activity. Both Wnt-antagonists and RAC1 inhibitors blocked fibronectin-induced RAC1 activation and inhibited the fibronectin-induced ID-MA phenotypes following specific WP stimulation by LWnt3ACM as well as Wnt3A recombinant protein. To test a direct involvement of RAC1-activation in WP-mediated ID-MA phenotypes, we stimulated brain-metastasis specific MDA-MB231BR cells with LWnt3ACM. LWnt3ACM-stimulated fibronectin-directed migration was blocked by

G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer

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Hollmén, Maija; Karaman, Sinem; Schwager, Simon; Lisibach, Angela; Christiansen, Ailsa J.; Maksimow, Mikael; Varga, Zsuzsanna; Jalkanen, Sirpa; Detmar, Michael

2016-01-01

ABSTRACT Tumor-associated macrophages (TAMs) have been implicated in the promotion of breast cancer growth and metastasis, and a strong infiltration by TAMs has been associated with estrogen receptor (ER)-negative tumors and poor prognosis. However, the molecular mechanisms behind these observations are unclear. We investigated macrophage activation in response to co-culture with several breast cancer cell lines (T47D, MCF-7, BT-474, SKBR-3, Cal-51 and MDA-MB-231) and found that high granulocyte colony-stimulating factor (G-CSF) secretion by the triple-negative breast cancer (TNBC) cell line MDA-MB-231 gave rise to immunosuppressive HLA-DRlo macrophages that promoted migration of breast cancer cells via secretion of TGF-α. In human breast cancer samples (n = 548), G-CSF was highly expressed in TNBC (p CSF blockade in the 4T1 mammary tumor model promoted maturation of MHCIIhi blood monocytes and TAMs and significantly reduced lung metastasis, anti-CSF-1R treatment promoted MHCIIloF4/80hiMRhi anti-inflammatory TAMs and enhanced lung metastasis in the presence of high G-CSF levels. Combined anti-G-CSF and anti-CSF-1R therapy significantly increased lymph node metastases, possibly via depletion of the so-called “gate-keeper” subcapsular sinus macrophages. These results indicate that G-CSF promotes the anti-inflammatory phenotype of tumor-induced macrophages when CSF-1R is inhibited and therefore caution against the use of M-CSF/CSF-1R targeting agents in tumors with high G-CSF expression. PMID:27141367

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

International Nuclear Information System (INIS)

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

alterations in breast tumors associated with poor survival, immune response or with a BRCAness phenotype will allow the use of a more personalized treatment in these patients

Intravital multiphoton imaging reveals multicellular streaming as a crucial component of in vivo cell migration in human breast tumors

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Patsialou, Antonia; Bravo-Cordero, Jose Javier; Wang, Yarong; Entenberg, David; Liu, Huiping; Clarke, Michael; Condeelis, John S.

2014-01-01

Metastasis is the main cause of death in breast cancer patients. Cell migration is an essential component of almost every step of the metastatic cascade, especially the early step of invasion inside the primary tumor. In this report, we have used intravital multiphoton microscopy to visualize the different migration patterns of human breast tumor cells in live primary tumors. We used xenograft tumors of MDA-MB-231 cells as well as a low passage xenograft tumor from orthotopically injected patient-derived breast tumor cells. Direct visualization of human tumor cells in vivo shows two patterns of high-speed migration inside primary tumors: a. single cells and b. multicellular streams (i.e., cells following each other in a single file but without cohesive cell junctions). Critically, we found that only streaming and not random migration of single cells was significantly correlated with proximity to vessels, with intravasation and with numbers of elevated circulating tumor cells in the bloodstream. Finally, although the two human tumors were derived from diverse genetic backgrounds, we found that their migratory tumor cells exhibited coordinated gene expression changes that led to the same end-phenotype of enhanced migration involving activating actin polymerization and myosin contraction. Our data are the first direct visualization and assessment of in vivo migration within a live patient-derived breast xenograft tumor. PMID:25013744

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

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

2013-02-01

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

Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: implications for breast cancer and DCIS therapy with autophagy inhibitors.

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Martinez-Outschoorn, Ubaldo E; Pavlides, Stephanos; Whitaker-Menezes, Diana; Daumer, Kristin M; Milliman, Janet N; Chiavarina, Barbara; Migneco, Gemma; Witkiewicz, Agnieszka K; Martinez-Cantarin, Maria P; Flomenberg, Neal; Howell, Anthony; Pestell, Richard G; Lisanti, Michael P; Sotgia, Federica

2010-06-15

Loss of stromal caveolin 1 (Cav-1) is a novel biomarker for cancer-associated fibroblasts that predicts poor clinical outcome in breast cancer and DCIS patients. We hypothesized that epithelial cancer cells may have the ability to drive Cav-1 downregulation in adjacent normal fibroblasts, thereby promoting the cancer associated fibroblast phenotype. To test this hypothesis directly, here we developed a novel co-culture model employing (i) human breast cancer cells (MCF7), and (ii) immortalized fibroblasts (hTERT-BJ1), which are grown under defined experimental conditions. Importantly, we show that co-culture of immortalized human fibroblasts with MCF7 breast cancer cells leads to Cav-1 downregulation in fibroblasts. These results were also validated using primary cultures of normal human mammary fibroblasts co-cultured with MCF7 cells. In this system, we show that Cav-1 downregulation is mediated by autophagic/lysosomal degradation, as pre-treatment with lysosome-specific inhibitors rescues Cav-1 expression. Functionally, we demonstrate that fibroblasts co-cultured with MCF7 breast cancer cells acquire a cancer associated fibroblast phenotype, characterized by Cav-1 downregulation, increased expression of myofibroblast markers and extracellular matrix proteins, and constitutive activation of TGFβ/Smad2 signaling. siRNA-mediated Cav-1 downregulation mimics several key changes that occur in co-cultured fibroblasts, clearly indicating that a loss of Cav-1 is a critical initiating factor, driving stromal fibroblast activation during tumorigenesis. As such, this co-culture system can now be used as an experimental model for generating "synthetic" cancer associated fibroblasts (CAFs). More specifically, these "synthetic" CAFs could be used for drug screening to identify novel therapeutics that selectively target the Cav-1-negative tumor micro-environment. Our findings also suggest that chloroquine, or other autophagy/lysosome inhibitors, may be useful as anti

Bilateral malignant phyllodes tumor of the breast | Odik | Nigerian ...

African Journals Online (AJOL)

... biphasic tumors, arising from the intra-lobular breast stroma. It constitutes less than 1%of all breast tumors. Bilateralmalignant phyllodes tumor is uncommon.We report a case of 32-year oldmultiparouswoman who died of multi-organ metastatic disease. The diagnosis was based on histology report of the breast specimen.

Apparent diffusion coefficients of breast tumors. Clinical application

International Nuclear Information System (INIS)

Hatakenaka, Masamitsu; Soeda, Hiroyasu; Yabuuchi, Hidetake; Matsuo, Yoshio; Kamitani, Takeshi; Oda, Yoshinao; Tsuneyoshi, Masazumi; Honda, Hiroshi

2008-01-01

The purpose of this study was to evaluate the usefulness of apparent diffusion coefficient (ADC) for the differential diagnosis of breast tumors and to determine the relation between ADC and tumor cellularity. One hundred and thirty-six female patients (age range, 17-83 years; average age, 51.7 years) with 140 histologically proven breast tumors underwent diffusion-weighted magnetic resonance (MR) imaging (DWI) using the spin-echo echo-planar technique, and the ADCs of the tumors were calculated using 3 different b values, 0, 500, and 1000 s/mm 2 . The diagnoses consisted of fibroadenoma (FA, n=16), invasive ductal carcinoma, not otherwise specified (IDC, n=117), medullary carcinoma (ME, n=3) and mucinous carcinoma (MU, n=4). Tumor cellularity was calculated from surgical specimens. The ADCs of breast tumors and cellularity were compared between different histological types by analysis of variance and Scheffe's post hoc test. The correlation between tumor cellularity and ADC was analyzed by Pearson correlation test. Significant differences were observed in ADCs between FA and all types of cancers (P 2 =0.451). The ADC may potentially help in differentiating benign and malignant breast tumors. Tumor ADC correlates inversely with tumor cellularity. (author)

Imaging of breast tumors using MR-elastography

International Nuclear Information System (INIS)

Lorenzen, J.; Sinkus, R.; Leussler, C.; Dargatz, M.; Roeschmann, P.; Schrader, D.; Lorenzen, M.

2001-01-01

Purpose: Imaging of breast tumors using MR-Elastography. Material and method: Low-frequency mechanical waves are transmitted into breast-tissue by means of an oscillator. The local characteristics of the mechanical wave are determined by the elastic properties of the tissue. By means of a motion-sensitive spin-echo-sequence these waves can be displayed within the phase of the MR image. Subsequently, these images can be used to reconstruct the local distribution of elasticity. In-vivo measurements were performed in 3 female patients with malignant tumors of the breast. Results: All patients tolerated the measurement set-up without any untoward sensation in the contact area of skin and oscillator. The waves completely penetrated the breast, encompassing the axilla and regions close to the chest wall. All tumors were localized by MRE as structures of markedly stiffer tissue when compared to the surrounding tissue. Furthermore, in one patient, a metastasis in an axillary lymph node was detected. In all patients, local regions of increased elasticity were found in the remaining parenchyma of the breast, which, however, did not reach the high levels of elasticity found in the tumors. Conclusion: MRE is an imaging modality enabling adjunct tissue differentiation of mammary tumors. (orig.) [de

Hypermethylation pattern of ESR and PgR genes and lacking estrogen and progesterone receptors in human breast cancer tumors: ER/PR subtypes.

Science.gov (United States)

Pirouzpanah, Saeed; Taleban, Forough-Azam; Mehdipour, Parvin; Sabour, Siamak; Atri, Morteza

2018-02-14

The option of endocrine therapy in breast cancer remains conventionally promising. We aimed to investigate how accurately the pattern of hypermethylation at estrogen receptor (ESR) and progesterone receptor (PgR) genes may associate with relative expression and protein status of ER, PR and the combinative phenotype of ER/PR. In this consecutive case-series, we enrolled 139 primary diagnosed breast cancer. Methylation specific PCR was used to assess the methylation status (individual test). Tumor mRNA expression levels were evaluated using real-time RT-PCR. Immunohistochemistry data was used to present hormonal receptor status of a tumor (as test reference). Methylation at ESR1 was comparably frequent in ER-breast tumors (83.0%, PPR- conditions (Cramer's V= 0.44, PPR (77.1%, PPR expressions (55.6%, PPR- (64.4%, PPR-, the hypermethylation of PgRb seem another epigenetic signalling variable actively associate with methylated ESR1 to show lack of ER+/PR+ tumors in breast cancer.

FGFR2 promotes breast tumorigenicity through maintenance of breast tumor-initiating cells.

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Sungeun Kim

Full Text Available Emerging evidence suggests that some cancers contain a population of stem-like TICs (tumor-initiating cells and eliminating TICs may offer a new strategy to develop successful anti-cancer therapies. As molecular mechanisms underlying the maintenance of the TIC pool are poorly understood, the development of TIC-specific therapeutics remains a major challenge. We first identified and characterized TICs and non-TICs isolated from a mouse breast cancer model. TICs displayed increased tumorigenic potential, self-renewal, heterogeneous differentiation, and bipotency. Gene expression analysis and immunostaining of TICs and non-TICs revealed that FGFR2 was preferentially expressed in TICs. Loss of FGFR2 impaired self-renewal of TICs, thus resulting in marked decreases in the TIC population and tumorigenic potential. Restoration of FGFR2 rescued the defects in TIC pool maintenance, bipotency, and breast tumor growth driven by FGFR2 knockdown. In addition, pharmacological inhibition of FGFR2 kinase activity led to a decrease in the TIC population which resulted in suppression of breast tumor growth. Moreover, human breast TICs isolated from patient tumor samples were found enriched in a FGFR2+ population that was sufficient to initiate tumor growth. Our data suggest that FGFR2 is essential in sustaining the breast TIC pool through promotion of self-renewal and maintenance of bipotent TICs, and raise the possibility of FGFR2 inhibition as a strategy for anti-cancer therapy by eradicating breast TICs.

Adjuvant radiotherapy for phyllodes tumor of the breast

International Nuclear Information System (INIS)

Chaney, Arthur W.; Pollack, Alan; Zagars, Gunar K.

1997-01-01

Purpose/Objective: The role of radiotherapy for the treatment of phyllodes tumors of the breast remains controversial. Adjuvant radiotherapy is often cited in the existing literature as not providing any benefit over surgical treatment alone. The data supporting this belief are anecdotal. There are also anecdotal reports that radiotherapy may have a role in cases wherein the risk of local failure is high. As with breast carcinomas, conservative surgery (wide local excision) for phyllodes tumors is associated with about a 50% local recurrence rate; diffuse or bulky disease and/or malignant histology are also associated with high local failure rates. We are unaware of any series that examines the role of adjuvant radiotherapy in the management of phyllodes tumor of the breast. We present here a retrospective study of eight patients so treated at MD Anderson Cancer Center. Materials and Methods: Eight patients have been treated with radiotherapy for non-metastatic phyllodes tumor of the breast at MD Anderson Cancer Center between December 1988 and August 1993. All patients were female; the median age was 43 years, with a range of 19 to 62 years. All patients presented with a breast mass, which was associated with pain in one patient, and was ulcerative in three. Results: Tumor size ranged from 3.5 to 16 cm, with a median diameter of 10.4 cm. Six patients had tumors in the upper outer quadrant, and two patients had upper inner tumors. Five patients had malignant tumors, two patients were classified as benign, and one was of indeterminate malignant potential. All five of the malignant tumors displayed stromal overgrowth on pathologic review. The remaining benign and indeterminate tumors lacked this feature. One patient with a benign tumor had a history of two prior recurrences. Primary surgery consisted of either lumpectomy in two patients or mastectomy in six patients. Axillary level I/II lymph node dissections were performed in 5 patients and no involvement was seen

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

Science.gov (United States)

2011-01-01

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 treatment. Boswellia sacra

Pathogenesis and progression of fibroepithelial breast tumors

NARCIS (Netherlands)

Kuijper, Arno

2006-01-01

Fibroadenoma and phyllodes tumor are fibroepithelial breast tumors. These tumors are biphasic, i.e. they are composed of stroma and epithelium. The behavior of fibroadenomas is benign, whereas phyllodes tumors can recur and even metastasize. Classification criteria for both tumors show considerable

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

that ADAM12 deficiency reduces breast tumor progression in the PyMT model. However, the catalytic activity of ADAM12 appears to be dispensable for its tumor-promoting effect. Interestingly, we demonstrate that ADAM12 endogenously expressed in tumor-associated stroma in the PyMT model does not influence......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...... 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...

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

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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

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

A model of tumor architecture and spatial interactions with tumor microenvironment in breast carcinoma

Science.gov (United States)

Ben Cheikh, Bassem; Bor-Angelier, Catherine; Racoceanu, Daniel

2017-03-01

Breast carcinomas are cancers that arise from the epithelial cells of the breast, which are the cells that line the lobules and the lactiferous ducts. Breast carcinoma is the most common type of breast cancer and can be divided into different subtypes based on architectural features and growth patterns, recognized during a histopathological examination. Tumor microenvironment (TME) is the cellular environment in which tumor cells develop. Being composed of various cell types having different biological roles, TME is recognized as playing an important role in the progression of the disease. The architectural heterogeneity in breast carcinomas and the spatial interactions with TME are, to date, not well understood. Developing a spatial model of tumor architecture and spatial interactions with TME can advance our understanding of tumor heterogeneity. Furthermore, generating histological synthetic datasets can contribute to validating, and comparing analytical methods that are used in digital pathology. In this work, we propose a modeling method that applies to different breast carcinoma subtypes and TME spatial distributions based on mathematical morphology. The model is based on a few morphological parameters that give access to a large spectrum of breast tumor architectures and are able to differentiate in-situ ductal carcinomas (DCIS) and histological subtypes of invasive carcinomas such as ductal (IDC) and lobular carcinoma (ILC). In addition, a part of the parameters of the model controls the spatial distribution of TME relative to the tumor. The validation of the model has been performed by comparing morphological features between real and simulated images.

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

PURPOSE: Women who received irradiation for Hodgkin's lymphoma have a strong increased risk for developing breast cancer. Approximately 90% of the breast cancers in these patients can be attributed to their radiation treatment, rendering such series extremely useful to determine whether a common...... 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...

Basal (18)F-FDG PET/CT as a predictive biomarker of tumor response for neoadjuvant therapy in breast cancer.

Science.gov (United States)

García Vicente, A M; Soriano Castrejón, A; Pruneda-González, R E; Fernández Calvo, G; Muñoz Sánchez, M M; Álvarez Cabellos, R; Espinosa Aunión, R; Relea Calatayud, F

2016-01-01

To explore the relation between tumor kinetic assessed by (18)F-FDG PET and final neoadjuvant chemotherapy (NC) response within a molecular phenotype perspective. Prospective study included 144 women with breast cancer. All patients underwent a dual-time point (18)F-FDG PET/CT previous to NC. The retention index (RI), between SUV-1 and SUV-2 was calculated. Molecular subtypes were re-grouped in low, intermediate and high-risk biological phenotypes. After NC, all residual primary tumor specimens were histopathologically classified in tumor regression grades (TRG) and response groups. The relation between SUV-1, SUV-2 and RI with the TRG and response groups was evaluated in all molecular subtypes and in accordance with the risk categories. Responder's lesions showed significant greater SUVmax compared to non-responders. The RI value did not show any significant relation with response. Attending to molecular phenotypes, statistical differences were observed with greater SUV for responders having high-risk molecular subtypes. Glycolytic tumor characteristics showed a significant correlation with NC response and dependence of risk phenotype. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

Influence of mammographic density on the diagnostic accuracy of tumor size assessment and association with breast cancer tumor characteristics

International Nuclear Information System (INIS)

Fasching, Peter A.; Heusinger, Katharina; Loehberg, Christian R.; Wenkel, Evelyn; Lux, Michael P.; Schrauder, Michael; Koscheck, Thomas; Bautz, Werner; Schulz-Wendtland, Ruediger; Beckmann, Matthias W.; Bani, Mayada R.

2006-01-01

Purpose: The accuracy of breast cancer staging involves the estimation of the tumor size for the initial decision-making in the treatment. We investigated the accuracy of tumor size estimation and the association between tumor characteristics and breast density (BD). Materials and methods: A total of 434 women with a primary diagnosis of breast cancer were included in this prospective study at a specialist breast unit. Estimated tumor characteristics included tumor size, nodal status, estrogen/progesterone receptor status, Ki-67, HER2/neu, vascular invasion. Radiomorphological data included tumor size as assessed by mammography, breast ultrasonography, and clinical examination, and American College of Radiology (ACR) categories for BD. Results: BD did not have a significant impact on the assessment of tumor size using breast ultrasound (deviation from ACR categories 1-4: 0.55-0.68 cm; P = 0.331). The deviation in mammography was significantly different dependent on BD (0.42-0.9 cm; P 2 cm). Conclusion: Breast ultrasonography is more accurate than mammography for assessing tumor size in breasts with a higher BD. The difference in tumor size assessment needs to be taken into consideration in the design of clinical trials and treatment decisions

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

International Nuclear Information System (INIS)

Marsden, Carolyn G; Wright, Mary Jo; Carrier, Latonya; Moroz, Krzysztof; Pochampally, Radhika; Rowan, Brian G

2012-01-01

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. 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). 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 × 10 3 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 samples. Tumorspheres isolated under defined culture

The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients

International Nuclear Information System (INIS)

Medrek, Catharina; Pontén, Fredrik; Jirström, Karin; Leandersson, Karin

2012-01-01

Tumor associated macrophages (TAMs) are alternatively activated macrophages that enhance tumor progression by promoting tumor cell invasion, migration and angiogenesis. TAMs have an anti-inflammatory function resembling M2 macrophages. CD163 is regarded as a highly specific monocyte/macrophage marker for M2 macrophages. In this study we evaluated the specificity of using the M2 macrophage marker CD163 as a TAM marker and compared its prognostic value with the more frequently used pan-macrophage marker CD68. We also analyzed the prognostic value of the localization of CD163 + and CD68 + myeloid cells in human breast cancer. The extent of infiltrating CD163 + or CD68 + myeloid cells in tumor nest versus tumor stroma was evaluated by immunohistochemistry in tissue microarrays with tumors from 144 breast cancer cases. Spearman’s Rho and χ 2 tests were used to examine the correlations between CD163 + or CD68 + myeloid cells and clinicopathological parameters. Kaplan Meier analysis and Cox proportional hazards modeling were used to assess the impact of CD163 + and CD68 + myeloid cells in tumor stroma and tumor nest, respectively, on recurrence free survival, breast cancer specific and overall survival. We found that infiltration of CD163 + and CD68 + macrophages into tumor stroma, but not into tumor nest, were of clinical relevance. CD163 + macrophages in tumor stroma positively correlated with higher grade, larger tumor size, Ki67 positivity, estrogen receptor negativity, progesterone receptor negativity, triple-negative/basal-like breast cancer and inversely correlated with luminal A breast cancer. Some CD163 + areas lacked CD68 expression, suggesting that CD163 could be used as a general anti-inflammatory myeloid marker with prognostic impact. CD68 + macrophages in tumor stroma positively correlated to tumor size and inversely correlated to luminal A breast cancer. More importantly, CD68 in tumor stroma was an independent prognostic factor for reduced breast cancer

Detecting somatostatin receptor in breast tumor tissue and its clinical significance

International Nuclear Information System (INIS)

Zhang Yongjian; Yu Xian; Lin Wei; Ding Xuan; Huang Shizhang; Lu Guangming

2002-01-01

The authors observe the difference of somatostatin receptor (SSR) between benign and malignant breast tumor and the relation between SSR and estrogen receptor (ER) or progesterone receptor (PR) in breast tumor tissue, and to predict the clinical value of detecting breast tumor by SSR receptor imaging. These tissues excised from operation in breast tumor were divided into 4 groups: breast malignant tumor group (BMTG) and its control group (C1G), breast benign tumor group (BBTG) and its control group (C2G). SSR was detected by radioligand binding assay (RBA) and ER, PR by LsAB method in these groups. Results is: (1) The SSR express quantity is 108.6 +- 67.3 fmol/mg pr, 37.2 +- 9.6 fmol/mg pr, 43.4 +- 12.6 fmol/mg pr 33.9 +- 10.2 fmol/mg pr respectively in BMTG, C1G, BBTG, C2G. The SSR of BMTG is the most among these groups, the difference is obvious, P 0.05); (2) The correlation coefficient of SSR and ER is 0.859, SSR and PR is 0.750. Most breast tumor tissues express high density SSR, the authors suppose that malignant tumor can been distinguished from benign tumor preliminarily by SSR receptor imaging. There is a good correlation between SSR and ER, PR, detecting SSR may predict the quality of tumor and the prognosis of the patient

Ipsilateral Breast Tumor Relapse: Local Recurrence Versus New Primary Tumor and the Effect of Whole-Breast Radiotherapy on the Rate of New Primaries

International Nuclear Information System (INIS)

Gujral, Dorothy M.; Sumo, Georges; Owen, John R.; Ashton, Anita; Bliss, Judith M.; Haviland, Joanne; Yarnold, John R.

2011-01-01

Purpose: The justification for partial breast radiotherapy after breast conservation surgery assumes that ipsilateral breast tumor relapses (IBTR) outside the index quadrant are mostly new primary (NP) tumors that develop despite radiotherapy. We tested the hypothesis that whole-breast radiotherapy (WBRT) is ineffective in preventing NP by comparing development rates in irradiated and contralateral breasts after tumor excision and WBRT. Methods and Materials: We retrospectively reviewed 1,410 women with breast cancer who were entered into a prospective randomized trial of radiotherapy fractionation and monitored annually for ipsilateral breast tumor relapses (IBTR) and contralateral breast cancer (CLBC). Cases of IBTR were classified into local recurrence (LR) or NP tumors based on location and histology and were subdivided as definite or likely depending on clinical data. Rates of ipsilateral NP and CLBC were compared over a 15-year period of follow-up. Results: At a median follow-up of 10.1 years, there were 150 documented cases of IBTR: 118 (79%) cases were definite or likely LR; 27 (18%) cases were definite or likely NP; and 5 (3%) cases could not be classified. There were 71 cases of CLBC. The crude proportion of definite-plus-likely NP was 1.9% (27/1,410) patients compared with 5% (71/1,410) CLBC patients. Cumulative incidence rates at 5, 10, and 15 years were 0.8%, 2.0%, and 3.5%, respectively, for definite-plus-likely NP and 2.4%, 5.8%, and 7.9%, respectively for CLBC, suggesting a difference in the rates of NP and CLBC. Conclusions: This analysis suggests that WBRT reduces the rate of ipsilateral NP tumors. The late presentation of NP has implications for the reporting of trials that are testing partial breast radiotherapy.

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...

Alpha-1 antitrypsin phenotypes in patients with lung, prostate and breast cancer

International Nuclear Information System (INIS)

El-Akawi, Zeyad J.; Al-Hindawi, Fatin K.

2004-01-01

Determination of Alpha1-antitryspin (AT) phenotypes in Jordanian patients with lung, prostate and breast cancerto find a prevalent phenotype that could be recommended for the diagnosis of cancer. This study was conducted at Jordan University of Science and Technology, School of Medicine Jordan during the period May 2001 to May 2002. Alpha1-antitryspin (AT) phenotypes for 83 Jordanian cancer patients distributed as follows, 25 lung cancer, 25 prostate cancer and 33 with breast cancer were tested using isoelectric focusing gel electrophoresis and immunofluxation techniques. Isoelectric focusing results demonstrated that 96% of lung cancer patients were of PiMM phenotype and 4% of PiFM phenotype. All prostate cancer patients (100%) were found to be of PiMM and 3% PiMS. These findings demonstrated that there was no significant differences in the distribution of AT phenotypes among Jordanian patients with lung, prostae and breast cancerand they matched those reported for healthy individuals. Thus, we can nor recommand a given AT phentype for early diagnosis of the above mentioned types of cancer. (author)

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

International Nuclear Information System (INIS)

Baek, Ji Eun; Kim, Sung Hun; Lee, Ah Won

2014-01-01

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

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)

Martínez-Galán, Joaquina; Ríos, Sandra; Delgado, Juan Ramón; Torres-Torres, Blanca; Núñez, María Isabel; López-Peñalver, Jesús; Del Moral, Rosario; Ruiz De Almodóvar, José Mariano; Menjón, Salomón; Concha, Ángel; Chamorro, Clara

2014-01-01

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

Molecular biology of breast cancer metastasis Molecular expression of vascular markers by aggressive breast cancer cells

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Hendrix, Mary JC; Seftor, Elisabeth A; Kirschmann, Dawn A; Seftor, Richard EB

2000-01-01

During embryogenesis, the formation of primary vascular networks occurs via the processes of vasculogenesis and angiogenesis. In uveal melanoma, vasculogenic mimicry describes the 'embryonic-like' ability of aggressive, but not nonaggressive, tumor cells to form networks surrounding spheroids of tumor cells in three-dimensional culture; these recapitulate the patterned networks seen in patients' aggressive tumors and correlates with poor prognosis. The molecular profile of these aggressive tumor cells suggests that they have a deregulated genotype, capable of expressing vascular phenotypes. Similarly, the embryonic-like phenotype expressed by the aggressive human breast cancer cells is associated with their ability to express a variety of vascular markers. These studies may offer new insights for consideration in breast cancer diagnosis and therapeutic intervention strategies

Mesenchymal Tumors of the Breast: Imaging and the Histopathologic Correlation

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Kim, Bo Mi; Kim, Eun Kyung; You, Jae Kyoung; Kim, Yee Jeong

2011-01-01

Various benign and malignant mesenchymal tumors can occur in the breast. Most radiologists are unfamiliar with the imaging features of these tumors and the imaging features have not been described in the radiologic literature. It is important that radiologists should be familiar with the broad spectrum of imaging features of rare mesenchymal breast tumors. In this pictorial review, we demonstrate the sonographic findings and the corresponding pathologic findings of various mesenchymal tumors of the breast as defined by the World Health Organization classification system

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

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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.

[Tumor and tumor-like benign mesenchymal lesions of the breast].

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Bisceglia, M; Nirchio, V; Carosi, I; Cappucci, U; Decata, A; Paragone, T; Di Mattia, A L

1995-02-01

All the spectrum is encompassed of those miscellaneous pathologic entities occurring in the mammary stroma which are on record up to date other than "mixed fibroepithelial" tumors (fibroadenomas and phyllodes tumors) and tumors both "pure" and "mixed" originating from myoepithelium (adenomyoepitheliomas and pleomorphic adenomas). Also they were excluded those dysreactive-autoimmune diseases (sarcoidosis, sclerosing lymphocytic lobulitis, lobular granulomatous mastitis) and those inflammatory-infectious conditions (tuberculosis, actinomycosis, foreign body reactions, Mondor's disease) which can mimick breast tumors clinically or on image analysis, but on the contrary not evoking the idea of a tumor on histology. Specifically, inflammatory pseudotumor, myofibroblastoma, leiomyoma, neurinoma/neurofibroma, benign fibrous histiocytoma, hemangiopericytoma, fibromatosis, nodular fascitis, variants of lipoma, mesenchymoma, amartoma and its variants, hemangiomas, pseudoangiomatous hyperplasia of stroma, amyloid tumor, granular cell tumor, are consecutively described and discussed, with a large list of references enclosed to each rubric. Most of the pictures are taken from personally observed lesions of the breast. Only few pictures referred to are from their analogue lesions which occurred in soft parts of other locations, with specific mention of that when it was the case. Of note after reviewing the literature the fact that no glomus tumor, nor Kaposi's sarcoma either sporadic or in the context of any immunodeficiency, nor myelolipoma has been recorded yet.

A signature of epithelial-mesenchymal plasticity and stromal activation in primary tumor modulates late recurrence in breast cancer independent of disease subtype.

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Cheng, Qing; Chang, Jeffrey T; Gwin, William R; Zhu, Jun; Ambs, Stefan; Geradts, Joseph; Lyerly, H Kim

2014-07-25

Despite improvements in adjuvant therapy, late systemic recurrences remain a lethal consequence of both early- and late-stage breast cancer. A delayed recurrence is thought to arise from a state of tumor dormancy, but the mechanisms that govern tumor dormancy remain poorly understood. To address the features of breast tumors associated with late recurrence, but not confounded by variations in systemic treatment, we compiled breast tumor gene expression data from 4,767 patients and established a discovery cohort consisting of 743 lymph node-negative patients who did not receive systemic neoadjuvant or adjuvant therapy. We interrogated the gene expression profiles of the 743 tumors and identified gene expression patterns that were associated with early and late disease recurrence among these patients. We applied this classification to a subset of 46 patients for whom expression data from microdissected tumor epithelium and stroma was available, and identified a distinct gene signature in the stroma and also a corresponding tumor epithelium signature that predicted disease recurrence in the discovery cohort. This tumor epithelium signature was then validated as a predictor for late disease recurrence in the entire cohort of 4,767 patients. We identified a novel 51-gene signature from microdissected tumor epithelium associated with late disease recurrence in breast cancer independent of the molecular disease subtype. This signature correlated with gene expression alterations in the adjacent tumor stroma and describes a process of epithelial to mesenchymal transition (EMT) and tumor-stroma interactions. Our findings suggest that an EMT-related gene signature in the tumor epithelium is related to both stromal activation and escape from disease dormancy in breast cancer. The presence of a late recurrence gene signature in the primary tumor also suggests that intrinsic features of this tumor regulate the transition of disseminated tumor cells into a dormant phenotype with

Differential diagnosis of breast tumors on the basis of radiothermometric findings

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V. I. Vidyukov

2016-01-01

Full Text Available The paper presents a method for the differential diagnosis of breast tumors in accordance with radiothermometric findings, which is based on the authors’ developed diagnostic technique (Patent No. 2532372 dated 5 September 2014. The radiometric method was used to examine 119 patients with malignant breast tumors, 53 patients with benign breast tumors, and 60 women without breast involvement. The data were obtained in 3 institutions: the Russian Medical Academy of Postgraduate Education, the N.N. Blokhin Russian Cancer Research Center, and Moscow Oncology Dispensary Five. A microwave radiothermometer was used to measure core and skin temperatures in 9 symmetrical points of each breast. Using the findings as a basis, the authors proposed quantitative criteria that ensured that breast tumors should be differentially diagnosed with high specificity.

Clear cell hidradenocarcinoma of the breast: a very rare breast skin tumor.

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Mezzabotta, Maurizio; Declich, Paolo; Cardarelli, Mery; Bellone, Stefano; Pacilli, Paolo; Riggio, Eliana; Pallino, Antonio

2012-01-01

Hidradenocarcinoma is an uncommon malignant intradermal tumor of sweat gland origin with a predilection for the face and extremities. It is encountered equally in males and females, usually in the second half of life. These tumors tend to be locally aggressive. In our case, the tumor was located relatively superficially but without any apparent connection to the overlying skin. The typical disease course includes local and sometimes multiple recurrences, and some patients develop regional lymph node and distant metastases. These type of tumors in the parenchyma of the breast are extremely rare. We report a case of hidradenocarcinoma in a 77-year-old woman who presented with a palpable inflammatory nodule in the right breast.

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

Optically measured microvascular blood flow contrast of malignant breast tumors.

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Regine Choe

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

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

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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

Nature and Nurture: What Determines Tumor Metabolic Phenotypes?

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Mayers, Jared R; Vander Heiden, Matthew G

2017-06-15

Understanding the genetic basis of cancer has led to therapies that target driver mutations and has helped match patients with more personalized drugs. Oncogenic mutations influence tumor metabolism, but other tumor characteristics can also contribute to their metabolic phenotypes. Comparison of isogenic lung and pancreas tumor models suggests that use of some metabolic pathways is defined by lineage rather than by driver mutation. Lung tumors catabolize circulating branched chain amino acids (BCAA) to extract nitrogen for nonessential amino acid and nucleotide synthesis, whereas pancreatic cancer obtains amino acids from catabolism of extracellular protein. These differences in amino acid metabolism translate into distinct pathway dependencies, as genetic disruption of the enzymes responsible for utilization of BCAA nitrogen limits the growth of lung tumors, but not pancreatic tumors. These data argue that some cancer metabolic phenotypes are defined by cancer tissue-of-origin and environment and that these features constrain the influence of genetic mutations on metabolism. A better understanding of the factors defining tumor nutrient utilization could be exploited to help improve cancer therapy. Cancer Res; 77(12); 3131-4. ©2017 AACR . ©2017 American Association for Cancer Research.

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

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

2000-01-01

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

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

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

1995-01-01

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

Breast-conserving surgery in locally advanced breast cancer submitted to neoadjuvant chemotherapy. Safety and effectiveness based on ipsilateral breast tumor recurrence and long-term follow-up

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Guilherme Freire Angotti Carrara

Full Text Available OBJECTIVE: To evaluate ipsilateral breast tumor recurrence after breast-conserving surgery for locally advanced breast cancer. METHODS: A retrospective observational cohort study was performed in patients with locally advanced breast cancer submitted to breast-conserving surgery after neoadjuvant chemotherapy based on an adriamycin-cyclophosphamide-paclitaxel regimen. We evaluated the clinical, pathologic, immunohistochemistry, and surgical factors that contribute to ipsilateral breast tumor recurrence and locoregional recurrence. A Kaplan-Meier analysis and Cox model were used to evaluate the main factors related to disease-free survival. RESULTS: Of the 449 patients who received neoadjuvant chemotherapy, 98 underwent breast-conserving surgery. The average diameter of the tumors was 5.3 cm, and 87.2% reached a size of up to 3 cm. Moreover, 86.7% were classified as clinical stage III, 74.5% had T3-T4 tumors, 80.5% had N1-N2 axilla, and 89.8% had invasive ductal carcinoma. A pathologic complete response was observed in 27.6% of the tumors, and 100.0% of samples had free margins. The 5-year actuarial overall survival rate was 81.2%, and the mean follow-up was 72.8 months. The rates of ipsilateral breast tumor recurrence and locoregional recurrence were 11.2% and 15.3%, respectively. Multifocal morphology response was the only factor related to ipsilateral breast tumor recurrence disease-free survival (p=0.04. A multivariate analysis showed that the pathologic response evaluation criteria in solid tumors (RECIST-breast cutoff was the only factor related to locoregional recurrence disease-free survival (p=0.01. CONCLUSIONS: Breast-conserving surgery is a safe and effective therapy for selected locally advanced breast tumors.

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.

Associations between pathologic tumor features and preadjuvant therapy cognitive performance in women diagnosed with breast cancer.

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Koleck, Theresa A; Bender, Catherine M; Sereika, Susan M; Ryan, Christopher M; Ghotkar, Puja; Brufsky, Adam M; Jankowitz, Rachel C; McAuliffe, Priscilla F; Clark, Beth Z; Conley, Yvette P

2017-02-01

Intertumor heterogeneity has been proposed as a potential mechanism to account for variability in cognitive performance in women diagnosed with breast cancer. The purpose of this study was to explore associations between variation in pathologic tumor features (PTFs) and variability in preadjuvant therapy cognitive performance in postmenopausal women newly diagnosed with early-stage breast cancer. Participants (N = 329) completed a comprehensive battery of neuropsychological tests to evaluate cognitive performance after primary surgery but prior to initiation of adjuvant anastrozole±chemotherapy. PTF data were abstracted from medical records. Robust multiple linear regression models were fit to estimate associations between individual PTFs and the cognitive function composite domain scores. All models controlled for age, estimated intelligence, and levels of depressive symptoms, anxiety, fatigue, and pain. Diagnosis of a HER2-positive tumor contributed to poorer verbal (b = -0.287, P = 0.018), visual (b = -0.270, P = 0.001), and visual working (b = -0.490, P Breast Cancer Assay Recurrence Score ® .) Our results suggest that certain PTFs related to more aggressive tumor phenotypes or inferior breast cancer prognosis may be implicated in poorer preadjuvant therapy cognitive performance. Follow-up studies that include a cognitive assessment before primary surgery should be conducted to further delineate the role of intertumor heterogeneity on cognitive performance. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Decreased Usage of Specific Scrib Exons Defines a More Malignant Phenotype of Breast Cancer With Worsened Survival

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Gergana Metodieva

2016-06-01

Full Text Available SCRIB is a polarity regulator known to be abnormally expressed in cancer at the protein level. Here we report that, in breast cancer, an additional and hidden dimension of deregulations exists: an unexpected SCRIB exon usage pattern appears to mark a more malignant tumor phenotype and significantly correlates with survival. Conserved exons encoding the leucine-rich repeats tend to be overexpressed while others are underused. Mechanistic studies revealed that the underused exons encode part of the protein necessary for interaction with Vimentin and Numa1, a protein which is required for proper positioning of the mitotic spindle. Thus, the inclusion/exclusion of specific SCRIB exons is a mechanistic hallmark of breast cancer, which could potentially be exploited to develop more efficient diagnostics and therapies.

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

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Smita Srivastava

2016-01-01

Full Text Available 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.

Risk factors, pathological and phenotypic features of male breast cancer in Greece.

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Tsoukalas, Nikolaos; Moirogiorgou, Evangelia; Tolia, Maria; Pistamaltzian, Nikolaos; Bournakis, Evangelos; Papadimitriou, Konstantinos; Demiri, Stamatina; Panopoulos, Christos; Koumakis, Georgios; Efremidis, Anna

2014-03-01

Breast cancer (BC) in males is a rare disease and comprises 0.5-1% of all BC cases. Due to its rarity, there are limited data regarding risk factors, biology and relevant treatment. A prospective observational study of demographic, clinical and histological characteristics of serially-admitted men with breast cancer was carried out from 1999 to 2009. Data were recorded and analyzed from a database including 1,315 cases of BC. Registered data concerned age, initial presentation, family and lifestyle history (risk factors), histological features, phenotypic subtypes and TNM staging. Twenty two men with BC were identified, with a median age of 63 years. The most common initial presentation was a palpable lump in 12 patients, nipple contraction in three and ulceration in three. According to their medical history, nine men were overweight, 10 suffered from hypertension and 12 were smokers. The most prevalent phenotype was luminal-A followed by triple-negative type. BC in none of the cases was HER 2-amplified. The majority of cases were grade II or III and stage II or III. In the present small study, we confirm that BC in males is rare. It is a disease of middle-age and presents at advanced stages. Most of patients had 1-3 risk factors for BC. Expression of hormonal receptors occurs in the majority of BC tumors in males and with rarity in HER 2 amplification.

Characterization of adjacent breast tumors using oligonucleotide microarrays

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Unger, Meredith A; Rishi, Mazhar; Clemmer, Virginia B; Hartman, Jennifer L; Keiper, Elizabeth A; Greshock, Joel D; Chodosh, Lewis A; Liebman, Michael N; Weber, Barbara L

2001-01-01

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

Evaluation of Tumor Angiogenesis with a Second-Generation US Contrast Medium in a Rat Breast Tumor Model

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Ko, Eun Young; Lee, Sang Hoon; Kim, Hak Hee; Kim, Sung Moon; Shin, Myung Jin; Kim, Nam Kug; Gong, Gyung Yub

2008-01-01

Tumor angiogenesis is an important factor for tumor growth, treatment response and prognosis. Noninvasive imaging methods for the evaluation of tumor angiogenesis have been studied, but a method for the quantification of tumor angiogenesis has not been established. This study was designed to evaluate tumor angiogenesis in a rat breast tumor model by the use of a contrast enhanced ultrasound (US) examination with a second-generation US contrast agent. The alkylating agent 19N-ethyl-N-nitrosourea (ENU) was injected into the intraperitoneal cavity of 30-day-old female Sprague-Dawley rats. Three to four months later, breast tumors were detected along the mammary lines of the rats. A total of 17 breast tumors larger than 1 cm in nine rats were evaluated by gray-scale US, color Doppler US and contrast-enhanced US using SonoVue. The results were recorded as digital video images; time-intensity curves and hemodynamic parameters were analyzed. Pathological breast tumor specimens were obtained just after the US examinations. The tumor specimens were stained with hematoxylin and eosin (H and E) and the expression of CD31, an endothelial cell marker, was determined by immunohistochemical staining. We also evaluated the pathological diagnosis of the tumors and the microvessel density (MVD). Spearman's correlation and the Kruskal-Wallis test were used for the analysis. The pathological diagnoses were 11 invasive ductal carcinomas and six benign intraductal epithelial proliferations. The MVD did not correlate with the pathological diagnosis. However, blood volume (BV) showed a statistically significant correlation with MVD (Spearman's correlation, p < 0.05). Contrast-enhanced US using a second-generation US contrast material was useful for the evaluation of tumor angiogenesis of breast tumors in the rat

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.

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.

Impact of breast cancer family history on tumor detection and tumor size in women newly-diagnosed with invasive breast cancer.

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Schwab, Fabienne Dominique; Bürki, Nicole; Huang, Dorothy Jane; Heinzelmann-Schwarz, Viola; Schmid, Seraina Margaretha; Vetter, Marcus; Schötzau, Andreas; Güth, Uwe

2014-03-01

This study evaluated the impact of family history (FH) on tumor detection, the patient's age and tumor size at diagnosis in breast cancer (BC). Furthermore, we investigated whether the impact of FH on these features was dependent on degree of relationship, number of relatives with a BC history, or the age of the affected relative at the time that her BC was diagnosed. Out of the entire cohort (n = 1,037), 244 patients (23.5%) had a positive FH; 159 (15.3%) had first-degree relatives affected with BC and 85 patients (8.2%) had second-degree affected relatives. Compared to women who had no BC-affected relatives, the tumors of women who had positive FH were more often found by radiological breast examination (RBE: 31.7%/27.2%, p = 0.008), and they were smaller (general tumor size: 21.8 mm/26.4 mm, p = 0.003; size of tumors found by breast self-examination (BSE): 26.1 mm/30.6 mm, p = 0.041). However, this positive effect of increased use of BC screening and smaller tumor sizes was only observed in patients whose first-degree relatives were affected (comparison with second-degree affected relatives: RBE: 43.8%/24.7%; odds ratio 2.38, p = 0.007; general tumor size: 19.3 mm/26.3 mm; mean difference (MD) -6.9, p = 0.025; tumor size found by BSE: 22.5 mm/31.0 mm; MD -8.5, p = 0.044). When more second-degree relatives or older relatives were diagnosed with BC, the tumors of these patients were similarly often detected by RBE (relationship: 24.7%/27.2%, p = 0.641; age: 33.7 %/27.2 %, p = 0.177) and had similar tumor sizes (general size: 26.3 mm/26.4 mm, p = 0.960; BSE: 31.0 mm/30.6 mm, p = 0.902) as those of women without a FH. Women with a positive FH generally use mammography screening more often and perceive changes in the breast earlier than women without such history. The increased awareness of BC risk decreases if the relationship is more distant.

Genetic Susceptibility Factors in Aggressive Breast Cancer in African-American Women and the Effects of Carcinogens and Modifiers

National Research Council Canada - National Science Library

Crawford, Keith

1999-01-01

.... Sigma 2 selective agents CB64D and CB 184 possess similar potency in MCF-7 breast tumor cells and breast tumors with mutations in the p53 tumor Suppressor gene that are phenotypically resistant...

Morphologic classification of ductal breast tumors on ultrasound : differential diagnosis of benign and malignant tumors

International Nuclear Information System (INIS)

Won, Mi Sook; Chung, Soo Young; Yang, Ik; Lee, Yul; Park, Hai Jung; Lee, Myoung Hwan; Yoon, In Sook; Koh, Mi Gyoung

1997-01-01

To evaluate the morphologic differential diagnosis of benign and malignant ductal breast tumors, as seen on US US findings in 29 pathologically proven cases of ductal breast tumor were retrospectively reviewed. All patients were female and their mean age was 42 years. Nineteen tumors were benign and ten were malignant, and all ductal or cystic lesions showed solid masses. According to the location of the mural nodule, we classified the sonographic appearance of these tumors into three types:intraductal, intracystic and amorphic. The intraductal type was divided into three subtypes:incompletely obstructive, completely obstructive and multiple mural nodules. For the intracystic type, too, three subtypes were designated:the intracystic mural nodule (mural cyst), intracystic mural nodule with the duct (mural cyst+duct) and intracystic multiple mural nodules. The amorphic type is defined as an atypical ductal tumor with the mural nodule extending into adjacent parenchyma. The margin of the duct or cyst was smooth in 68.4% of benign, and irregular in 90% of malignant ductal tumors. Internal echogeneity of the duct or cyst usually showed homogeneity in both benign and malignant tumors. 73.7% of tumors connecting the duct were benign and 50% were malignant. In benign tumors, 52.6% of mural nodule had an irregular margin, while in malignant tumors, the corresponding proportion was 100%;both types usually showed heterogeneous hypoechogeneity. Among benign tumors, the most common morphologic type was the intraductal incompletely obstructive subtype (36.8%);among those that were malignant, the amorphic type was most common, accounting for 40% of tumors. No amorphic type was benign and no incompletely obstructive subtype was malignant. When ductal breast tumors are morphologically classified on the basis of sonographic findings, the intraductal incompletely obstructive subtype suggests benignancy, and the amorphic type, malignancy. The morphologic classification of ductal

A therapeutic and diagnostic dilemma: granular cell tumor of the breast.

Science.gov (United States)

Pergel, Ahmet; Yucel, Ahmet Fikret; Karaca, A Serdar; Aydin, Ibrahim; Sahin, Dursun Ali; Demirbag, Nilgun

2011-01-01

Six to eight percent of granular cell tumors are seen in the breast. Although mostly benign, they rarely have malignant features clinically and radiologically reminding of breast cancer. This may lead to a potential misdiagnosis of breast carcinoma and overtreatment of patients. The final diagnosis is made by immunohistochemical examination. We performed excisional biopsy on a patient who was diagnosed to have a breast mass. The histopathological examination of the mass revealed granular cell tumor.

The tumor macroenvironment and systemic regulation of breast cancer progression.

Science.gov (United States)

Castaño, Zafira; Tracy, Kristin; McAllister, Sandra S

2011-01-01

Breast cancer is the most common malignancy among women worldwide and is the most common cause of death for women between 35 and 50 years of age. Women with breast cancer are at risk of developing metastases for their entire lifetime and, despite local and systemic therapies, approximately 30% of breast cancer patients will relapse (Jemal et al., 2010). Nearly all breast cancer related deaths are due to metastatic disease, even though metastasis is considered to be an inefficient process. In some cases, tumor cells disseminate from primary sites at an early stage, but remain indolent for protracted periods of time before becoming overt, life-threatening tumors. Little is known about the mechanisms that cause these indolent tumors to grow into malignant disease. Because of this gap in our understanding, we are unable to predict which breast cancer patients are likely to experience disease relapse or develop metastases years after treatment of their primary tumor. A better understanding of the mechanisms and signals involved in the exit of tumor cells from dormancy would not only allow for more accurate selection of patients that would benefit from systemic therapy, but could also lead to the development of more targeted therapies to inhibit the signals that promote disease progression. In this review, we address the systemic, or "macroenvironmental", contribution to tumor initiation and progression and what is known about how a pro-tumorigenic systemic environment is established.

Clinicopathological study of rare invasive epithelial tumors of breast: An institutional study

Directory of Open Access Journals (Sweden)

Karthik Kasireddy

2016-01-01

Full Text Available Introduction: Invasive breast cancer (BC is the most common carcinoma in women. It accounts for 22% of all female cancers. Most tumors are derived from mammary duct epithelium, and up to 75% of BCs are ductal carcinomas. The second most common tumor is invasive lobular carcinoma. However, there are many variants which are less common but well defined by the World Health Organization classification. They comprise <10% of breast tumors. Their clinical behavior differs greatly. Hence, it is important to know their main histomorphological features to make the best treatment of choice and to foresee prognosis. Aims and Objectives: To study the histomorphological features, incidence, and clinical features of rare invasive epithelial tumors of the breast. Materials and Methods: This study was done in the department of pathology, Sri Devaraj Urs Medical College, Kolar. All the neoplastic breast lesions over a period of 5 years (July 2010-September 2015 are included in the study. Clinical features and other details (estrogen receptor/progesterone receptor, human epidermal receptor-2, lymph nodes are obtained from the department (surgery records. Specimens are received and preserved in 10% formalin and are subjected to routine histopathological processing. Hematoxylin and eosin sections are studied, and a morphological diagnosis is given. All rare invasive epithelial breast tumors will be reviewed meticulously. Results and Conclusion: A total number of invasive epithelial tumors of breast were 105. The most common presenting symptom was breast lump. Rare invasive epithelial breast tumors account to 28.5%. The age range from 15 to 70 years. Most common, rare invasive epithelial tumor in our study is medullary carcinoma. Hence, it is imperative to always maintain a Hawks vigil during microscopic diagnosis to know prognosis of the condition and to facilitate early and prompt treatment to the patient.

A Therapeutic and Diagnostic Dilemma: Granular Cell Tumor of the Breast

Directory of Open Access Journals (Sweden)

Ahmet Pergel

2011-01-01

Full Text Available Six to eight percent of granular cell tumors are seen in the breast. Although mostly benign, they rarely have malignant features clinically and radiologically reminding of breast cancer. This may lead to a potential misdiagnosis of breast carcinoma and overtreatment of patients. The final diagnosis is made by immunohistochemical examination. We performed excisional biopsy on a patient who was diagnosed to have a breast mass. The histopathological examination of the mass revealed granular cell tumor.

Breast tumor size assessment: comparison of conventional ultrasound and contrast-enhanced ultrasound.

Science.gov (United States)

Jiang, Yu-Xin; Liu, He; Liu, Ji-Bin; Zhu, Qing-Li; Sun, Qiang; Chang, Xiao-Yan

2007-12-01

Accurate assessment of tumor size is necessary when selecting patients for breast-conserving surgery. In the study of breast contrast-enhanced ultrasound (CEUS), we found that tumor size discrepancy between CEUS and conventional ultrasound (US) existed in some breast lesions, for which the reasons are not clear. Breast CEUS examinations were performed in 104 patients with breast lesions. The measurement of the 104 breast tumors on conventional US was obtained and compared with the measurement on CEUS. A difference in measuring tumor size of >3 mm for tumors up to 1.7 cm and 4 mm for tumors >or=1.7 cm, was defined as a significant discrepancy between conventional US and CEUS. The histopathological examination of size discrepancy was performed and the margin characteristics of breast cancers with larger measurements were compared with those with unchanged measurements. Among the 104 lesions (43 malignant, 60 benign, 1 borderline), the size of 27 breast cancers and one granulomatous mastitis appeared larger at CEUS. Pathologic examinations of the region corresponding to the measurement discrepancy were mainly ductal carcinomas in situ (DCIS), invasive carcinoma with a DCIS component, adenosis with lobular hyperplasia in breast cancers and inflammatory cell infiltration in one granulomatous mastitis. Well-defined margin characteristics were significantly different between breast cancers with larger measurements at CEUS and those with unchanged measurements of size (p = 0.002), whereas no significant difference was found between the two groups in ill-defined, spiculated, hyperechoic halo, microlobulated and angulated margins (p = 0.463, 0.117, 0.194, 0.666 and 0.780, respectively). This initial study suggests that significant discrepancy of breast lesion measurement between conventional US and CEUS is more likely presented in breast cancer than benign lesions. The pathologic findings corresponding to the region of size increased at CEUS are malignant in most malignant

Dose determination in breast tumor in brachytherapy using Iridium-192

International Nuclear Information System (INIS)

Okuno, S.F.

1984-01-01

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) [pt

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

International Nuclear Information System (INIS)

Garvin, Stina; Dabrosin, Charlotta

2008-01-01

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

Pulsed terahertz imaging of breast cancer in freshly excised murine tumors

Science.gov (United States)

Bowman, Tyler; Chavez, Tanny; Khan, Kamrul; Wu, Jingxian; Chakraborty, Avishek; Rajaram, Narasimhan; Bailey, Keith; El-Shenawee, Magda

2018-02-01

This paper investigates terahertz (THz) imaging and classification of freshly excised murine xenograft breast cancer tumors. These tumors are grown via injection of E0771 breast adenocarcinoma cells into the flank of mice maintained on high-fat diet. Within 1 h of excision, the tumor and adjacent tissues are imaged using a pulsed THz system in the reflection mode. The THz images are classified using a statistical Bayesian mixture model with unsupervised and supervised approaches. Correlation with digitized pathology images is conducted using classification images assigned by a modal class decision rule. The corresponding receiver operating characteristic curves are obtained based on the classification results. A total of 13 tumor samples obtained from 9 tumors are investigated. The results show good correlation of THz images with pathology results in all samples of cancer and fat tissues. For tumor samples of cancer, fat, and muscle tissues, THz images show reasonable correlation with pathology where the primary challenge lies in the overlapping dielectric properties of cancer and muscle tissues. The use of a supervised regression approach shows improvement in the classification images although not consistently in all tissue regions. Advancing THz imaging of breast tumors from mice and the development of accurate statistical models will ultimately progress the technique for the assessment of human breast tumor margins.

3D tumor measurement in cone-beam CT breast imaging

Science.gov (United States)

Chen, Zikuan; Ning, Ruola

2004-05-01

Cone-beam CT breast imaging provides a digital volume representation of a breast. With a digital breast volume, the immediate task is to extract the breast tissue information, especially for suspicious tumors, preferably in an automatic manner or with minimal user interaction. This paper reports a program for three-dimensional breast tissue analysis. It consists of volumetric segmentation (by globally thresholding), subsegmentation (connection-based separation), and volumetric component measurement (volume, surface, shape, and other geometrical specifications). A combination scheme of multi-thresholding and binary volume morphology is proposed to fast determine the surface gradients, which may be interpreted as the surface evolution (outward growth or inward shrinkage) for a tumor volume. This scheme is also used to optimize the volumetric segmentation. With a binary volume, we decompose the foreground into components according to spatial connectedness. Since this decomposition procedure is performed after volumetric segmentation, it is called subsegmentation. The subsegmentation brings the convenience for component visualization and measurement, in the whole support space, without interference from others. Upon the tumor component identification, we measure the following specifications: volume, surface area, roundness, elongation, aspect, star-shapedness, and location (centroid). A 3D morphological operation is used to extract the cluster shell and, by delineating the corresponding volume from the grayscale volume, to measure the shell stiffness. This 3D tissue measurement is demonstrated with a tumor-borne breast specimen (a surgical part).

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

International Nuclear Information System (INIS)

Welch, D.R.

1984-01-01

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

Knockout and transgenic mice of Trp53: what have we learned about p53 in breast cancer?

International Nuclear Information System (INIS)

Blackburn, Anneke C; Jerry, D Joseph

2002-01-01

The human p53 tumor suppressor gene TP53 is mutated at a high frequency in sporadic breast cancer, and Li-Fraumeni syndrome patients who carry germline mutations in one TP53 allele have a high incidence of breast cancer. In the 10 years since the first knockout of the mouse p53 tumor suppressor gene (designated Trp53) was published, much has been learned about the contribution of p53 to biology and tumor suppression in the breast through the use of p53 transgenic and knockout mice. The original mice deficient in p53 showed no mammary gland phenotype. However, studies using BALB/c-Trp53-deficient mice have demonstrated a delayed involution phenotype and a mammary tumor phenotype. Together with other studies of mutant p53 transgenes and p53 bitransgenics, a greater understanding has been gained of the role of p53 in involution, of the regulation of p53 activity by hormones, of the effect of mouse strain and modifier genes on tumor phenotype, and of the cooperation between p53 and other oncogenic pathways, chemical carcinogens and hormonal stimulation in mammary tumorigenesis. Both p53 transgenic and knockout mice are important in vivo tools for understanding breast cancer, and are yet to be exploited for developing therapeutic strategies in breast cancer

The expression of VE-cadherin in breast cancer cells modulates cell dynamics as a function of tumor differentiation and promotes tumor-endothelial cell interactions.

Science.gov (United States)

Rezaei, Maryam; Cao, Jiahui; Friedrich, Katrin; Kemper, Björn; Brendel, Oliver; Grosser, Marianne; Adrian, Manuela; Baretton, Gustavo; Breier, Georg; Schnittler, Hans-Joachim

2018-01-01

The cadherin switch has profound consequences on cancer invasion and metastasis. The endothelial-specific vascular endothelial cadherin (VE-cadherin) has been demonstrated in diverse cancer types including breast cancer and is supposed to modulate tumor progression and metastasis, but underlying mechanisms need to be better understood. First, we evaluated VE-cadherin expression by tissue microarray in 392 cases of breast cancer tumors and found a diverse expression and distribution of VE-cadherin. Experimental expression of fluorescence-tagged VE-cadherin (VE-EGFP) in undifferentiated, fibroblastoid and E-cadherin-negative MDA-231 (MDA-VE-EGFP) as well as in differentiated E-cadherin-positive MCF-7 human breast cancer cell lines (MCF-VE-EGFP), respectively, displayed differentiation-dependent functional differences. VE-EGFP expression reversed the fibroblastoid MDA-231 cells to an epithelial-like phenotype accompanied by increased β-catenin expression, actin and vimentin remodeling, increased cell spreading and barrier function and a reduced migration ability due to formation of VE-cadherin-mediated cell junctions. The effects were largely absent in both MDA-VE-EGFP and in control MCF-EGFP cell lines. However, MCF-7 cells displayed a VE-cadherin-independent planar cell polarity and directed cell migration that both developed in MDA-231 only after VE-EGFP expression. Furthermore, VE-cadherin expression had no effect on tumor cell proliferation in monocultures while co-culturing with endothelial cells enhanced tumor cell proliferation due to integration of the tumor cells into monolayer where they form VE-cadherin-mediated cell contacts with the endothelium. We propose an interactive VE-cadherin-based crosstalk that might activate proliferation-promoting signals. Together, our study shows a VE-cadherin-mediated cell dynamics and an endothelial-dependent proliferation in a differentiation-dependent manner.

β class II tubulin predominates in normal and tumor breast tissues

International Nuclear Information System (INIS)

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

2003-01-01

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

Circulating tumor cells in breast cancer.

Science.gov (United States)

Bidard, Francois-Clement; Proudhon, Charlotte; Pierga, Jean-Yves

2016-03-01

Over the past decade, technically reliable circulating tumor cell (CTC) detection methods allowed the collection of large datasets of CTC counts in cancer patients. These data can be used either as a dynamic prognostic biomarker or as tumor material for "liquid biopsy". Breast cancer appears to be the cancer type in which CTC have been the most extensively studied so far, with level-of-evidence-1 studies supporting the clinical validity of CTC count in both early and metastatic stage. This review summarizes and discusses the clinical results obtained in breast cancer patients, the issues faced by the molecular characterization of CTC and the biological findings about cancer biology and metastasis that were obtained from CTC. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

MED12 exon 2 mutations in phyllodes tumors of the breast

International Nuclear Information System (INIS)

Nagasawa, Satoi; Maeda, Ichiro; Fukuda, Takayo; Wu, Wenwen; Hayami, Ryosuke; Kojima, Yasuyuki; Tsugawa, Ko-ichiro; Ohta, Tomohiko

2015-01-01

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

Giant phyllodes tumor of the breast: a clinical observation

OpenAIRE

A. A. Volchenko; D. D. Pak; F. N. Usov; E. Yu. Fetisova

2012-01-01

The paper describes a case of giant phyllodes tumor of the breast. Phyllodes tumor is a rare type of fibroepithelial tumor composed of epithelial and connective tissue with the predominant development of a connective tissue component. Surgery is the only radical treatment.

Efficacy of helical CT in evaluating local tumor extent of breast cancer

International Nuclear Information System (INIS)

Ozaki, Yutaka

2001-01-01

The purpose of this study is to clarify the diagnostic accuracy of helical CT (HCT) in the determination of local tumor extent of breast cancer. One hundred forty consecutive patients with breast cancer, including 87 invasive ductal carcinomas without extensive intraductal components (EIC), 44 invasive ductal carcinomas with EIC, 2 non-invasive ductal carcinomas, and 7 invasive lobular carcinomas, were included in the study. Three-dimensional tumor diameter including whole extent was measured on HCT, and the amount of invasion to fat tissue, skin, pectoral muscle, and chest wall was estimated using a three-step scale. These results were then compared with the pathological findings. Breast cancers appeared as areas of high attenuation compared with the surrounding breast tissue in all patients. Tumor extent was correctly diagnosed by HCT to within a maximum difference of 1 cm in 88 patients (63%) and within 2 cm in 122 patients (87%). Sensitivity, specificity, and accuracy in diagnosing muscular invasion of breast cancer using HCT were 100%, 99%, and 99%, respectively. Sensitivity, specificity, and accuracy in diagnosing skin invasion of breast cancer using HCT were 84%, 93%, and 91%, respectively. HCT was able to visualize all of the tumors and detect the correct tumor extent in most patients. (author)

Efficacy of helical CT in evaluating local tumor extent of breast cancer

Energy Technology Data Exchange (ETDEWEB)

Ozaki, Yutaka [Juntendo Univ., Chiba (Japan). Urayasu Hospital

2001-04-01

The purpose of this study is to clarify the diagnostic accuracy of helical CT (HCT) in the determination of local tumor extent of breast cancer. One hundred forty consecutive patients with breast cancer, including 87 invasive ductal carcinomas without extensive intraductal components (EIC), 44 invasive ductal carcinomas with EIC, 2 non-invasive ductal carcinomas, and 7 invasive lobular carcinomas, were included in the study. Three-dimensional tumor diameter including whole extent was measured on HCT, and the amount of invasion to fat tissue, skin, pectoral muscle, and chest wall was estimated using a three-step scale. These results were then compared with the pathological findings. Breast cancers appeared as areas of high attenuation compared with the surrounding breast tissue in all patients. Tumor extent was correctly diagnosed by HCT to within a maximum difference of 1 cm in 88 patients (63%) and within 2 cm in 122 patients (87%). Sensitivity, specificity, and accuracy in diagnosing muscular invasion of breast cancer using HCT were 100%, 99%, and 99%, respectively. Sensitivity, specificity, and accuracy in diagnosing skin invasion of breast cancer using HCT were 84%, 93%, and 91%, respectively. HCT was able to visualize all of the tumors and detect the correct tumor extent in most patients. (author)

Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome

International Nuclear Information System (INIS)

Arpino, Grazia; Bardou, Valerie J; Clark, Gary M; Elledge, Richard M

2004-01-01

Invasive lobular carcinoma (ILC) comprises approximately 10% of breast cancers and appears to have a distinct biology. Because it is less common than infiltrating ductal carcinoma (IDC), few data have been reported that address the biologic features of ILC in the context of their clinical outcome. In the present study we undertook an extensive comparison of ILC and IDC using a large database to provide a more complete and reliable assessment of their biologic phenotypes and clinical behaviors. The clinical and biological features of 4140 patients with ILC were compared with those of 45,169 patients with IDC (not otherwise specified). The median follow-up period was 87 months. In comparison with IDC, ILC was significantly more likely to occur in older patients, to be larger in size, to be estrogen and progesterone receptor positive, to have lower S-phase fraction, to be diploid, and to be HER-2, p53, and epidermal growth factor receptor negative. It was more common for ILC than for IDC to metastasize to the gastrointestinal tract and ovary. The incidence of contralateral breast cancer was higher for ILC patients than for IDC patients (20.9% versus 11.2%; P < 0.0001). Breast preservation was modestly less frequent in ILC patients than in IDC patients. The 5-year disease-free survival was 85.7% for ILC and 83.5% for IDC (P = 0.13). The 5-year overall survival was 85.6% for ILC and 84.1% for IDC (P = 0.64). Despite the fact that the biologic phenotype of ILC is quite favorable, these patients do not have better clinical outcomes than do patients with IDC. At present, management decisions should be based on individual patient and tumor biologic characteristics, and not on lobular histology

Giant phyllodes tumor of the breast: a clinical observation

Directory of Open Access Journals (Sweden)

A. A. Volchenko

2012-01-01

Full Text Available The paper describes a case of giant phyllodes tumor of the breast. Phyllodes tumor is a rare type of fibroepithelial tumor composed of epithelial and connective tissue with the predominant development of a connective tissue component. Surgery is the only radical treatment.

Audit of fibroepithelial tumors of the breast in a Nigerian tertiary ...

African Journals Online (AJOL)

2016-01-15

Jan 15, 2016 ... Dr. AO Daramola,. Department of Anatomic and Molecular Pathology, ... accounts for the vast majority of benign breast tumor especially in the young.[1] .... subtypes except in very few ambiguous conditions where ... and prognosis of patients with phyllodes tumor of the breast: An analysis of. 170 cases.

Second harmonic generation reveals matrix alterations during breast tumor progression

Science.gov (United States)

Burke, Kathleen; Tang, Ping; Brown, Edward

2013-03-01

Alteration of the extracellular matrix in tumor stroma influences efficiency of cell locomotion away from the primary tumor into surrounding tissues and vasculature, thereby affecting metastatic potential. We study matrix changes in breast cancer through the use of second harmonic generation (SHG) of collagen in order to improve the current understanding of breast tumor stromal development. Specifically, we utilize a quantitative analysis of the ratio of forward to backward propagating SHG signal (F/B ratio) to monitor collagen throughout ductal and lobular carcinoma development. After detection of a significant decrease in the F/B ratio of invasive but not in situ ductal carcinoma compared with healthy tissue, the collagen F/B ratio is investigated to determine the evolution of fibrillar collagen changes throughout tumor progression. Results are compared with the progression of lobular carcinoma, whose F/B signature also underwent significant evolution during progression, albeit in a different manner, which offers insight into varying methods of tissue penetration and collagen manipulation between the carcinomas. This research provides insights into trends of stromal reorganization throughout breast tumor development.

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

Active Roles of Tumor Stroma in Breast Cancer Metastasis

International Nuclear Information System (INIS)

Khamis, Z.I.; Sang, Q.A.; Sahab, Z.J.

2012-01-01

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

Active Roles of Tumor Stroma in Breast Cancer Metastasis

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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.

Expression and Significance of CYR61 Expression in Breast Cancer Tumor Specimens

National Research Council Canada - National Science Library

Lupu, Ruth

2002-01-01

Breast cancer often progresses from an estrogen (ER)-dependent, non-metastatic, antiestrogen-sensitive phenotype to an ER-independent, antiestrogen-resistant, highly invasive, and metastatic phenotype...

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

International Nuclear Information System (INIS)

Olsson, Eleonor; Lövgren, Kristina; Fernö, Mårten; Grabau, Dorthe; Borg, Åke; Hegardt, Cecilia; Honeth, Gabriella; Bendahl, Pär-Ola; Saal, Lao H; Gruvberger-Saal, Sofia; Ringnér, Markus; Vallon-Christersson, Johan; Jönsson, Göran; Holm, Karolina

2011-01-01

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

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

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Vallon-Christersson Johan

2011-09-01

Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusions 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

Dissecting Tumor-Stromal Interactions in Breast Cancer Bone Metastasis

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Yibin Kang

2016-06-01

Full Text Available Bone metastasis is a frequent occurrence in breast cancer, affecting more than 70% of late stage cancer patients with severe complications such as fracture, bone pain, and hypercalcemia. The pathogenesis of osteolytic bone metastasis depends on cross-communications between tumor cells and various stromal cells residing in the bone microenvironment. Several growth factor signaling pathways, secreted micro RNAs (miRNAs and exosomes are functional mediators of tumor-stromal interactions in bone metastasis. We developed a functional genomic approach to systemically identified molecular pathways utilized by breast cancer cells to engage the bone stroma in order to generate osteolytic bone metastasis. We showed that elevated expression of vascular cell adhesion molecule 1 (VCAM1 in disseminated breast tumor cells mediates the recruitment of pre-osteoclasts and promotes their differentiation to mature osteoclasts during the bone metastasis formation. Transforming growth factor β (TGF-β is released from bone matrix upon bone destruction, and signals to breast cancer to further enhance their malignancy in developing bone metastasis. We furthered identified Jagged1 as a TGF-β target genes in tumor cells that engaged bone stromal cells through the activation of Notch signaling to provide a positive feedback to promote tumor growth and to activate osteoclast differentiation. Substantially change in miRNA expression was observed in osteoclasts during their differentiation and maturation, which can be exploited as circulating biomarkers of emerging bone metastasis and therapeutic targets for the treatment of bone metastasis. Further research in this direction may lead to improved diagnosis and treatment strategies for bone metastasis.

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

International Nuclear Information System (INIS)

Moshina, Nataliia; Ursin, Giske; Hoff, Solveig Roth; Akslen, Lars A; Roman, Marta; Sebuødegård, Sofie; Hofvind, Solveig

2015-01-01

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

Claudin-Low Breast Cancer; Clinical & Pathological Characteristics.

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Kay Dias

Full Text Available Claudin-low breast cancer is a molecular type of breast cancer originally identified by gene expression profiling and reportedly associated with poor survival. Claudin-low tumors have been recognised to preferentially display a triple-negative phenotype, however only a minority of triple-negative breast cancers are claudin-low. We sought to identify an immunohistochemical profile for claudin-low tumors that could facilitate their identification in formalin fixed paraffin embedded tumor material. First, an in silico collection of ~1600 human breast cancer expression profiles was assembled and all claudin-low tumors identified. Second, genes differentially expressed between claudin-low tumors and all other molecular subtypes of breast cancer were identified. Third, a number of these top differentially expressed genes were tested using immunohistochemistry for expression in a diverse panel of breast cancer cell lines to determine their specificity for claudin-low tumors. Finally, the immunohistochemical panel found to be most characteristic of claudin-low tumors was examined in a cohort of 942 formalin fixed paraffin embedded human breast cancers with >10 years clinical follow-up to evaluate the clinico-pathologic and survival characteristics of this tumor subtype. Using this approach we determined that claudin-low breast cancer is typically negative for ER, PR, HER2, claudin 3, claudin 4, claudin 7 and E-cadherin. Claudin-low tumors identified with this immunohistochemical panel, were associated with young age of onset, higher tumor grade, larger tumor size, extensive lymphocytic infiltrate and a circumscribed tumor margin. Patients with claudin-low tumors had a worse overall survival when compared to patients with luminal A type breast cancer. Interestingly, claudin-low tumors were associated with a low local recurrence rate following breast conserving therapy. In conclusion, a limited panel of antibodies can facilitate the identification of

Benign tumors of the breast in Kano, Northern Nigeria: A 10-year experience and review of literature

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Mohammed Ibrahim Imam

2016-01-01

Full Text Available Background: Benign breast tumors are common worldwide and various reports suggest an increasing incidence in Nigeria which necessitates an urgent need to differentiate it from malignant tumors. The study was carried out to classify and determine the pattern, frequency, age, and sex distribution of benign breast tumors seen in a tertiary hospital. Materials and Methods: This was a 10-year retrospective study of all benign breast tumors diagnosed at the Pathology Department of a teaching hospital from January 1 2001 to December 31 2010. Results: A total of 1566 breast tumors were diagnosed during the study period, 1035 cases of benign breast tumors constituting 66.3% of all breast tumors were seen. The female to male ratio was 72.9:1. The overall mean age for benign breast tumor was 29 years with a peak age occurrence in the third decade. Fibroadenoma (FA was the most common benign breast tumor followed by fibrocystic change and they accounted for 47.1% and 25.4% of benign breast tumors with mean age of 24.7 years and 33.4 years, respectively. FA has a peak occurrence in the third decade while fibrocystic change has a peak occurrence in the fourth decade. Other major tumors encountered were tubular adenoma (6.0%, lactating adenoma (5.6%, benign phyllodes (4.8%, sclerosing adenoma (3.3%, and blunt duct adenoma (2.5%. Gynecomastia (1.4% was the only benign breast tumor seen in males.Conclusions: Benign breast tumors are quite common, presenting mostly as FA and fibrocystic change. The tumors are seen in both sexes with a striking female preponderance and occurred predominantly in young females with a peak in the third decade. The findings are generally similar to the most previous studies from Nigeria, Africa, and the Western world with minimal variations.

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

International Nuclear Information System (INIS)

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

2012-01-01

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

Assessment of basal-like breast cancer by circulating tumor DNA analysis.

Science.gov (United States)

Wei, Wei; Zhang, Xianyu; Sun, Shanshan; Xia, Bingshu; Liang, Xiaoshuan; Cui, Yan; Gao, Song; Pang, Da

2018-05-01

Standardized methods for the detection and assessment of circulating tumor DNA (ctDNA) in breast cancer are not sufficient. In the present study, the method and the potential application of ctDNA in the diagnosis of breast cancer were explored. DNA was extracted from the tumor tissues, plasma and peripheral blood cells of 11 patients with early-stage invasive breast cancer. Primers were designed against the exons of phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit α, p53, epidermal growth factor receptor, Akt and phosphatase and tensin homolog. The amplicon-based method for whole-exon sequencing was performed. The associations between the ctDNA mutant frequency with the tumor DNA mutant frequency, and the ctDNA concentration with clinical data were analyzed. A linear association was identified between the concentration of ctDNA and the tumor volume for the 3 patients with basal-like breast cancer, and not in other subtypes. The mutation frequency differed the least between ctDNA and tissue DNA in basal-like breast cancer. ctDNA retained the constituent ratio of gene mutations identified in the corresponding tumor tissue. The ctDNA detection rate depended to a certain extent on the mutation frequency in tumor tissue; for example, a mutant locus with a mutation frequency of >30% in tissues presented a detection rate of >40% in plasma samples, whereas a locus with a mutation frequency of <10% in tissue was associated with a detection rate of ≤1% in the plasma. Therefore, ctDNA may reflect the mutations observed in cancer. Compared with other subtypes, ctDNA may be a more sensitive biomarker for the assessment of mutation and cancer burden in basal-like breast cancer relative to other subtypes.

Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer

Science.gov (United States)

Shu, Guangwen; Wan, Dingrong; He, Feng; Loaec, Morgann; Ding, Yali; Li, Jun; Dovat, Sinisa; Yang, Gaungzhong; Song, Chunhua

2016-01-01

Chemotherapy is the main treatment for patients with breast cancer metastases, but natural alternatives have been receiving attention for their potential as novel anti-tumor reagents. Amplexicaule A (APA) is a flavonoid glucoside isolated from rhizomes of Polygonum amplexicaule D. Don var. sinense Forb (PADF). We found that APA has anti-tumor effects in a breast cancer xenograft mouse model and induces apoptosis in breast cancer cell lines. APA increased levels of cleaved caspase-3,-8,-9 and PARP, which resulted from suppression of MCL-1 and BCL-2 expression in the cells. APA also inactivated the Akt/mTOR pathway in breast cancer cells. Thus, APA exerts a strong anti-tumor effect on breast cancer cells, most likely through induction of apoptosis. Our study is the first to identify this novel anti-tumor compound and provides a new strategy for isolation and separation of single compounds from herbs. PMID:26943775

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

International Nuclear Information System (INIS)

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

2010-01-01

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

The role of lipolysis stimulated lipoprotein receptor in breast cancer and directing breast cancer cell behavior.

Directory of Open Access Journals (Sweden)

Denise K Reaves

Full Text Available The claudin-low molecular subtype of breast cancer is of particular interest for clinically the majority of these tumors are poor prognosis, triple negative, invasive ductal carcinomas. Claudin-low tumors are characterized by cancer stem cell-like features and low expression of cell junction and adhesion proteins. Herein, we sought to define the role of lipolysis stimulated lipoprotein receptor (LSR in breast cancer and cancer cell behavior as LSR was recently correlated with tumor-initiating features. We show that LSR was expressed in epithelium, endothelium, and stromal cells within the healthy breast tissue, as well as in tumor epithelium. In primary breast tumor bioposies, LSR expression was significantly correlated with invasive ductal carcinomas compared to invasive lobular carcinomas, as well as ERα positive tumors and breast cancer cell lines. LSR levels were significantly reduced in claudin-low breast cancer cell lines and functional studies illustrated that re-introduction of LSR into a claudin-low cell line suppressed the EMT phenotype and reduced individual cell migration. However, our data suggest that LSR may promote collective cell migration. Re-introduction of LSR in claudin-low breast cancer cell lines reestablished tight junction protein expression and correlated with transepithelial electrical resistance, thereby reverting claudin-low lines to other intrinsic molecular subtypes. Moreover, overexpression of LSR altered gene expression of pathways involved in transformation and tumorigenesis as well as enhanced proliferation and survival in anchorage independent conditions, highlighting that reestablishment of LSR signaling promotes aggressive/tumor initiating cell behaviors. Collectively, these data highlight a direct role for LSR in driving aggressive breast cancer behavior.

Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice

Directory of Open Access Journals (Sweden)

Shoya Shiromizu

2018-04-01

Full Text Available Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule. Keywords: l-asparaginase, Asparagine, Solid tumor, Chrono-pharmacotherapy

Triple-negative breast cancer: present challenges and new perspectives

NARCIS (Netherlands)

Podo, Franca; Buydens, Lutgarde M. C.; Degani, Hadassa; Hilhorst, Riet; Klipp, Edda; Gribbestad, Ingrid S.; van Huffel, Sabine; van Laarhoven, Hanneke W. M.; Luts, Jan; Monleon, Daniel; Postma, Geert J.; Schneiderhan-Marra, Nicole; Santoro, Filippo; Wouters, Hans; Russnes, Hege G.; Sørlie, Therese; Tagliabue, Elda; Børresen-Dale, Anne-Lise

2010-01-01

Triple-negative breast cancers (TNBC), characterized by absence of estrogen receptor (ER), progesterone receptor (PR) and lack of overexpression of human epidermal growth factor receptor 2 (HER2), are typically associated with poor prognosis, due to aggressive tumor phenotype(s), only partial

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.

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

KAUST Repository

Boulbes, Delphine R.; Arold, Stefan T.; Chauhan, Gaurav B.; Blachno, Korina V.; Deng, Nanfu; Chang, Wei-Chao; Jin, Quanri; Huang, Tzu-Hsuan; Hsu, Jung-Mao; Brady, Samuel W.; Bartholomeusz, Chandra; Ladbury, John E.; Stone, Steve; Yu, Dihua; Hung, Mien-Chie; Esteva, Francisco J.

2014-01-01

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.

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.

BAG3 promotes stem cell-like phenotype in breast cancer by upregulation of CXCR4 via interaction with its transcript.

Science.gov (United States)

Liu, Bao-Qin; Zhang, Song; Li, Si; An, Ming-Xin; Li, Chao; Yan, Jing; Wang, Jia-Mei; Wang, Hua-Qin

2017-07-13

BAG3 is an evolutionarily conserved co-chaperone expressed at high levels and has a prosurvival role in many tumor types. The current study reported that BAG3 was induced under specific floating culture conditions that enrich breast cancer stem cell (BCSC)-like cells in spheres. Ectopic BAG3 overexpression increased CD44 + /CD24 - CSC subpopulations, first-generation and second-generation mammosphere formation, indicating that BAG3 promotes CSC self-renewal and maintenance in breast cancer. We further demonstrated that mechanically, BAG3 upregulated CXCR4 expression at the post-transcriptional level. Further studies showed that BAG3 interacted with CXCR4 mRNA and promoted its expression via its coding and 3'-untranslational regions. BAG3 was also found to be positively correlated with CXCR4 expression and unfavorable prognosis in patients with breast cancer. Taken together, our data demonstrate that BAG3 promotes BCSC-like phenotype through CXCR4 via interaction with its transcript. Therefore, this study establishes BAG3 as a potential adverse prognostic factor and a therapeutic target of breast cancer.

Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice.

Science.gov (United States)

Shiromizu, Shoya; Kusunose, Naoki; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro

2018-04-01

Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule. Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Biologic role of activated leukocyte cell adhesion molecule overexpression in breast cancer cell lines and clinical tumor tissue.

Science.gov (United States)

Hein, Sibyll; Müller, Volkmar; Köhler, Nadine; Wikman, Harriet; Krenkel, Sylke; Streichert, Thomas; Schweizer, Michaela; Riethdorf, Sabine; Assmann, Volker; Ihnen, Maike; Beck, Katrin; Issa, Rana; Jänicke, Fritz; Pantel, Klaus; Milde-Langosch, Karin

2011-09-01

The activated leukocyte cell adhesion molecule (ALCAM) is overexpressed in many mammary tumors, but controversial results about its role and prognostic impact in breast cancer have been reported. Therefore, we evaluated the biologic effects of ALCAM expression in two breast cancer cell lines and a larger cohort of mammary carcinomas. By stable transfections, MCF7 cells with ALCAM overexpression and MDA-MB231 cells with reduced ALCAM levels were generated and analyzed in functional assays and cDNA microarrays. In addition, an immunohistochemical study on 347 patients with breast cancer with long-term follow-up and analysis of disseminated tumor cells (DTCs) was performed. In both cell lines, high ALCAM expression was associated with reduced cell motility. In addition, ALCAM silencing in MDA-MB231 cells resulted in lower invasive potential, whereas high ALCAM expression was associated with increased apoptosis in both cell lines. Among genes which were differentially expressed in clones with altered ALCAM expression, there was an overlap of 15 genes between both cell lines, among them cathepsin D, keratin 7, gelsolin, and ets2 whose deregulation was validated by western blot analysis. In MDA-MB231 cells, we observed a correlation with VEGF expression which was validated by enzyme-linked immuno sorbent assay (ELISA). Our IHC results on primary breast carcinomas showed that ALCAM expression was associated with an estrogen receptor-positive phenotype. In addition, strong ALCAM immunostaining correlated with nodal involvement and the presence of tumor cells in bone marrow. By Kaplan-Meier analysis, strong ALCAM expression in ductal carcinomas correlated with shorter recurrence-free intervals (P=0.048) and overall survival (OAS, P=0.003). Our results indicate that the biologic role of ALCAM in breast cancer is complex, but overexpression might be relevant for outcome in ductal carcinomas.

A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer

Directory of Open Access Journals (Sweden)

Paul Savage

2017-10-01

Full Text Available Summary: Therapies targeting epidermal growth factor receptor (EGFR have variable and unpredictable responses in breast cancer. Screening triple-negative breast cancer (TNBC patient-derived xenografts (PDXs, we identify a subset responsive to EGFR inhibition by gefitinib, which displays heterogeneous expression of wild-type EGFR. Deep single-cell RNA sequencing of 3,500 cells from an exceptional responder identified subpopulations displaying distinct biological features, where elevated EGFR expression was significantly enriched in a mesenchymal/stem-like cellular cluster. Sorted EGFRhi subpopulations exhibited enhanced stem-like features, including ALDH activity, sphere-forming efficiency, and tumorigenic and metastatic potential. EGFRhi cells gave rise to EGFRhi and EGFRlo cells in primary and metastatic tumors, demonstrating an EGFR-dependent expansion and hierarchical state transition. Similar tumorigenic EGFRhi subpopulations were identified in independent PDXs, where heterogeneous EGFR expression correlated with gefitinib sensitivity. This provides new understanding for an EGFR-dependent hierarchy in TNBC and for patient stratification for therapeutic intervention. : Savage et al. demonstrate that sensitivity to EGFR inhibitor, gefitinib, in triple-negative breast cancer is paradoxically associated with EGFR heterogeneity. Using single-cell RNA sequencing in conjunction with functional assays, they identify TNBC tumors in which EGFR expression identifies cells with tumor-initiating capacity whose proliferative expansion is sensitive to EGFR inhibition. Keywords: breast cancer, tumor heterogeneity, patient-derived xenograft, single-cell RNA sequencing, EGFR inhibition, therapeutic response, tumor-initiating cell, cell hierarchy, BRCA1 mutation

Impact of the Tumor Microenvironment on Tumor-Infiltrating Lymphocytes: Focus on Breast Cancer

Directory of Open Access Journals (Sweden)

Ivan J Cohen

2017-09-01

Full Text Available Immunotherapy is revolutionizing cancer care across disciplines. The original success of immune checkpoint blockade in melanoma has already been translated to Food and Drug Administration–approved therapies in a number of other cancers, and a large number of clinical trials are underway in many other disease types, including breast cancer. Here, we review the basic requirements for a successful antitumor immune response, with a focus on the metabolic and physical barriers encountered by lymphocytes entering breast tumors. We also review recent clinical trials of immunotherapy in breast cancer and provide a number of interesting questions that will need to be answered for successful breast cancer immunotherapy.

FIBROMATOSIS (DESMOID TUMOR OF THE BREAST. Fibromatosis (tumor desmoide de mama

Directory of Open Access Journals (Sweden)

Zhaneta P Boceska

2016-03-01

Full Text Available El tumor desmoide (fibromatosis es una entidad patológica extremadamente rara que se desarrolla de la fascia muscular y la aponeusorsis. Aunque sin potencial metastático, estos tumores son localmente muy agresivos y tienden a infiltrarse en los tejidos circundantes. Nosotros presentamos un caso de tumour desmoide de mama, que tuvo apariencias clínicas sugestivas a carcinoma. La paciente, de 56 años presentó una masa palpable de mama derecho. La citología por aspiracion con aguja fina (AGF no detectó ninguna célula maligna, por lo que se hizo una escisión local conservadora. La paciente no recibió ningun tratamiento postoperatorio adicional, y continúa viva y sana en los siguientes 18 meses. Desmoid tumor (fibromatosis is extremely rare benign pathological entity that develops from muscular fasciae and aponeuroses. Although without metastatic potential, these tumors are locally very aggressive and tend to infiltrate the surrounding tissues. We present a case of a desmoid tumor of the breast that had clinical appearance suggestive of carcinoma. The patient was 56 years old female with a previous history of surgical trauma who presented with a palpable mass in the right breast. A fine needle aspiration (FNA cytology did not reveal any malignant cells, thus conservative local excision was performed. The patient did not receive any additional postoperative treatment and was alive and free of disease after 18 months of follow-up. 

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

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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.

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

International Nuclear Information System (INIS)

Erez, Neta; Glanz, Sarah; Raz, Yael; Avivi, Camilla; Barshack, Iris

2013-01-01

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

NF1 truncating mutations associated to aggressive clinical phenotype with elephantiasis neuromatosa and solid malignancies.

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Ponti, Giovanni; Martorana, Davide; Pellacani, Giovanni; Ruini, Cristel; Loschi, Pietro; Baccarani, Alessio; De Santis, Giorgio; Pollio, Annamaria; Neri, Tauro Maria; Mandel, Victor Desmond; Maiorana, Antonio; Maccio, Livia; Maccaferri, Monia; Tomasi, Aldo

2014-06-01

Von Recklinghausen disease is a syndrome characterized by a wide phenotypic variability giving rise to both, cutaneous and visceral benign and malignant neoplasms. The first include cutaneous neurofibromas, subcutaneous and plexiform neurofibromas. The latter can undergo malignant transformation and/or determine elephantiasis neuromatosa. Visceral tumors may include malignant peripheral nerve sheet tumors, gastrointestinal stromal tumors, cerebral gliomas and abdominal neurofibromas. In the present study, the authors discuss the clinical and biomolecular characterization of a cohort of 20 families with a diagnosis of type 1 neurofibromatosis. Clinically, the cohort includes three probands with elephantiasis neuromatosa and a peculiarly high incidence of breast and gastrointestinal cancer. Among the 14 NF1 mutations documented, 10 encoding for a truncated protein have been associated to particularly aggressive clinical phenotypes including elephantiasis neuromatosa, malignant peripheral nerve sheet tumors, breast cancer, gastrointestinal stromal tumors. This effect on protein synthesis, rather than the type of NF1 mutation, is the key to the explanation of the genotype-phenotype correlations in the context of neurofibromatosis type 1. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Genomic Heterogeneity of Breast Tumor Pathogenesis

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Ellsworth, Rachel E.; Hooke, Jeffrey A.; Shriver, Craig D.; Ellsworth, Darrell L.

2009-01-01

Pathological grade is a useful prognostic factor for stratifying breast cancer patients into favorable (low-grade, well-differentiated tumors) and less favorable (high-grade, poorly-differentiated tumors) outcome groups. Under the current system of tumor grading, however, a large proportion of tumors are characterized as intermediate-grade, making determination of optimal treatments difficult. In an effort to increase objectivity in the pathological assessment of tumor grade, differences in chromosomal alterations and gene expression patterns have been characterized in low-grade, intermediate-grade, and high-grade disease. In this review, we outline molecular data supporting a linear model of progression from low-grade to high-grade carcinomas, as well as contradicting genetic data suggesting that low-grade and high-grade tumors develop independently. While debate regarding specific pathways of development continues, molecular data suggest that intermediate-grade tumors do not comprise an independent disease subtype, but represent clinical and molecular hybrids between low-grade and high-grade tumors. Finally, we discuss the clinical implications associated with different pathways of development, including a new clinical test to assign grade and guide treatment options. PMID:20689613

E-cadherin expression phenotypes associated with molecular subtypes in invasive non-lobular breast cancer: evidence from a retrospective study and meta-analysis.

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Liu, Jiang-Bo; Feng, Chen-Yi; Deng, Miao; Ge, Dong-Feng; Liu, De-Chun; Mi, Jian-Qiang; Feng, Xiao-Shan

2017-08-01

This retrospective study and meta-analysis was designed to explore the relationship between E-cadherin (E-cad) expression and the molecular subtypes of invasive non-lobular breast cancer, especially in early-stage invasive ductal carcinoma (IDC). A total of 156 post-operative cases of early-stage IDCs were retrospectively collected for the immunohistochemistry (IHC) detection of E-cad expression. The association of E-cad expression with molecular subtypes of early-stage IDCs was analyzed. A literature search was conducted in March 2016 to retrieve publications on E-cad expression in association with molecular subtypes of invasive non-lobular breast cancer, and a meta-analysis was performed to estimate the relational statistics. E-cad was expressed in 82.7% (129/156) of early-stage IDCs. E-cad expression was closely associated with the molecular types of early-stage IDCs (P cancer (TNBC) than in other molecular subtypes (TNBC vs. luminal A: RR = 3.45, 95% CI = 2.79-4.26; TNBC vs. luminal B: RR = 2.41, 95% CI = 1.49-3.90; TNBC vs. HER2-enriched: RR = 1.95, 95% CI = 1.24-3.07). Early-stage IDCs or invasive non-lobular breast cancers with the TNBC molecular phenotype have a higher risk for the loss of E-cad expression than do tumors with non-TNBC molecular phenotypes, suggesting that E-cad expression phenotypes were closely related to molecular subtypes and further studies are needed to clarify the underlying mechanism.

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....

The use of breast conserving surgery: linking insurance claims with tumor registry data

International Nuclear Information System (INIS)

Maskarinec, Gertraud; Dhakal, Sanjaya; Yamashiro, Gladys; Issell, Brian F

2002-01-01

The purpose of this study was to use insurance claims and tumor registry data to examine determinants of breast conserving surgery (BCS) in women with early stage breast cancer. Breast cancer cases registered in the Hawaii Tumor Registry (HTR) from 1995 to 1998 were linked with insurance claims from a local health plan. We identified 722 breast cancer cases with stage I and II disease. Surgical treatment patterns and comorbidities were identified using diagnostic and procedural codes in the claims data. The HTR database provided information on demographics and disease characteristics. We used logistic regression to assess determinants of BCS vs. mastectomy. The linked data set represented 32.8% of all early stage breast cancer cases recorded in the HTR during the study period. Due to the nature of the health plan, 79% of the cases were younger than 65 years. Women with early stage breast cancer living on Oahu were 70% more likely to receive BCS than women living on the outer islands. In the univariate analysis, older age at diagnosis, lower tumor stage, smaller tumor size, and well-differentiated tumor grade were related to receiving BCS. Ethnicity, comorbidity count, menopausal and marital status were not associated with treatment type. In addition to developing solutions that facilitate access to radiation facilities for breast cancer patients residing in remote locations, future qualitative research may help to elucidate how women and oncologists choose between BCS and mastectomy

MiR-190b, the highest up-regulated miRNA in ERα-positive compared to ERα-negative breast tumors, a new biomarker in breast cancers?

International Nuclear Information System (INIS)

Cizeron-Clairac, Geraldine; Lallemand, François; Vacher, Sophie; Lidereau, Rosette; Bieche, Ivan; Callens, Celine

2015-01-01

MicroRNAs (miRNAs) show differential expression across breast cancer subtypes and have both oncogenic and tumor-suppressive roles. Numerous microarray studies reported different expression patterns of miRNAs in breast cancers and found clinical interest for several miRNAs but often with contradictory results. Aim of this study is to identify miRNAs that are differentially expressed in estrogen receptor positive (ER + ) and negative (ER − ) breast primary tumors to better understand the molecular basis for the phenotypic differences between these two sub-types of carcinomas and to find potential clinically relevant miRNAs. We used the robust and reproductive tool of quantitative RT-PCR in a large cohort of well-annotated 153 breast cancers with long-term follow-up to identify miRNAs specifically differentially expressed between ER + and ER − breast cancers. Cytotoxicity tests and transfection experiments were then used to examine the role and the regulation mechanisms of selected miRNAs. We identified a robust collection of 20 miRNAs significantly deregulated in ER + compared to ER − breast cancers : 12 up-regulated and eight down-regulated miRNAs. MiR-190b retained our attention as it was the miRNA the most strongly over-expressed in ER + compared to ER − with a fold change upper to 23. It was also significantly up-regulated in ER + /Normal breast tissue and down-regulated in ER − /Normal breast tissue. Functional experiments showed that miR-190b expression is not directly regulated by estradiol and that miR-190b does not affect breast cancer cell lines proliferation. Expression level of miR-190b impacts metastasis-free and event-free survival independently of ER status. This study reveals miR-190b as the highest up-regulated miRNA in hormone-dependent breast cancers. Due to its specificity and high expression level, miR-190b could therefore represent a new biomarker in hormone-dependent breast cancers but its exact role carcinogenesis remains to

[Right Hemi-Colectomy for a Metastatic Transverse Colon Tumor from Breast Cancer Following Bilateral Breast Cancer Resection - A Case Report].

Science.gov (United States)

Okamura, Shu; Yanagisawa, Tetsu; Ohishi, Kazuhito; Murata, Kohei; Nushijima, Yoichiro; Hamano, Rie; Fukuchi, Nariaki; Ebisui, Chikara; Yokouchi, Hideoki; Kinuta, Masakatsu

2016-11-01

We herein report the case of a 75-year-old female patient who underwent 4 surgeries for bilateral breast cancer and its recurrence. When she presented at a clinic with an irritable colon, a fist-sized tumor was palpated in the right upper abdomen at her first medical examination. Abdominal CT scan at the clinic revealed a tumor with a maximum diameter of 10 cm on the right side of the transverse colon and multiple swollen mesenteric lymph nodes. Therefore, the patient was referred to our hospital for surgery. Colonoscopy revealed stenosis of the same lesion with an edematous mucosa and sclerosis. Using immunohistochemistry, a biopsy specimen from the lesion tested positive for CK AE1+AE3, and negative for CD20(-)and CD3 (-). As a result, the tumor was diagnosed as a poorly differentiated adenocarcinoma. We performed right hemicolectomy to avoid her intestinal obstruction. Tumor cells were mainly present at the subserosa, according to HEstaining. Using immunostaining, the cells were tested for the following markers: CDX2(-), GCDFP15(weakly positive), CK7(strongly positive), CD20(partially positive), E R(+), PgR(-), and HER2(1+), characterizing the tumor as metastasis of breast cancer. Although gastro-intestinal metastasis from breast cancer is rare, and colon metastasis is even rarer, it might be necessary to rule out the possibility of a metastatic colon tumor from breast cancer when treating patients with a colon tumor who have undergone surgery for breast cancer.

Granular cell tumor of the breast: a report of the three cases

International Nuclear Information System (INIS)

Mellado, M.; Pina, L.; Cojo, R.; Arias-Camison, I.

2000-01-01

Granular cell tumors (GCT) of the breast are uncommon benign neoplasms that are usually indistinguishable from breast cancer with respect to their clinical and radiological presentation. FNAB can be a usefull diagnostic tool, but histological examination is essential for the correct diagnosis. This benign tumor should be considered among the diagnostic possibilities in the presence of a lesion with mammographic and ultrasonographic indications of highly probable malignancy. We present three cases of breast GCT that mimicked primary breast cancer. Benign neoplasm was diagnosed and local excision was carried out rather than mastectomy and lymphadenectomy. (Author) 9 refs

Semi-automated delineation of breast cancer tumors and subsequent materialization using three-dimensional printing (rapid prototyping).

Science.gov (United States)

Schulz-Wendtland, Rüdiger; Harz, Markus; Meier-Meitinger, Martina; Brehm, Barbara; Wacker, Till; Hahn, Horst K; Wagner, Florian; Wittenberg, Thomas; Beckmann, Matthias W; Uder, Michael; Fasching, Peter A; Emons, Julius

2017-03-01

Three-dimensional (3D) printing has become widely available, and a few cases of its use in clinical practice have been described. The aim of this study was to explore facilities for the semi-automated delineation of breast cancer tumors and to assess the feasibility of 3D printing of breast cancer tumors. In a case series of five patients, different 3D imaging methods-magnetic resonance imaging (MRI), digital breast tomosynthesis (DBT), and 3D ultrasound-were used to capture 3D data for breast cancer tumors. The volumes of the breast tumors were calculated to assess the comparability of the breast tumor models, and the MRI information was used to render models on a commercially available 3D printer to materialize the tumors. The tumor volumes calculated from the different 3D methods appeared to be comparable. Tumor models with volumes between 325 mm 3 and 7,770 mm 3 were printed and compared with the models rendered from MRI. The materialization of the tumors reflected the computer models of them. 3D printing (rapid prototyping) appears to be feasible. Scenarios for the clinical use of the technology might include presenting the model to the surgeon to provide a better understanding of the tumor's spatial characteristics in the breast, in order to improve decision-making in relation to neoadjuvant chemotherapy or surgical approaches. J. Surg. Oncol. 2017;115:238-242. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Imaging findings in phyllodes tumors of the breast

International Nuclear Information System (INIS)

Tan Hongna; Zhang Shengjian; Liu Haiquan; Peng Weijun; Li Ruimin; Gu Yajia; Wang Xiaohong; Mao Jian; Shen Xigang

2012-01-01

Purpose: To study the radiological appearance and pathological features of breast phyllodes tumors (PTs), and to enhance the recognition of the tumor. Materials and methods: Clinical and imaging findings were retrospectively reviewed in 24 women with PTs confirmed by surgical pathology. All of the 24 patients had preoperative MRI and sonography, and 10 had preoperative mammography. Results: The histologic findings were benign, borderline and malignant PTs in 16.7% (4/24), 45.8% (11/24) and 37.5% (9/24) of cases, respectively. The tumor size (p = 0.001), irregular shape on sonographic imaging (p = 0.039), internal non-enhanced septations (p = 0.009), silt-like changes in enhanced images (p = 0.006) and signal changes from T2-weighted to enhanced images on MRI (p = 0.001) correlated significantly with the histologic grade; the BI-RADS category of the MRI could reflect the PT's histologic grade with a correlation coefficient of 0.440 (p = 0.031). If the category BI-RADS ≥4a was considered to be a suspicious malignant lesion, the diagnostic accuracy of mammography, US and MRI would be 70% (7/10), 62.5% (15/24) and 95.8% (23/24), respectively. Conclusion: The tumor size and several US and MRI findings can be used to help preoperatively determine the histologic grade of breast PTs. When a patient presents with a progressively enlarging, painless breast mass, MRI should be recommended first.

Asymmetric Cancer Hallmarks in Breast Tumors on Different Sides of the Body.

Directory of Open Access Journals (Sweden)

Emanuel M Campoy

Full Text Available During the last decades it has been established that breast cancer arises through the accumulation of genetic and epigenetic alterations in different cancer related genes. These alterations confer the tumor oncogenic abilities, which can be resumed as cancer hallmarks (CH. The purpose of this study was to establish the methylation profile of CpG sites located in cancer genes in breast tumors so as to infer their potential impact on 6 CH: i.e. sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, induction of angiogenesis, genome instability and invasion and metastasis. For 51 breast carcinomas, MS-MLPA derived-methylation profiles of 81 CpG sites were converted into 6 CH profiles. CH profiles distribution was tested by different statistical methods and correlated with clinical-pathological data. Unsupervised Hierarchical Cluster Analysis revealed that CH profiles segregate in two main groups (bootstrapping 90-100%, which correlate with breast laterality (p = 0.05. For validating these observations, gene expression data was obtained by RealTime-PCR in a different cohort of 25 tumors and converted into CH profiles. This analyses confirmed the same clustering and a tendency of association with breast laterality (p = 0.15. In silico analyses on gene expression data from TCGA Breast dataset from left and right breast tumors showed that they differed significantly when data was previously converted into CH profiles (p = 0.033. We show here for the first time, that breast carcinomas arising on different sides of the body present differential cancer traits inferred from methylation and expression profiles. Our results indicate that by converting methylation or expression profiles in terms of Cancer Hallmarks, it would allow to uncover veiled associations with clinical features. These results contribute with a new finding to the better understanding of breast tumor behavior, and can moreover serve as proof of

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)

Jang, Ji-Young; Lee, Jong-Kuen; Jeon, Yoon-Kyung; Kim, Chul-Woo

2013-01-01

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

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

International Nuclear Information System (INIS)

Li, Zidong; Chen, Bo; Wu, Yiqing; Jin, Feng; Xia, Yongjing; Liu, Xiangjun

2010-01-01

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

Tungsten Targets the Tumor Microenvironment to Enhance Breast Cancer Metastasis

Science.gov (United States)

Bolt, Alicia M.; Sabourin, Valérie; Molina, Manuel Flores; Police, Alice M.; Negro Silva, Luis Fernando; Plourde, Dany; Lemaire, Maryse; Ursini-Siegel, Josie; Mann, Koren K.

2015-01-01

The number of individuals exposed to high levels of tungsten is increasing, yet there is limited knowledge of the potential human health risks. Recently, a cohort of breast cancer patients was left with tungsten in their breasts following testing of a tungsten-based shield during intraoperative radiotherapy. While monitoring tungsten levels in the blood and urine of these patients, we utilized the 66Cl4 cell model, in vitro and in mice to study the effects of tungsten exposure on mammary tumor growth and metastasis. We still detect tungsten in the urine of patients’ years after surgery (mean urinary tungsten concentration at least 20 months post-surgery = 1.76 ng/ml), even in those who have opted for mastectomy, indicating that tungsten does not remain in the breast. In addition, standard chelation therapy was ineffective at mobilizing tungsten. In the mouse model, tungsten slightly delayed primary tumor growth, but significantly enhanced lung metastasis. In vitro, tungsten did not enhance 66Cl4 proliferation or invasion, suggesting that tungsten was not directly acting on 66Cl4 primary tumor cells to enhance invasion. In contrast, tungsten changed the tumor microenvironment, enhancing parameters known to be important for cell invasion and metastasis including activated fibroblasts, matrix metalloproteinases, and myeloid-derived suppressor cells. We show, for the first time, that tungsten enhances metastasis in an animal model of breast cancer by targeting the microenvironment. Importantly, all these tumor microenvironmental changes are associated with a poor prognosis in humans. PMID:25324207

Effect of Depleting Tumor-Associated Macrophages on Breast Cancer Growth and Response to Chemotherapy

National Research Council Canada - National Science Library

Tsan, Min-Fu; Gao, Baochong

2005-01-01

Tumor-associated macrophages may comprise up to 50% of the tumor mass in breast cancer and are capable of producing estrogen and angiogenic cytokines that regulate the growth and angiogenesis of breast cancer...

Heparanase augments insulin receptor signaling in breast carcinoma

Science.gov (United States)

Goldberg, Rachel; Sonnenblick, Amir; Hermano, Esther; Hamburger, Tamar; Meirovitz, Amichay; Peretz, Tamar; Elkin, Michael

2017-01-01

Recently, growing interest in the potential link between metabolic disorders (i.e., diabetes, obesity, metabolic syndrome) and breast cancer has mounted, including studies which indicate that diabetic/hyperinsulinemic women have a significantly higher risk of bearing breast tumors that are more aggressive and associated with higher death rates. Insulin signaling is regarded as a major contributor to this phenomenon; much less is known about the role of heparan sulfate-degrading enzyme heparanase in the link between metabolic disorders and cancer. In the present study we analyzed clinical samples of breast carcinoma derived from diabetic/non-diabetic patients, and investigated effects of heparanase on insulin signaling in breast carcinoma cell lines, as well as insulin-driven growth of breast tumor cells. We demonstrate that heparanase activity leads to enhanced insulin signaling and activation of downstream tumor-promoting pathways in breast carcinoma cells. In agreement, heparanase enhances insulin-induced proliferation of breast tumor cells in vitro. Moreover, analyzing clinical data from diabetic breast carcinoma patients, we found that concurrent presence of both diabetic state and heparanase in tumor tissue (as opposed to either condition alone) was associated with more aggressive phenotype of breast tumors in the patient cohort analyzed in our study (two-sided Fisher's exact test; p=0.04). Our findings highlight the emerging role of heparanase in powering effect of hyperinsulinemic state on breast tumorigenesis and imply that heparanase targeting, which is now under intensive development/clinical testing, could be particularly efficient in a growing fraction of breast carcinoma patients suffering from metabolic disorders. PMID:28038446

Breast cancer tumor classification using LASSO method selection approach

International Nuclear Information System (INIS)

Celaya P, J. M.; Ortiz M, J. A.; Martinez B, M. R.; Solis S, L. O.; Castaneda M, R.; Garza V, I.; Martinez F, M.; Ortiz R, J. M.

2016-10-01

Breast cancer is one of the leading causes of deaths worldwide among women. Early tumor detection is key in reducing breast cancer deaths and screening mammography is the widest available method for early detection. Mammography is the most common and effective breast cancer screening test. However, the rate of positive findings is very low, making the radiologic interpretation monotonous and biased toward errors. In an attempt to alleviate radiological workload, this work presents a computer-aided diagnosis (CAD x) method aimed to automatically classify tumor lesions into malign or benign as a means to a second opinion. The CAD x methos, extracts image features, and classifies the screening mammogram abnormality into one of two categories: subject at risk of having malignant tumor (malign), and healthy subject (benign). In this study, 143 abnormal segmentation s (57 malign and 86 benign) from the Breast Cancer Digital Repository (BCD R) public database were used to train and evaluate the CAD x system. Percentile-rank (p-rank) was used to standardize the data. Using the LASSO feature selection methodology, the model achieved a Leave-one-out-cross-validation area under the receiver operating characteristic curve (Auc) of 0.950. The proposed method has the potential to rank abnormal lesions with high probability of malignant findings aiding in the detection of potential malign cases as a second opinion to the radiologist. (Author)

Breast cancer tumor classification using LASSO method selection approach

Energy Technology Data Exchange (ETDEWEB)

Celaya P, J. M.; Ortiz M, J. A.; Martinez B, M. R.; Solis S, L. O.; Castaneda M, R.; Garza V, I.; Martinez F, M.; Ortiz R, J. M., E-mail: morvymm@yahoo.com.mx [Universidad Autonoma de Zacatecas, Av. Ramon Lopez Velarde 801, Col. Centro, 98000 Zacatecas, Zac. (Mexico)

2016-10-15

Breast cancer is one of the leading causes of deaths worldwide among women. Early tumor detection is key in reducing breast cancer deaths and screening mammography is the widest available method for early detection. Mammography is the most common and effective breast cancer screening test. However, the rate of positive findings is very low, making the radiologic interpretation monotonous and biased toward errors. In an attempt to alleviate radiological workload, this work presents a computer-aided diagnosis (CAD x) method aimed to automatically classify tumor lesions into malign or benign as a means to a second opinion. The CAD x methos, extracts image features, and classifies the screening mammogram abnormality into one of two categories: subject at risk of having malignant tumor (malign), and healthy subject (benign). In this study, 143 abnormal segmentation s (57 malign and 86 benign) from the Breast Cancer Digital Repository (BCD R) public database were used to train and evaluate the CAD x system. Percentile-rank (p-rank) was used to standardize the data. Using the LASSO feature selection methodology, the model achieved a Leave-one-out-cross-validation area under the receiver operating characteristic curve (Auc) of 0.950. The proposed method has the potential to rank abnormal lesions with high probability of malignant findings aiding in the detection of potential malign cases as a second opinion to the radiologist. (Author)

Dietary quercetin exacerbates the development of estrogen-induced breast tumors in female ACI rats

International Nuclear Information System (INIS)

Singh, Bhupendra; Mense, Sarah M.; Bhat, Nimee K.; Putty, Sandeep; Guthiel, William A.; Remotti, Fabrizio; Bhat, Hari K.

2010-01-01

Phytoestrogens are plant compounds that structurally mimic the endogenous estrogen 17β-estradiol (E 2 ). Despite intense investigation, the net effect of phytoestrogen exposure on the breast remains unclear. The objective of the current study was to examine the effects of quercetin on E 2 -induced breast cancer in vivo. Female ACI rats were given quercetin (2.5 g/kg food) for 8 months. Animals were monitored weekly for palpable tumors, and at the end of the experiment, rats were euthanized, breast tumor and different tissues excised so that they could be examined for histopathologic changes, estrogen metabolic activity and oxidant stress. Quercetin alone did not induce mammary tumors in female ACI rats. However, in rats implanted with E 2 pellets, co-exposure to quercetin did not protect rats from E 2 -induced breast tumor development with 100% of the animals developing breast tumors within 8 months of treatment. No changes in serum quercetin levels were observed in quercetin and quercetin + E 2 -treated groups at the end of the experiment. Tumor latency was significantly decreased among rats from the quercetin + E 2 group relative to those in the E 2 group. Catechol-O-methyltransferase (COMT) activity was significantly downregulated in quercetin-exposed mammary tissue. Analysis of 8-isoprostane F 2α (8-iso-PGF 2α ) levels as a marker of oxidant stress showed that quercetin did not decrease E 2 -induced oxidant stress. These results indicate that quercetin (2.5 g/kg food) does not confer protection against breast cancer, does not inhibit E 2 -induced oxidant stress and may exacerbate breast carcinogenesis in E 2 -treated ACI rats. Inhibition of COMT activity by quercetin may expose breast cells chronically to E 2 and catechol estrogens. This would permit longer exposure times to the carcinogenic metabolites of E 2 and chronic exposure to oxidant stress as a result of metabolic redox cycling to estrogen metabolites, and thus quercetin may exacerbate E 2 -induced

Effect of Depleting Tumor-Associated Macrophages on Breast Cancer Growth and Response to Chemotherapy

National Research Council Canada - National Science Library

Tsan, Min-Fu

2004-01-01

Tumor-associated macrophages (TAM) may comprise up to 50% of the tumor mass in breast cancer and are capable of producing estrogen and angiogenic cytokines that regulate the growth and angiogenesis of breast cancer...

The association between metabolic health, obesity phenotype and the risk of breast cancer.

Science.gov (United States)

Park, Yong-Moon Mark; White, Alexandra J; Nichols, Hazel B; O'Brien, Katie M; Weinberg, Clarice R; Sandler, Dale P

2017-06-15

Beyond the current emphasis on body mass index (BMI), it is unknown whether breast cancer risk differs between metabolically healthy and unhealthy normal weight or overweight/obese women. The Sister Study is a nationwide prospective cohort study. Data came from 50,884 cohort participants aged 35 to 74 years enrolled from 2003 through 2009. Cox proportional hazards models were used to estimate multivariable adjusted hazard ratios (HR) and 95% confidence intervals (CIs) for breast cancer risk. Metabolic abnormalities considered included: high waist circumference (≥88 cm); elevated blood pressure (≥130/85 mm Hg or antihypertensive medication); previously diagnosed diabetes or antidiabetic drug treatment; and cholesterol-lowering medication use. During follow-up (mean, 6.4 years), 1,388 invasive breast cancers were diagnosed at least 1 year after enrollment. Compared to women with BMI women with a BMI women with a BMI ≥25 kg/m 2 and no metabolic abnormalities (metabolically healthy overweight/obese phenotype) (HR = 1.24, 95% CI: 0.99-1.55). Furthermore, risk of postmenopausal breast cancer was consistently elevated in women with normal BMI and central obesity (normal weight central obesity phenotype) regardless of the criterion used to define central obesity, with HR for waist circumference ≥88 cm, waist circumference ≥80 cm, and waist-hip ratio ≥0.85 of 1.58, 95% CI: 1.02-2.46; 1.38, 95% CI: 1.09-1.75; and 1.38, 95% CI: 1.02-1.85, respectively. There was an inverse association between premenopausal breast cancer and metabolically healthy overweight/obese phenotype (HR = 0.71, 95% CI: 0.52-0.97). Our findings suggest that postmenopausal women who are metabolically unhealthy or have central adiposity may be at increased risk for breast cancer despite normal BMI. © 2017 UICC.

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.

Combined calcitriol and menadione reduces experimental murine triple negative breast tumor.

Science.gov (United States)

Bohl, Luciana; Guizzardi, Solange; Rodríguez, Valeria; Hinrichsen, Lucila; Rozados, Viviana; Cremonezzi, David; Tolosa de Talamoni, Nori; Picotto, Gabriela

2017-10-01

Calcitriol (D) or 1,25(OH) 2 D 3 inhibits the growth of several tumor cells including breast cancer cells, by activating cell death pathways. Menadione (MEN), a glutathione-depleting compound, may be used to potentiate the antiproliferative actions of D on cancer cells. We have previously shown in vitro that MEN improved D-induced growth arrest on breast cancer cell lines, inducing oxidative stress and DNA damage via ROS generation. Treatment with MEN+D resulted more effective than D or MEN alone. To study the in vivo effect of calcitriol, MEN or their combination on the development of murine transplantable triple negative breast tumor M-406 in its syngeneic host. Tumor M-406 was inoculated s.c., and when tumors reached the desired size, animals were randomly assigned to one of four groups receiving daily i.p. injections of either sterile saline solution (controls, C), MEN, D, or both (MEN+D). Body weight and tumor volume were recorded three times a week. Serum calcium was determined before and at the end of the treatment, at which time tumor samples were obtained for histological examination. None of the drugs, alone or in combination, affected mice body weight in the period studied. The combined treatment reduced tumor growth rate (C vs. MEN+D, P<0.05) and the corresponding histological sections exhibited small remaining areas of viable tumor only in the periphery. A concomitant DNA fragmentation was observed in all treated groups and MEN potentiated the calcitriol effect on tumor growth. As previously observed in vitro, treatment with MEN and D delayed tumor growth in vivo more efficiently than the individual drugs, with evident signals of apoptosis induction. Our results propose an alternative protocol to treat triple negative breast cancer, using GSH depleting drugs together with calcitriol, which would allow lower doses of the steroid to maintain the antitumor effect while diminishing its adverse pharmacological effects. Copyright © 2017. Published by

18F-Fluoride PET/CT tumor burden quantification predicts survival in breast cancer.

Science.gov (United States)

Brito, Ana E; Santos, Allan; Sasse, André Deeke; Cabello, Cesar; Oliveira, Paulo; Mosci, Camila; Souza, Tiago; Amorim, Barbara; Lima, Mariana; Ramos, Celso D; Etchebehere, Elba

2017-05-30

In bone-metastatic breast cancer patients, there are no current imaging biomarkers to identify which patients have worst prognosis. The purpose of our study was to investigate if skeletal tumor burden determined by 18F-Fluoride PET/CT correlates with clinical outcomes and may help define prognosis throughout the course of the disease. Bone metastases were present in 49 patients. On multivariable analysis, skeletal tumor burden was significantly and independently associated with overall survival (p breast cancer patients (40 for primary staging and the remainder for restaging after therapy). Clinical parameters, primary tumor characteristics and skeletal tumor burden were correlated to overall survival, progression free-survival and time to bone event. The median follow-up time was 19.5 months. 18F-Fluoride PET/CT skeletal tumor burden is a strong independent prognostic imaging biomarker in breast cancer patients.

Molecular Biology In Young Women With Breast Cancer: From Tumor Gene Expression To DNA Mutations.

Science.gov (United States)

Gómez-Flores-Ramos, Liliana; Castro-Sánchez, Andrea; Peña-Curiel, Omar; Mohar-Betancourt, Alejandro

2017-01-01

Young women with breast cancer (YWBC) represent roughly 15% of breast cancer (BC) cases in Latin America and other developing regions. Breast tumors occurring at an early age are more aggressive and have an overall worse prognosis compared to breast tumors in postmenopausal women. The expression of relevant proliferation biomarkers such as endocrine receptors and human epidermal growth factor receptor 2 appears to be unique in YWBC. Moreover, histopathological, molecular, genetic, and genomic studies have shown that YWBC exhibit a higher frequency of aggressive subtypes, differential tumor gene expression, increased genetic susceptibility, and specific genomic signatures, compared to older women with BC. This article reviews the current knowledge on tumor biology and genomic signatures in YWBC.

Influences of tumor stroma on the malignant phenotype

DEFF Research Database (Denmark)

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

2008-01-01

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......, 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...

Differential pattern and prognostic significance of CD4+, FOXP3+ and IL-17+ tumor infiltrating lymphocytes in ductal and lobular breast cancers

International Nuclear Information System (INIS)

Droeser, Raoul; Zlobec, Inti; Kilic, Ergin; Güth, Uwe; Heberer, Michael; Spagnoli, Giulio; Oertli, Daniel; Tapia, Coya

2012-01-01

Clinical relevance of tumor infiltrating lymphocytes (TILs) in breast cancer is controversial. Here, we used a tumor microarray including a large series of ductal and lobular breast cancers with long term follow up data, to analyze clinical impact of TIL expressing specific phenotypes and distribution of TILs within different tumor compartments and in different histological subtypes. A tissue microarray (TMA) including 894 ductal and 164 lobular breast cancers was stained with antibodies recognizing CD4, FOXP3, and IL-17 by standard immunohistochemical techniques. Lymphocyte counts were correlated with clinico-pathological parameters and survival. CD4 + lymphocytes were more prevalent than FOXP3 + TILs whereas IL-17 + TILs were rare. Increased numbers of total CD4 + and FOXP3 + TIL were observed in ductal, as compared with lobular carcinomas. High grade (G3) and estrogen receptor (ER) negative ductal carcinomas displayed significantly (p < 0.001) higher CD4 + and FOXP3 + lymphocyte infiltration while her2/neu over-expression in ductal carcinomas was significantly (p < 0.001) associated with higher FOXP3 + TIL counts. In contrast, lymphocyte infiltration was not linked to any clinico-pathological parameters in lobular cancers. In univariate but not in multivariate analysis CD4 + infiltration was associated with significantly shorter survival in patients bearing ductal, but not lobular cancers. However, a FOXP3 + /CD4 + ratio > 1 was associated with improved overall survival even in multivariate analysis (p = 0.033). Ductal and lobular breast cancers appear to be infiltrated by different lymphocyte subpopulations. In ductal cancers increased CD4 + and FOXP3 + TIL numbers are associated with more aggressive tumor features. In survival analysis, absolute numbers of TILs do not represent major prognostic indicators in ductal and lobular breast cancer. Remarkably however, a ratio > 1 of total FOXP3 + /CD4 + TILs in ductal carcinoma appears to represent an independent

Cystine addiction of triple-negative breast cancer associated with EMT augmented death signaling.

Science.gov (United States)

Tang, X; Ding, C-K; Wu, J; Sjol, J; Wardell, S; Spasojevic, I; George, D; McDonnell, D P; Hsu, D S; Chang, J T; Chi, J-T

2017-07-27

Despite the advances in the diagnosis and treatment of breast cancer, breast cancers still cause significant mortality. For some patients, especially those with triple-negative breast cancer, current treatments continue to be limited and ineffective. Therefore, there remains an unmet need for a novel therapeutic approach. One potential strategy is to target the altered metabolic state that is rewired by oncogenic transformation. Specifically, this rewiring may render certain outside nutrients indispensable. To identify such a nutrient, we performed a nutrigenetic screen by removing individual amino acids to identify possible addictions across a panel of breast cancer cells. This screen revealed that cystine deprivation triggered rapid programmed necrosis, but not apoptosis, in the basal-type breast cancer cells mostly seen in TNBC tumors. In contrast, luminal-type breast cancer cells are cystine-independent and exhibit little death during cystine deprivation. The cystine addiction phenotype is associated with a higher level of cystine-deprivation signatures noted in the basal type breast cancer cells and tumors. We found that the cystine-addicted breast cancer cells and tumors have strong activation of TNFα and MEKK4-p38-Noxa pathways that render them susceptible to cystine deprivation-induced necrosis. Consistent with this model, silencing of TNFα and MEKK4 dramatically reduces cystine-deprived death. In addition, the cystine addiction phenotype can be abrogated in the cystine-addictive cells by miR-200c, which converts the mesenchymal-like cells to adopt epithelial features. Conversely, the introduction of inducers of epithelial-mesenchymal transition (EMT) in cystine-independent breast cancer cells conferred the cystine-addiction phenotype by modulating the signaling components of cystine addiction. Together, our data reveal that cystine-addiction is associated with EMT in breast cancer during tumor progression. These findings provide the genetic and

Contribution of an alveolar cell of origin to the high-grade malignant phenotype of pregnancy-associated breast cancer.

Science.gov (United States)

Haricharan, S; Hein, S M; Dong, J; Toneff, M J; Aina, O H; Rao, P H; Cardiff, R D; Li, Y

2014-12-11

Pregnancy-associated breast cancers (PABCs) are tumors diagnosed during pregnancy or up to 5 years following parturition, and are usually high-grade, connective tissue-rich, and estrogen receptor (ER)/progesterone receptor-negative. Little is known about the cellular origin of PABCs or the mechanisms by which PABCs are initiated. Using the RCAS retrovirus to deliver the ErbB2 oncogene into the mammary epithelium of our previously reported MMTV-tva transgenic mice, we detected high-grade, poorly differentiated, stroma-rich and ER-negative tumors during pregnancy and lactation. These high-grade and stroma-rich tumors were less frequent in involuted mice or in age-matched nulliparous mice. More importantly, by generating a WAP-tva transgenic line for expression of ErbB2 selectively in WAP(+) mammary alveolar cells, we found that tumors had similar morphological phenotypes (high grade, poorly differentiated, stroma-rich and ER-negative), irrespective of the time since pregnancy and even in the absence of pregnancy. These data suggest that PABCs arise preferentially from an alveolar cell population that expands during pregnancy and lactation. This somatic mouse model may also be useful for preclinical testing of new prophylactic and therapeutic strategies against PABC.

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

Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer

OpenAIRE

Xiang, Meixian; Su, Hanwen; Shu, Guangwen; Wan, Dingrong; He, Feng; Loaec, Morgann; Ding, Yali; Li, Jun; Dovat, Sinisa; Yang, Gaungzhong; Song, Chunhua

2016-01-01

Chemotherapy is the main treatment for patients with breast cancer metastases, but natural alternatives have been receiving attention for their potential as novel anti-tumor reagents. Amplexicaule A (APA) is a flavonoid glucoside isolated from rhizomes of Polygonum amplexicaule D. Don var. sinense Forb (PADF). We found that APA has anti-tumor effects in a breast cancer xenograft mouse model and induces apoptosis in breast cancer cell lines. APA increased levels of cleaved caspase-3,-8,-9 and ...

A human breast cell model of pre-invasive to invasive transition

Energy Technology Data Exchange (ETDEWEB)

Bissell, Mina J; Rizki, Aylin; Weaver, Valerie M.; Lee, Sun-Young; Rozenberg, Gabriela I.; Chin, Koei; Myers, Connie A.; Bascom, Jamie L.; Mott, Joni D.; Semeiks, Jeremy R.; Grate, Leslie R.; Mian, I. Saira; Borowsky, Alexander D.; Jensen, Roy A.; Idowu, Michael O.; Chen, Fanqing; Chen, David J.; Petersen, Ole W.; Gray, Joe W.; Bissell, Mina J.

2008-03-10

A crucial step in human breast cancer progression is the acquisition of invasiveness. There is a distinct lack of human cell culture models to study the transition from pre-invasive to invasive phenotype as it may occur 'spontaneously' in vivo. To delineate molecular alterations important for this transition, we isolated human breast epithelial cell lines that showed partial loss of tissue polarity in three-dimensional reconstituted-basement membrane cultures. These cells remained non-invasive; however, unlike their non-malignant counterparts, they exhibited a high propensity to acquire invasiveness through basement membrane in culture. The genomic aberrations and gene expression profiles of the cells in this model showed a high degree of similarity to primary breast tumor profiles. The xenograft tumors formed by the cell lines in three different microenvironments in nude mice displayed metaplastic phenotypes, including squamous and basal characteristics, with invasive cells exhibiting features of higher grade tumors. To find functionally significant changes in transition from pre-invasive to invasive phenotype, we performed attribute profile clustering analysis on the list of genes differentially expressed between pre-invasive and invasive cells. We found integral membrane proteins, transcription factors, kinases, transport molecules, and chemokines to be highly represented. In addition, expression of matrix metalloproteinases MMP-9,-13,-15,-17 was up regulated in the invasive cells. Using siRNA based approaches, we found these MMPs to be required for the invasive phenotype. This model provides a new tool for dissection of mechanisms by which pre-invasive breast cells could acquire invasiveness in a metaplastic context.

The Impact of Epithelial Stromal Interactions on Human Breast Tumor Heterogeneity

Science.gov (United States)

2016-12-01

Identification of a novel tumor  necrosis  factor‐alpha‐inducible gene, SCC‐S2, containing the consensus sequence of a death effector domain of fas...microdissected breast cancer microvasculature identifies distinct tumor  vascular  subtypes. Breast Cancer Res 2012;14:R120. 32. Iorio MV,  Ferracin M

Nuclear DNA but not mtDNA controls tumor phenotypes in mouse cells

International Nuclear Information System (INIS)

Akimoto, Miho; Niikura, Mamoru; Ichikawa, Masami; Yonekawa, Hiromichi; Nakada, Kazuto; Honma, Yoshio; Hayashi, Jun-Ichi

2005-01-01

Recent studies showed high frequencies of homoplasmic mtDNA mutations in various human tumor types, suggesting that the mutated mtDNA haplotypes somehow contribute to expression of tumor phenotypes. We directly addressed this issue by isolating mouse mtDNA-less (ρ 0 ) cells for complete mtDNA replacement between normal cells and their carcinogen-induced transformants, and examined the effect of the mtDNA replacement on expression of tumorigenicity, a phenotype forming tumors in nude mice. The results showed that genome chimera cells carrying nuclear DNA from tumor cells and mtDNA from normal cells expressed tumorigenicity, whereas those carrying nuclear DNA from normal cells and mtDNA from tumor cells did not. These observations provided direct evidence that nuclear DNA, but not mtDNA, is responsible for carcinogen-induced malignant transformation, although it remains possible that mtDNA mutations and resultant respiration defects may influence the degree of malignancy, such as invasive or metastatic properties

Overexpression of prostate tumor overexpressed 1 correlates with tumor progression and predicts poor prognosis in breast cancer

International Nuclear Information System (INIS)

Lei, Fangyong; Zhang, Longjuan; Li, Xinghua; Lin, Xi; Wu, Shu; Li, Fengyan; Liu, Junling

2014-01-01

Prostate tumor overexpressed 1 (PTOV1) was demonstrated to play an important role in cancer progression and was correlated with unfavorable clinical outcome. However, the clinical role of PTOV1 in cancer remains largely unknown. This study aimed to investigate the expression and clinicopathological significance of PTOV1 in breast cancer. The mRNA and protein expression levels of PTOV1 were analyzed in 12 breast cancer cell lines and eight paired breast cancer tumors by semi-quantitative real time-PCR and western blotting, respectively. Immunohistochemistry was performed to assess PTOV1 protein expression in 169 paraffin-embedded, archived breast cancer samples. Survival analysis and Cox regression analysis were performed to investigate the clinicopathological significance of PTOV1 expression. Our data revealed that PTOV1 was frequently overexpressed in breast cancer cell lines compared to normal human breast epithelial cells and in primary breast cancer samples compared to adjacent noncancerous breast tissues, at both the mRNA and protein levels. Moreover, high expression of PTOV1 in breast cancer is strongly associated with clinicopathological characteristics and estrogen receptor expression status (P = 0.003). Breast cancer patients with higher PTOV1 expression had substantially shorter survival times than patients with lower PTOV1 expression (P < 0.001). Univariate and multivariate analysis revealed that PTOV1 might be an independent prognostic factor for breast cancer patients (P = 0.005). Our study showed that PTOV1 is upregulated in breast cancer cell lines and clinical samples, and its expression was positively associated with progression and aggressiveness of breast cancer, suggesting that PTOV1 could serve as an independent prognostic marker

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. PMID:25609959

Deciphering the Correlation between Breast Tumor Samples and Cell Lines by Integrating Copy Number Changes and Gene Expression Profiles

Directory of Open Access Journals (Sweden)

Yi Sun

2015-01-01

Full Text Available Breast cancer is one of the most common cancers with high incident rate and high mortality rate worldwide. Although different breast cancer cell lines were widely used in laboratory investigations, accumulated evidences have indicated that genomic differences exist between cancer cell lines and tissue samples in the past decades. The abundant molecular profiles of cancer cell lines and tumor samples deposited in the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas now allow a systematical comparison of the breast cancer cell lines with breast tumors. We depicted the genomic characteristics of breast primary tumors based on the copy number variation and gene expression profiles and the breast cancer cell lines were compared to different subgroups of breast tumors. We identified that some of the breast cancer cell lines show high correlation with the tumor group that agrees with previous knowledge, while a big part of them do not, including the most used MCF7, MDA-MB-231, and T-47D. We presented a computational framework to identify cell lines that mostly resemble a certain tumor group for the breast tumor study. Our investigation presents a useful guide to bridge the gap between cell lines and tumors and helps to select the most suitable cell line models for personalized cancer studies.

The CpG island methylator phenotype: What's in a name?

NARCIS (Netherlands)

L.A.E. Hughes (Laura A.); V. Melotte (Veerle); J.D. Schrijver (Joachim De); M.P.M. de Maat (Moniek); V.T.H.B.M. Smit (Vincent); J.V.M.G. Bovée (Judith); P.J. French (Pim); P.A. van den Brandt (Piet); L. Schouten (Leo); T. Meyer (Thorsten); W. van Criekinge (Wim); N. Ahuja (Nita); J.G. Herman (James); M.P. Weijenberg (Matty); M. van Engeland (Manon)

2013-01-01

textabstractAlthough the CpG island methylator phenotype (CIMP) was first identified and has been most extensively studied in colorectal cancer, the term "CIMP" has been repeatedly used over the past decade to describe CpG island promoter methylation in other tumor types, including bladder, breast,

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.

Clinicopathological characteristics of duodenal epithelial neoplasms: Focus on tumors with a gastric mucin phenotype (pyloric gland-type tumors.

Directory of Open Access Journals (Sweden)

Takehiro Mitsuishi

Full Text Available Epithelial tumors less commonly occur in the duodenum than in the stomach or large intestine. The clinicopathological characteristics of duodenal epithelial tumors remain a matter of debate. We therefore studied resected specimens to investigate the clinicopathological characteristics of duodenal epithelial tumors.Among duodenal epithelial tumors resected endoscopically or surgically in our hospital, we studied the clinicopathological characteristics of 110 adenomas or intramucosal carcinomas. The grade of atypia of all tumors was classified into 3 groups according to the World Health Organization (WHO 2010 classification. The tumors were immunohistochemically evaluated to determine the frequency of differentiation toward fundic glands.As for patient characteristics, there were 76 men (75.2% and 25 women (24.8%, with a median age of 65 years (range, 34 to 84. The tumors most commonly arose in the first to second part of the duodenum. Many lesions were flat, and the median tumor diameter was 8.0 mm. The lesions were classified into 2 types according to mucin phenotype: intestinal-type tumors (98 lesions, 89.1% and gastric-type tumors (12 lesions, 10.9%. Intestinal-type tumors were subdivided into 2 groups: tubular-type tumors (91 lesions, 82.7% and tubulovillous-type tumors (7 lesions, 6.4%. Gastric-type tumors were classified into 2 types: foveolar type (3 lesions, 2.7% and pyloric gland-type (PG tumors (9 lesions, 8.2%. The grade of atypia was significantly higher in gastric-type tumors (p<0.01. PG tumors were gastric-type tumors characterized by pyloric glands and findings suggesting differentiation toward fundic glands.About 10% of the duodenal tumors had a gastric-type mucin phenotype. Gastric-type tumors showed high-grade atypia. In particular, PG tumors showed similarities to PG tumors of the stomach, such as differentiation toward fundic glands.

Role of Erbin in ErbB2-dependent breast tumor growth

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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

2014-01-01

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. PMID:25288731

Modeling triple-negative breast cancer heterogeneity: effects of stromal macrophages, fibroblasts and tumor vasculature.

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Norton, Kerri-Ann; Jin, Kideok; Popel, Aleksander S

2018-05-08

A hallmark of breast tumors is its spatial heterogeneity that includes its distribution of cancer stem cells and progenitor cells, but also heterogeneity in the tumor microenvironment. In this study we focus on the contributions of stromal cells, specifically macrophages, fibroblasts, and endothelial cells on tumor progression. We develop a computational model of triple-negative breast cancer based on our previous work and expand it to include macrophage infiltration, fibroblasts, and angiogenesis. In vitro studies have shown that the secretomes of tumor-educated macrophages and fibroblasts increase both the migration and proliferation rates of triple-negative breast cancer cells. In vivo studies also demonstrated that blocking signaling of selected secreted factors inhibits tumor growth and metastasis in mouse xenograft models. We investigate the influences of increased migration and proliferation rates on tumor growth, the effect of the presence on fibroblasts or macrophages on growth and morphology, and the contributions of macrophage infiltration on tumor growth. We find that while the presence of macrophages increases overall tumor growth, the increase in macrophage infiltration does not substantially increase tumor growth and can even stifle tumor growth at excessive rates. Copyright © 2018. Published by Elsevier Ltd.

Iatrogenic displacement of tumor cells to the sentinel node after surgical excision in primary breast cancer

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Tvedskov, Tove F; Jensen, Maj-Britt; Kroman, Niels

2012-01-01

Isolated tumor cells (ITC) are more common in the sentinel node (SN) after needle biopsy of a breast cancer, indicating iatrogenic displacement of tumor cells. We here investigate whether similar iatrogenic displacement occurs after surgical excision of a breast tumor. We compared the incidence...

Canonical and Non-Canonical NF-κB Signaling Promotes Breast Cancer Tumor-Initiating Cells

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Kendellen, Megan F.; Bradford, Jennifer W.; Lawrence, Cortney L.; Clark, Kelly S.; Baldwin, Albert S.

2014-01-01

Tumor-initiating cells (TICs) are a sub-population of cells that exhibit a robust ability to self-renew and contribute to the formation of primary tumors, the relapse of previously treated tumors, and the development of metastases. TICs have been identified in various tumors, including those of the breast, and are particularly enriched in the basal-like and claudin-low subtypes of breast cancer. The signaling pathways that contribute to the function and maintenance of TICs are under intense study. We explored the potential involvement of the NF-κB family of transcription factors in TICs in cell lines that are representative of basal-like and claudin-low breast cancer. NF-κB was found to be activated in breast cancer cells that form tumorspheres efficiently. Moreover, both canonical and non-canonical NF-κB signaling is required for these cells to self-renew in vitro and to form xenograft tumors efficiently in vivo using limiting dilutions of cells. Consistent with this, canonical and non-canonical NF-κB signaling is activated in TICs isolated from breast cancer cell lines. Experimental results indicate that NF-κB promotes the function of TICs by stimulating epithelial-to-mesenchymal transition (EMT) and by upregulating the expression of the inflammatory cytokines IL-1β and IL-6. The results suggest the use of NF-κB inhibitors for clinical therapy of certain breast cancers. PMID:23474754

T cell receptor sequencing of early-stage breast cancer tumors identifies altered clonal structure of the T cell repertoire.

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Beausang, John F; Wheeler, Amanda J; Chan, Natalie H; Hanft, Violet R; Dirbas, Frederick M; Jeffrey, Stefanie S; Quake, Stephen R

2017-11-28

Tumor-infiltrating T cells play an important role in many cancers, and can improve prognosis and yield therapeutic targets. We characterized T cells infiltrating both breast cancer tumors and the surrounding normal breast tissue to identify T cells specific to each, as well as their abundance in peripheral blood. Using immune profiling of the T cell beta-chain repertoire in 16 patients with early-stage breast cancer, we show that the clonal structure of the tumor is significantly different from adjacent breast tissue, with the tumor containing ∼2.5-fold greater density of T cells and higher clonality compared with normal breast. The clonal structure of T cells in blood and normal breast is more similar than between blood and tumor, and could be used to distinguish tumor from normal breast tissue in 14 of 16 patients. Many T cell sequences overlap between tissue and blood from the same patient, including ∼50% of T cells between tumor and normal breast. Both tumor and normal breast contain high-abundance "enriched" sequences that are absent or of low abundance in the other tissue. Many of these T cells are either not detected or detected with very low frequency in the blood, suggesting the existence of separate compartments of T cells in both tumor and normal breast. Enriched T cell sequences are typically unique to each patient, but a subset is shared between many different patients. We show that many of these are commonly generated sequences, and thus unlikely to play an important role in the tumor microenvironment. Copyright © 2017 the Author(s). Published by PNAS.

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.

Sentinel node biopsy and concomitant probe-guided tumor excision of nonpalpable breast cancer.

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van Rijk, Maartje C; Tanis, Pieter J; Nieweg, Omgo E; Loo, Claudette E; Olmos, Renato A Valdés; Oldenburg, Hester S A; Rutgers, Emiel J Th; Hoefnagel, Cornelis A; Kroon, Bin B R

2007-02-01

Preliminary data have shown encouraging results of a single intratumoral radiopharmaceutical injection that enables both sentinel node biopsy and probe-guided excision of the primary tumor in patients with nonpalpable breast cancer. The aim of the study was to evaluate this approach in a large group of patients. Lymphoscintigraphy was performed in 368 patients with nonpalpable breast cancer after intratumoral injection of (99m)Tc-nanocolloid (.2 mL, 123 MBq, 3.3 mCi) guided by ultrasound or stereotaxis. The sentinel node was pursued with the aid of vital blue dye (1.0 mL, intratumoral) and a gamma ray detection probe. In case of breast-conserving surgery, the probe was used to guide the excision. At least one sentinel node could be identified intraoperatively in 357 patients (97%), of whom 69 had involved nodes (19%). Age over 60 years was associated with less frequent nonaxillary lymphatic drainage and absence of internal mammary chain dissemination. Tumor-free margins were obtained in 262 (89%) of the 293 patients who underwent segmental excision. Re-excision of the primary tumor bed was performed in six patients (2%). During a median follow-up of 22 months, one breast recurrence and one axillary recurrence were observed. Lymphatic mapping and probe-guided tumor excision of nonpalpable breast cancer by intralesional administration of a single dose of (99m)Tc-nanocolloid and blue dye resulted in 97% identification of the sentinel node and in tumor-free margins in 89% of the patients who underwent breast-conserving surgery. Longer follow-up is needed to substantiate the accuracy and safety of this technique.

Contrast-enhanced color Doppler ultrasound characteristics in hypervascular breast tumors: comparison with MRI

International Nuclear Information System (INIS)

Alamo, L.; Fischer, U.

2001-01-01

The aim of this study was to evaluate the accuracy of contrast-enhanced color Doppler ultrasound (CE-US) in comparison with contrast-enhanced MR imaging (CE-MRI) in the discrimination of hypervascularized breast tumors. An additional CE-US of the breast was preoperatively performed in 40 patients with a hypervascular breast lesion detected on CE-MRI. The presence of blood flow signals and the morphological characteristics of the vessels in the breast lesions were evaluated pre- and post-contrast administration, as well as the dynamic aspects of the Doppler signal, including time interval to maximum signal enhancement and persistence of the signal enhancement. Twenty-three carcinomas and 17 fibroadenomas were explored. Considering initial signal enhancement > 100 % after the administration of contrast material as a criterion suggesting malignancy, CE-MRI showed a sensitivity of 100 % and a specificity of 76.5 % in the detection of malignant breast tumors. Color Doppler signals were consistently demonstrated in all carcinomas and in 68.7 % of fibroadenomas after the administration of Levovist, with CE-US showing a sensitivity of 95.6 % and a specificity of 5.9 %. Neither the mean number of vessels per tumor, nor the location of vessels, the time to maximum increase of the Doppler signal or the persistence of signal enhancement showed significant differences between benign and malignant lesions. Additional CE-US does not increase the low specificity of MRI in patients with hypervascularized breast tumors. (orig.)

Assessment of breast tumor size in electrical impedance scanning

International Nuclear Information System (INIS)

Kim, Sungwhan

2012-01-01

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. (paper)

Breast Cancer Screening in Denmark: A Cohort Study of Tumor Size and Overdiagnosis.

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Jørgensen, Karsten Juhl; Gøtzsche, Peter C; Kalager, Mette; Zahl, Per-Henrik

2017-03-07

Effective breast cancer screening should detect early-stage cancer and prevent advanced disease. To assess the association between screening and the size of detected tumors and to estimate overdiagnosis (detection of tumors that would not become clinically relevant). Cohort study. Denmark from 1980 to 2010. Women aged 35 to 84 years. Screening programs offering biennial mammography for women aged 50 to 69 years beginning in different regions at different times. Trends in the incidence of advanced (>20 mm) and nonadvanced (≤20 mm) breast cancer tumors in screened and nonscreened women were measured. Two approaches were used to estimate the amount of overdiagnosis: comparing the incidence of advanced and nonadvanced tumors among women aged 50 to 84 years in screening and nonscreening areas; and comparing the incidence for nonadvanced tumors among women aged 35 to 49, 50 to 69, and 70 to 84 years in screening and nonscreening areas. Screening was not associated with lower incidence of advanced tumors. The incidence of nonadvanced tumors increased in the screening versus prescreening periods (incidence rate ratio, 1.49 [95% CI, 1.43 to 1.54]). The first estimation approach found that 271 invasive breast cancer tumors and 179 ductal carcinoma in situ (DCIS) lesions were overdiagnosed in 2010 (overdiagnosis rate of 24.4% [including DCIS] and 14.7% [excluding DCIS]). The second approach, which accounted for regional differences in women younger than the screening age, found that 711 invasive tumors and 180 cases of DCIS were overdiagnosed in 2010 (overdiagnosis rate of 48.3% [including DCIS] and 38.6% [excluding DCIS]). Regional differences complicate interpretation. Breast cancer screening was not associated with a reduction in the incidence of advanced cancer. It is likely that 1 in every 3 invasive tumors and cases of DCIS diagnosed in women offered screening represent overdiagnosis (incidence increase of 48.3%). None.

The quality of tumor size assessment by contrast-enhanced spectral mammography and the benefit of additional breast MRI.

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Lobbes, Marc B I; Lalji, Ulrich C; Nelemans, Patty J; Houben, Ivo; Smidt, Marjolein L; Heuts, Esther; de Vries, Bart; Wildberger, Joachim E; Beets-Tan, Regina G

2015-01-01

Background - Contrast-enhanced spectral mammography (CESM) is a promising new breast imaging modality that is superior to conventional mammography for breast cancer detection. We aimed to evaluate correlation and agreement of tumor size measurements using CESM. As additional analysis, we evaluated whether measurements using an additional breast MRI exam would yield more accurate results. Methods - Between January 1(st) 2013 and April 1(st) 2014, 87 consecutive breast cancer cases that underwent CESM were collected and data on maximum tumor size measurements were gathered. In 57 cases, tumor size measurements were also available for breast MRI. Histopathological results of the surgical specimen served as gold standard in all cases. Results - The Pearson's correlation coefficients (PCC) of CESM versus histopathology and breast MRI versus histopathology were all >0.9, p1 cm between the two imaging modalities and histopathological results, we did not observe any advantage of performing an additional breast MRI after CESM in any of the cases. Conclusion - Quality of tumor size measurement using CESM is good and matches the quality of these measurement assessed by breast MRI. Additional measurements using breast MRI did not improve the quality of tumor size measurements.

Tumor-infiltrating lymphocytes and ductal carcinoma in situ of the breast: friends or foes?

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Agahozo, Marie Colombe; Hammerl, Dora; Debets, Reno; Kok, Marleen; van Deurzen, Carolien H M

2018-02-20

In the past three decades, the detection rate of ductal carcinoma in situ of the breast has dramatically increased due to breast screening programs. As a consequence, about 20% of all breast cancer cases are detected in this early in situ stage. Some ductal carcinoma in situ cases will progress to invasive breast cancer, while other cases are likely to have an indolent biological behavior. The presence of tumor-infiltrating lymphocytes is seen as a promising prognostic and predictive marker in invasive breast cancer, mainly in HER2-positive and triple-negative subtypes. Here, we summarize the current understanding regarding immune infiltrates in invasive breast cancer and highlight recent observations regarding the presence and potential clinical significance of such immune infiltrates in patients with ductal carcinoma in situ. The presence of tumor-infiltrating lymphocytes, their numbers, composition, and potential relationship with genomic status will be discussed. Finally, we propose that a combination of genetic and immune markers may better stratify ductal carcinoma in situ subtypes with respect to tumor evolution.

Ultrasonic elastography features of phyllodes tumors of the breast: a clinical research.

Directory of Open Access Journals (Sweden)

Lu-Jing Li

Full Text Available The purpose of this study was to analyze the ultrasonic elastography features of phyllodes tumors of the breast comparing with fibroadenomas. A retrospective database was queried for the patients diagnosed as phyllodes tumors and fibroadenomas at Sun Yat-sen Memorial Hospital from January 2008 to August 2012. Three hundred and fifty lesions from 323 consecutive patients were included in the study. All the cases were examined by conventional ultrasonography and ultrasound elastography. Ultrasound elastography was used to calculate strain ratio of the lesions with bilateral breast tissue at the same depth as reference. There were 36 phyllodes tumors (27 benign, 8 borderline, 1 malignant and 314 fibroadenomas (158 the pericanalicular type, 103 the intracanalicular type, 53 other special types. The strain ratio for phyllodes tumors (3.19 ± 2.33 was significantly higher than for fibroadenomas (1.69 ± 0.88 (p<0.05. The Spearman(.s correlation coefficient between strain ratio of ultrasound elastography and pathological groups was significant, with a value of 0.17 (p<0.05. Ultrasound elastography could provide additional information to differentiate phyllodes tumors from fibroadenoma in breast.

MRI of breast tumors with emphasis on histopathologic correlation

International Nuclear Information System (INIS)

Kuwabara, Masako

1991-01-01

Breast MR imaging is now expected as the third most important diagnostic modality. The author investigated relationship between signal intensity of T2 weighted images (T2WI) and various pathological findings of 51 mass lesions in 51 female patients. T2WI were not effective in differentiation between malignant and benign lesions. High signal intensity areas defined visually well correlated with pathological tissues with large water content such as necrosis, edema, cyst, and dilatated ducts. There was also good correlation between low signal intensity areas and pathological tissue with less water content such as fibrosis, scar, and hyalinization. Signal intensity measured by tumor/fat ratio had no correlation with water content. It probably indicates that visually defined signal intensity is more reliable than the measured ratio. In conclusion, it is warrented to say that T2WI is a good tool for investigating secondary changes of breast tumors and helpful in diangosis of high intensity tumors described above. (author)

The correlation of background parenchymal enhancement in the contralateral breast with patient and tumor characteristics of MRI-screen detected breast cancers.

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Vreemann, Suzan; Gubern-Mérida, Albert; Borelli, Cristina; Bult, Peter; Karssemeijer, Nico; Mann, Ritse M

2018-01-01

Higher background parenchymal enhancement (BPE) could be used for stratification of MRI screening programs since it might be related to a higher breast cancer risk. Therefore, the purpose of this study is to correlate BPE to patient and tumor characteristics in women with unilateral MRI-screen detected breast cancer who participated in an intermediate and high risk screening program. As BPE in the affected breast may be difficult to discern from enhancing cancer, we assumed that BPE in the contralateral breast is a representative measure for BPE in women with unilateral breast cancer. This retrospective study was approved by our local institutional board and a waiver for consent was granted. MR-examinations of women with unilateral breast cancers screen-detected on breast MRI were evaluated by two readers. BPE in the contralateral breast was rated according to BI-RADS. Univariate analyses were performed to study associations. Observer variability was computed. Analysis included 77 breast cancers in 76 patients (age: 48±9.8 years), including 62 invasive and 15 pure ductal carcinoma in-situ cases. A negative association between BPE and tumor grade (p≤0.016) and a positive association with progesterone status (p≤0.021) was found. The correlation was stronger when only considering invasive disease. Inter-reader agreement was substantial. Lower BPE in the contralateral breast in women with unilateral breast cancer might be associated to higher tumor grade and progesterone receptor negativity. Great care should be taken using BPE for stratification of patients to tailored screening programs.

Anti-tumor effects of 125I radioactive particles implantation on transplantated tumor model of human breast cancer cells in nude mice

International Nuclear Information System (INIS)

Xiao Zhongdi; Liang Chunlin; Zhang Guoli; Jing Yue; Zhang Yucheng; Gai Baodong

2011-01-01

Objective: To study the anti-tumor effects of 125 I radioactive particles implantation on transplantated tumor model of human breast cancer cells in nude mice and clarify their anti-tumor mechanisms. Methods 120 nude mice transplantated with human breast cancer cells MCF-7 were randomly divided into 3 groups (n=40): 125 I radioactive particles implanted group, non-radioactive particles implanted group and non-particles implanted group. The articles were implanted into mice according to Pairs system principle. The expressions of Fas mRNA and protein and the activaties of caspase-3 and caspase-8 enzyme were detected by RT-PCR and Western blotting. The changes of cell cycle were detected by flow cytometry. Results: Compared with non-radioactive particles implanted group and non-particles implanted group, the size of cancer tissues in 125 I radioactive particles implanted group was reduced significantly (P 0 /G 1 phase was significantly increased (P 125 I radioactive particles into transplantated tumor model of human breast cancer cells can kill tumor cells, inhibit the growth cycle of tumor cells and induce the apoptosis of tumor cells in nude mice. (authors)

In vivo assessment of 111In-labeled hematoporphyrin derivative in breast tumor-bearing animals

International Nuclear Information System (INIS)

Wong, D.W.; Mandal, Ashis; Brown, Jerry; Reese, I.C.; Siegler, Richard; Hyman, Shigeyo

1989-01-01

The biological behavior of 111 In-labeled HPD has been investigated in tumor-bearing animals. Mice mammary adenocarcinomas and 7,12-dimethylbenz(a)anthracine induced breast tumors in Sprague-Dawley female rats were clearly visualized by 111 In-HPD nuclear scintigraphy. Optimal scans were obtained after a 48 h delay. In normal and tumor-bearing animals, the highest uptake of 111 In-HPD 72 h post-injection was found in the liver, the spleen and the kidneys. Depending on the size and the extent of necrosis, the uptake of 111 In-HPD by malignant breast tumors varied from 2.5% injected dose (ID) in mice to 1% ID in rats. Benign breast tumor uptake of 111 In-HPD was less than 1% ID. No significant amount of the radiopharmaceutical was found in pulmonary abscesses and abdominal cysts. Scintigrams of these infectious or inflammatory lesions were normal. Malignant tumor to blood, heart and lung ratios averaged 50:1, 10:1 and 3:1 respectively. Tumor to brain ratio ranged from 72 to 444:1. (author)

Adenosis tumor of the breast: a case report

International Nuclear Information System (INIS)

Yoon, Pyeong Ho; Oh, Ki Keun; Jung, Mi Kyeong; Jung, Woo Hee; Shim, Jung Yeon

1995-01-01

Adenosis tumor is a rare tumor of the breast and primarily consists of adenosis. Authors report a case of surgically proved adenosis tumor in a 31-year-old woman. Mammogram showed a lobulated, well-circumscribed mass with several surrounding radiolucent halos. In the center of the mass several linear radiolucent densities were seen with the appearance of a conglomerated well-circumscribed mass such as fibroadenoma. These linear radiolucent densities were consistent with the fat between the fibrous sclerosis in pathologic specimen. Ultrasonogram showed a well-circumscribed mass with homogeneous low echogenicity, partial posterior enhancement, and bilateral acoustic shadowings

Adenosis tumor of the breast: a case report

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Yoon, Pyeong Ho; Oh, Ki Keun; Jung, Mi Kyeong; Jung, Woo Hee; Shim, Jung Yeon [Yonsei University College of Medicine, Seoul (Korea, Republic of)

1995-05-15

Adenosis tumor is a rare tumor of the breast and primarily consists of adenosis. Authors report a case of surgically proved adenosis tumor in a 31-year-old woman. Mammogram showed a lobulated, well-circumscribed mass with several surrounding radiolucent halos. In the center of the mass several linear radiolucent densities were seen with the appearance of a conglomerated well-circumscribed mass such as fibroadenoma. These linear radiolucent densities were consistent with the fat between the fibrous sclerosis in pathologic specimen. Ultrasonogram showed a well-circumscribed mass with homogeneous low echogenicity, partial posterior enhancement, and bilateral acoustic shadowings.

Limited utility of tissue micro-arrays in detecting intra-tumoral heterogeneity in stem cell characteristics and tumor progression markers in breast cancer.

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Kündig, Pascale; Giesen, Charlotte; Jackson, Hartland; Bodenmiller, Bernd; Papassotirolopus, Bärbel; Freiberger, Sandra Nicole; Aquino, Catharine; Opitz, Lennart; Varga, Zsuzsanna

2018-05-08

Intra-tumoral heterogeneity has been recently addressed in different types of cancer, including breast cancer. A concept describing the origin of intra-tumoral heterogeneity is the cancer stem-cell hypothesis, proposing the existence of cancer stem cells that can self-renew limitlessly and therefore lead to tumor progression. Clonal evolution in accumulated single cell genomic alterations is a further possible explanation in carcinogenesis. In this study, we addressed the question whether intra-tumoral heterogeneity can be reliably detected in tissue-micro-arrays in breast cancer by comparing expression levels of conventional predictive/prognostic tumor markers, tumor progression markers and stem cell markers between central and peripheral tumor areas. We analyzed immunohistochemical expression and/or gene amplification status of conventional prognostic tumor markers (ER, PR, HER2, CK5/6), tumor progression markers (PTEN, PIK3CA, p53, Ki-67) and stem cell markers (mTOR, SOX2, SOX9, SOX10, SLUG, CD44, CD24, TWIST) in 372 tissue-micro-array samples from 72 breast cancer patients. Expression levels were compared between central and peripheral tumor tissue areas and were correlated to histopathological grading. 15 selected cases additionally underwent RNA sequencing for transcriptome analysis. No significant difference in any of the analyzed between central and peripheral tumor areas was seen with any of the analyzed methods/or results that showed difference. Except mTOR, PIK3CA and SOX9 (nuclear) protein expression, all markers correlated significantly (p < 0.05) with histopathological grading both in central and peripheral areas. Our results suggest that intra-tumoral heterogeneity of stem-cell and tumor-progression markers cannot be reliably addressed in tissue-micro-array samples in breast cancer. However, most markers correlated strongly with histopathological grading confirming prognostic information as expression profiles were independent on the site of the

The usefulness of US with contrast agent on breast tumors

International Nuclear Information System (INIS)

Jung, Hye An; Jung, Jung Im; Kim, Hak Hee; Son, Sang Bum; Byun, Jae Young; Lee, Jae Mun; Hahn, Sung Tae; Kim, Choon Yul

2000-01-01

To evaluate the usefulness of US with contrast agent breast tumors. Fifteen breast tumors in fourteen patients underwent color Doppler US before and after intravenous injection of a microbubble contrast agent (Levovist, Schering AG, Berlin, Germany). Benign lesions were 8 and malignant lesions were 7 among these. Real-time power Doppler ultrasonographic images were recorded on a videotape and representative images were color-printed. Tumor vascularity was analyzed on real-time images in regard to its presence or absence, and changes in diameter and number of vessels, presence or absence of blush around the vessels. Two observers reached a consensus. Results of malignant tumors were compared with those of benign tumors. Color Doppler signal intensity increased in 12 of 15 cases (80%). Number of vessel increased in 9 of 15 cases (60%) and diameter of vessel increased in 12 of 15 cases (80%). Vascular blush around the enhanced vessel was present in 5 of 15 patients (53%). Color Doppler signal increased in 5 of 8 benign lesions (63%) and 7 of 7 malignant lesions (100%). Number of vessel increased in 4 of 8 benign lesion (50%) and 5 of 7 malignant lesions (71%). Diameter of vessel increased in 5 of 8 benign lesions (63%) and 7 of 7 malignant lesions (100%). Blush around the enhanced vessel was present in one of 8 benign lesions (13%) and 4 of 7 malignant lesions (57%). The time to peak enhancement was shorter in malignant cases (mean=45 sec) than benign cases (mean=82 sec). US with contrast agent on breast tumors is effective to detect blood flow within the mass and may be helpful to differentiate malignant from benign lesions.

Clinical and ultrasonographic features of male breast tumors: A retrospective analysis.

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Yuan, Wei-Hsin; Li, Anna Fen-Yau; Chou, Yi-Hong; Hsu, Hui-Chen; Chen, Ying-Yuan

2018-01-01

The purpose of this study was to determine clinical and ultrasonographic characteristics of male breast tumors. The medical records of male patients with breast lesions were retrieved from an electronic medical record database and a pathology database and retrospectively reviewed. A total of 112 men (125 breast masses) with preoperative breast ultrasonography (US) were included (median age, 59.50 years; age range, 15-96 years). Data extracted included patient age, if the lesions were bilateral, palpable, and tender, and the presence of nipple discharge. Breast lesion features on static US images were reviewed by three experienced radiologists without knowledge of physical examination or pathology results, original breast US image interpretations, or surgical outcomes. The US features were documented according to the BI-RADS (Breast Imaging-Reporting and Data System) US lexicons. A forth radiologist compiled the data for analysis. Of the 125 breast masses, palpable tender lumps and bilateral synchronous masses were more likely to be benign than malignant (both, 100% vs 0%, P nipples were common in malignant lesions (P nipple, irregular shape, the presence of an echogenic halo, predominantly internal vascularity, and rich color flow signal on color Doppler ultrasound were significantly related to malignancy (all, P < 0.05). An echogenic halo and the presence of rich color flow signal were independent predictors of malignancy. Specific clinical and US characteristics of male breast tumors may help guide treatment, and determine if surgery or conservative treatment is preferable.

Differential Gene Expression in Primary Breast Tumors Associated with Lymph Node Metastasis

International Nuclear Information System (INIS)

Ellsworth, R.E.; Field, L.A.; Kane, J.L.; Love, B.; Hooke, J.A.; Shriver, C.D.

2011-01-01

Lymph node status remains one of the most useful prognostic indicators in breast cancer; however, current methods to assess nodal status disrupt the lymphatic system and may lead to secondary complications. Identification of molecular signatures discriminating lymph node-positive from lymph node-negative primary tumors would allow for stratification of patients requiring surgical assesment of lymph nodes. Primary breast tumors from women with negative (n=41) and positive (n=35) lymph node status matched for possible confounding factors were subjected to laser micro dissection and gene expression data generated. Although ANOVA analysis (P 1.5) revealed 13 differentially expressed genes, hierarchical clustering classified 90% of node-negative but only 66% of node-positive tumors correctly. The inability to derive molecular profiles of metastasis in primary tumors may reflect tumor heterogeneity, paucity of cells within the primary tumor with metastatic potential, influence of the microenvironment, or inherited host susceptibility to metastasis

Differential Gene Expression in Primary Breast Tumors Associated with Lymph Node Metastasis

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Ellsworth, Rachel E.; Field, Lori A.; Love, Brad; Kane, Jennifer L.; Hooke, Jeffrey A.; Shriver, Craig D.

2011-01-01

Lymph node status remains one of the most useful prognostic indicators in breast cancer; however, current methods to assess nodal status disrupt the lymphatic system and may lead to secondary complications. Identification of molecular signatures discriminating lymph node-positive from lymph node-negative primary tumors would allow for stratification of patients requiring surgical assesment of lymph nodes. Primary breast tumors from women with negative (n = 41) and positive (n = 35) lymph node status matched for possible confounding factors were subjected to laser microdissection and gene expression data generated. Although ANOVA analysis (P 1.5) revealed 13 differentially expressed genes, hierarchical clustering classified 90% of node-negative but only 66% of node-positive tumors correctly. The inability to derive molecular profiles of metastasis in primary tumors may reflect tumor heterogeneity, paucity of cells within the primary tumor with metastatic potential, influence of the microenvironment, or inherited host susceptibility to metastasis. PMID:22295210

Differential Gene Expression in Primary Breast Tumors Associated with Lymph Node Metastasis

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Rachel E. Ellsworth

2011-01-01

Full Text Available Lymph node status remains one of the most useful prognostic indicators in breast cancer; however, current methods to assess nodal status disrupt the lymphatic system and may lead to secondary complications. Identification of molecular signatures discriminating lymph node-positive from lymph node-negative primary tumors would allow for stratification of patients requiring surgical assesment of lymph nodes. Primary breast tumors from women with negative (=41 and positive (=35 lymph node status matched for possible confounding factors were subjected to laser microdissection and gene expression data generated. Although ANOVA analysis (1.5 revealed 13 differentially expressed genes, hierarchical clustering classified 90% of node-negative but only 66% of node-positive tumors correctly. The inability to derive molecular profiles of metastasis in primary tumors may reflect tumor heterogeneity, paucity of cells within the primary tumor with metastatic potential, influence of the microenvironment, or inherited host susceptibility to metastasis.

Specifically activated memory T cell subsets from cancer patients recognize and reject xenotransplanted autologous tumors

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Beckhove, Philipp; Feuerer, Markus; Dolenc, Mathias; Schuetz, Florian; Choi, Carmen; Sommerfeldt, Nora; Schwendemann, Jochen; Ehlert, Katrin; Altevogt, Peter; Bastert, Gunther; Schirrmacher, Volker; Umansky, Viktor

2004-01-01

Bone marrow of breast cancer patients was found to contain CD8+ T cells specific for peptides derived from breast cancer–associated proteins MUC1 and Her-2/neu. Most of these cells had a central or effector memory phenotype (CD45RA–CD62L+ or CD45RA–CD62L–, respectively). To test their in vivo function, we separated bone marrow–derived CD45RA+ naive or CD45RA–CD45RO+ memory T cells, stimulated them with autologous dendritic cells pulsed with tumor lysate, and transferred them into NOD/SCID mice bearing autologous breast tumors and normal skin transplants. CD45RA– memory but not CD45RA+ naive T cells infiltrated autologous tumor but not skin tissues after the transfer. These tumor-infiltrating cells had a central or effector memory phenotype and produced perforin. Many of them expressed the P-selectin glycoprotein ligand 1 and were found around P-selectin+ tumor endothelium. Tumor infiltration included cluster formation in tumor tissue by memory T cells with cotransferred dendritic cells. It was associated with the induction of tumor cell apoptosis and significant tumor reduction. We thus demonstrate selective homing of memory T cells to human tumors and suggest that tumor rejection is based on the recognition of tumor-associated antigens on tumor cells and dendritic cells by autologous specifically activated central and effector memory T cells. PMID:15232613

CAR T cell therapy for breast cancer: harnessing the tumor milieu to drive T cell activation.

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Bajgain, Pradip; Tawinwung, Supannikar; D'Elia, Lindsey; Sukumaran, Sujita; Watanabe, Norihiro; Hoyos, Valentina; Lulla, Premal; Brenner, Malcolm K; Leen, Ann M; Vera, Juan F

2018-05-10

The adoptive transfer of T cells redirected to tumor via chimeric antigen receptors (CARs) has produced clinical benefits for the treatment of hematologic diseases. To extend this approach to breast cancer, we generated CAR T cells directed against mucin1 (MUC1), an aberrantly glycosylated neoantigen that is overexpressed by malignant cells and whose expression has been correlated with poor prognosis. Furthermore, to protect our tumor-targeted cells from the elevated levels of immune-inhibitory cytokines present in the tumor milieu, we co-expressed an inverted cytokine receptor linking the IL4 receptor exodomain with the IL7 receptor endodomain (4/7ICR) in order to transform the suppressive IL4 signal into one that would enhance the anti-tumor effects of our CAR T cells at the tumor site. First (1G - CD3ζ) and second generation (2G - 41BB.CD3ζ) MUC1-specific CARs were constructed using the HMFG2 scFv. Following retroviral transduction transgenic expression of the CAR±ICR was assessed by flow cytometry. In vitro CAR/ICR T cell function was measured by assessing cell proliferation and short- and long-term cytotoxic activity using MUC1+ MDA MB 468 cells as targets. In vivo anti-tumor activity was assessed using IL4-producing MDA MB 468 tumor-bearing mice using calipers to assess tumor volume and bioluminescence imaging to track T cells. In the IL4-rich tumor milieu, 1G CAR.MUC1 T cells failed to expand or kill MUC1+ tumors and while co-expression of the 4/7ICR promoted T cell expansion, in the absence of co-stimulatory signals the outgrowing cells exhibited an exhausted phenotype characterized by PD-1 and TIM3 upregulation and failed to control tumor growth. However, by co-expressing 2G CAR.MUC1 (signal 1 - activation + signal 2 - co-stimulation) and 4/7ICR (signal 3 - cytokine), transgenic T cells selectively expanded at the tumor site and produced potent and durable tumor control in vitro and in vivo. Our findings demonstrate the feasibility of targeting breast

Phenotypic and Functional Properties of Tumor-Infiltrating Regulatory T Cells

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Gap Ryol Lee

2017-01-01

Full Text Available Regulatory T (Treg cells maintain immune homeostasis by suppressing excessive immune responses. Treg cells induce tolerance against self- and foreign antigens, thus preventing autoimmunity, allergy, graft rejection, and fetus rejection during pregnancy. However, Treg cells also infiltrate into tumors and inhibit antitumor immune responses, thus inhibiting anticancer therapy. Depleting whole Treg cell populations in the body to enhance anticancer treatments will produce deleterious autoimmune diseases. Therefore, understanding the precise nature of tumor-infiltrating Treg cells is essential for effectively targeting Treg cells in tumors. This review summarizes recent results relating to Treg cells in the tumor microenvironment, with particular emphasis on their accumulation, phenotypic, and functional properties, and targeting to enhance the efficacy of anticancer treatment.

Oestrogen receptors in tumors of breast cancer patients

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Levin, J; Kay, G; Da Fonseca, M [University of the Witwatersrand, Johannesburg (South Africa). Department of Nuclear Medicine; Lange, M [University of the Witwatersrand, Johannesburg (South Africa). Dept. of Surgery; De Moor, N G [University of the Witwatersrand, Johannesburg (South Africa). Department of Radiation Therapy; Savage, N [University of the Witwatersrand, Johannesburg (South Africa). Department of Physiological Chemistry

1978-04-15

Oestrogen receptors were measured in the cytoplasmic fraction of tumors from patients with breast cancer. Receptors were detected in 48% of patients, and 52% showed no receptors. A follow-up study of a small group of patients on hormone therapy is reported.

Nuclear medicine in breast cancer diagnostics: Primary tumor and lymphatic metastasis

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Sinilkin, I.; Medvedeva, A.; Chernov, V.; Slonimskaya, E.; Zelchan, R.; Bragina, O.

2017-09-01

The purpose of the study: to assess the possibility of using nuclear medicine techniques at the stages of diagnosis and treatment of breast cancer. Materials and Methods: The study included 290 patients with breast cancer and 70 patients with benign breast tumors. The study was used as a radiopharmaceutical 99mTc-MIBI, 199Tl for imaging tumors and colloid 99mTc-Aloteh for visualization sentinel lymph nodes (SLN), colloid was injected peritumoral in four points to 80 MBq one day prior to the planned operation. Results: The sensitivity of SPECT using both 99mTc-MIBI and 199Tl for breast cancer detection was shown to be rather high, being 98.5% and 98%, respectively. It should be noted that the sensitivity of SPECT in detection of small tumors (less than 1 cm in diameter) and multicentric tumors was not high irrespective of the radioisotope used (60% and 65% with 99mTc-MIBI and 65% and 59% with 199Tl, respectively). The difference in the sensitivity was found between 99mTc-MIBI and 199T for the detection of regional lymph node metastasis (91% vs 70%). SLN were detected in 31 patients. The most commonly SLN were defined in the axillary region of 96.7%. In 22 (70.9%) patients there was no metastasis SLN. The sensitivity of the method was 91.2%, specificity of 100%. Conclusion: The specificity of SPECT with 199Tl was higher than that with 99mTc-MIBI. The data obtained show that SPECT with 199Tl can be recommended for its use as an additional breast cancer detection method in cases when other imaging techniques and histological findings are not accurate enough. The clinical study of 99mTc-Aloteh, a new radiopharmaceutical agent, has shown that the studied colloid has high uptake level in SLN and can be successfully used for visualization of SLN in patients with breast cancer.

Label-Free Raman Imaging to Monitor Breast Tumor Signatures

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Ciubuc, John

Methods built on Raman spectroscopy have shown major potential in describing and discriminating between malignant and benign specimens. Accurate, real-time medical diagnosis benefits in substantial improvements through this vibrational optical method. Not only is acquisition of data possible in milliseconds and analysis in minutes, Raman allows concurrent detection and monitoring of all biological components. Besides validating a significant Raman signature distinction between non-tumorigenic (MCF-10A) and tumorigenic (MCF-7) breast epithelial cells, this study reveals a label-free method to assess overexpression of epidermal growth factor receptors (EGFR) in tumor cells. EGFR overexpression sires Raman features associated with phosphorylated threonine and serine, and modifications of DNA/RNA characteristics. Investigations by gel electrophoresis reveal EGF induction of phosphorylated Akt, agreeing with the Raman results. The analysis presented is a vital step toward Raman-based evaluation of EGF receptors in breast cancer cells. With the goal of clinically applying Raman-guided methods for diagnosis of breast tumors, the current results lay the basis for proving label-free optical alternatives in making prognosis of the disease.

Highly-sensitive and large-dynamic diffuse optical tomography system for breast tumor detection

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Du, Wenwen; Zhang, Limin; Yin, Guoyan; Zhang, Yanqi; Zhao, Huijuan; Gao, Feng

2018-02-01

Diffuse optical tomography (DOT) as a new functional imaging has important clinical applications in many aspects such as benign and malignant breast tumor detection, tumor staging and so on. For quantitative detection of breast tumor, a three-wavelength continuous-wave DOT prototype system combined the ultra-high sensitivity of the photon-counting detection and the measurement parallelism of the lock-in technique was developed to provide high temporal resolution, high sensitivity, large dynamic detection range and signal-to-noise ratio. Additionally, a CT-analogous scanning mode was proposed to cost-effectively increase the detection data. To evaluate the feasibility of the system, a series of assessments were conducted. The results demonstrate that the system can obtain high linearity, stability and negligible inter-wavelength crosstalk. The preliminary phantom experiments show the absorption coefficient is able to be successfully reconstructed, indicating that the system is one of the ideal platforms for optical breast tumor detection.

N-glycan signatures identified in tumor interstitial fluid and serum of breast cancer patients - association with tumor biology and clinical outcome.

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Terkelsen, Thilde; Haakensen, Vilde D; Saldova, Radka; Gromov, Pavel; Hansen, Merete Kjaer; Stöckmann, Henning; Lingjaerde, Ole Christian; Børresen-Dale, Anne-Lise; Papaleo, Elena; Helland, Åslaug; Rudd, Pauline M; Gromova, Irina

2018-04-26

Particular N-glycan structures are known to be associated with breast malignancies by coordinating various regulatory events within the tumor and corresponding microenvironment, thus implying that N-glycan patterns may be used for cancer stratification and as predictive or prognostic biomarkers. However, the association between N-glycans secreted by breast tumor and corresponding clinical relevance remain to be elucidated. We profiled N-glycans by HILIC UPLC across a discovery dataset composed of tumor interstitial fluids (TIF, n=85), paired normal interstitial fluids (NIF, n=54) and serum samples (n=28) followed by independent evaluation, with the ultimate goal of identifying tumor-related N-glycan patterns in blood of breast cancer patients. The segregation of N-linked oligosaccharides revealed 33 compositions, which exhibited differential abundances between TIF and NIF. TIFs were depleted of bisecting N-glycans, which are known to play essential roles in tumor suppression. An increased level of simple high mannose N-glycans in TIF strongly correlated with the presence of tumor infiltrating lymphocytes within tumor. At the same time, a low level of highly complex N-glycans in TIF inversely correlated with the presence of infiltrating lymphocytes within tumor. Survival analysis showed that patients exhibiting increased TIF abundance of GP24 had better outcomes, whereas low levels of GP10, GP23, GP38, and coreF were associated with poor prognosis. Levels of GP1, GP8, GP9, GP14, GP23, GP28, GP37, GP38, and coreF were significantly correlated between TIF and paired serum samples. Cross-validation analysis using an independent serum dataset supported the observed correlation between TIF and serum, for five out of nine N-glycan groups: GP8, GP9, GP14, GP23, and coreF. Collectively, our results imply that profiling of N-glycans from proximal breast tumor fluids is a promising strategy for determining tumor-derived glyco-signature(s) in the blood. N-glycans structures

G-protein-coupled receptor 81 promotes a malignant phenotype in breast cancer through angiogenic factor secretion.

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Lee, Yu Jin; Shin, Kyeong Jin; Park, Soo-Ah; Park, Kyeong Su; Park, Seorim; Heo, Kyun; Seo, Young-Kyo; Noh, Dong-Young; Ryu, Sung Ho; Suh, Pann-Ghill

2016-10-25

G-protein-coupled receptor 81 (GPR81) functions as a receptor for lactate and plays an important role in the regulation of anti-lipolytic effects in adipocytes. However, to data, a role for GPR81 in the tumor microenvironment has not been clearly defined. Here, GPR81 expression in breast cancer patients and several breast cancer cell lines was significantly increased compared with normal mammary tissues and cells. GPR81 knockdown resulted in impaired breast cancer growth and led to apoptosis both in vitro and in vivo. Furthermore, the inhibition of GPR81 signaling suppressed angiogenesis through a phosphoinositide 3-OH kinase (PI3K)/Akt-cAMP response element binding protein (CREB) pathway, which led to decreased production of the pro-angiogenic mediator amphiregulin (AREG). Overall, these findings identify GPR81 as a tumor-promoting receptor in breast cancer progression and suggest a novel mechanism that regulates GPR81-dependent activation of the PI3K/Akt signaling axis in tumor microenvironment.

[Common benign breast tumors including fibroadenoma, phyllodes tumors, and papillary lesions: Guidelines].

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Bendifallah, S; Canlorbe, G

2015-12-01

To provide guidelines for clinical practice from the French College of Obstetrics and Gynecology (CNGOF), based on the best evidence available, concerning common benign breast tumors: fibroadenoma (FA), phyllodes breast tumors (PBT), and papillary lesions (BPL). Bibliographical search in French and English languages by consultation of PubMed, Cochrane and international databases. In case of percutaneous biopsy diagnosis of FA, clinico-radiologic and pathologic discordance or complex FA or proliferative lesions or atypia with FA, a family history of cancer, it seems legitimate to discuss management in a multidisciplinary meeting. When surgery is proposed for FA, periareolar compared to direct incision is associated with more insensitive nipple but better aesthetic results (LE4). When surgery is proposed for FA, indirect incision is preferable for better cosmetic results (Grade C). Techniques of percutaneous destruction or resection can be used (Grade C). The WHO classification distinguishes three categories of phyllodes tumors (PBT): benign (grade 1), borderline (grade 2) and malignant (grade 3). For grade 1 PBT, the risk of local recurrence after surgical excision increases when PBT lesion is in contact with surgical limits (not in sano). After in sano resection, there is no correlation between margin size and the risk of recurrence (LE4). For grade 2 PBT, local recurrence after surgical excision increases for margins under 10mm margins (LE4). For grade 1-2 PBT, in sano excision is recommended. For grade 2 PBT, 10-mm margins are recommended (Grade C). No lymph node evaluation or neither systematic mastectomy is recommended (Grade C). Breast papillary lesion (BPL) without atypia, complete resection of radiologic signal is recommended (Grade C). For BPL with atypia, complete excisional surgery is recommended (Grade C). Copyright © 2015 Elsevier Masson SAS. All rights reserved.

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

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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

Tumor Cells Express FcγRl Which Contributes to Tumor Cell Growth and a Metastatic Phenotype

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M. Bud Nelson

2001-01-01

Full Text Available High levels of circulating immune complexes containing tumor-associated antigens are associated with a poor prognosis for individuals with cancer. The ability of B cells, previously exposed to tumor-associated antigens, to promote both in vitro and in vivo tumor growth formed the rationale to evaluate the mechanism by which immune complexes may promote tumor growth. In elucidating this mechanism, FcγRl expression by tumor cells was characterized by flow cytometry, polymerase chain reaction, and sequence analysis. Immune complexes containing shed tumor antigen and anti-shed tumor antigen Ab cross-linked FcγRl-expressing tumor cells, which resulted in an induction of tumor cell proliferation and of shed tumor antigen production. Use of selective tyrosine kinase inhibitors demonstrated that tumor cell proliferation induced by immune complex cross-linking of FcγRl is dependent on the tyrosine kinase signal transduction pathway. A selective inhibitor of phosphatidylinositol-3 kinase also inhibited this induction of tumor cell proliferation. These findings support a role for immune complexes and FcγRl expression by tumor cells in augmentation of tumor growth and a metastatic phenotype.

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

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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.

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

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Li, Yuanyuan; Chen, Huaping; Hardy, Tabitha M; Tollefsbol, Trygve O

2013-01-01

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.

Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation.

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Ahirwar, Dinesh K; Nasser, Mohd W; Ouseph, Madhu M; Elbaz, Mohamad; Cuitiño, Maria C; Kladney, Raleigh D; Varikuti, Sanjay; Kaul, Kirti; Satoskar, Abhay R; Ramaswamy, Bhuvaneswari; Zhang, Xiaoli; Ostrowski, Michael C; Leone, Gustavo; Ganju, Ramesh K

2018-05-03

The chemokine CXCL12 has been shown to regulate breast tumor growth, however, its mechanism in initiating distant metastasis is not well understood. Here, we generated a novel conditional allele of Cxcl12 in mice and used a fibroblast-specific Cre transgene along with various mammary tumor models to evaluate CXCL12 function in the breast cancer metastasis. Ablation of CXCL12 in stromal fibroblasts of mice significantly delayed the time to tumor onset and inhibited distant metastasis in different mouse models. Elucidation of mechanisms using in vitro and in vivo model systems revealed that CXCL12 enhances tumor cell intravasation by increasing vascular permeability and expansion of a leaky tumor vasculature. Furthermore, our studies revealed CXCL12 enhances permeability by recruiting endothelial precursor cells and decreasing endothelial tight junction and adherence junction proteins. High expression of stromal CXCL12 in large cohort of breast cancer patients was directly correlated to blood vessel density and inversely correlated to recurrence and overall patient survival. In addition, our analysis revealed that stromal CXCL12 levels in combination with number of CD31+ blood vessels confers poorer patient survival compared to individual protein level. However, no correlation was observed between epithelial CXCL12 and patient survival or blood vessel density. Our findings describe the novel interactions between fibroblasts-derived CXCL12 and endothelial cells in facilitating tumor cell intrvasation, leading to distant metastasis. Overall, our studies indicate that cross-talk between fibroblast-derived CXCL12 and endothelial cells could be used as novel biomarker and strategy for developing tumor microenvironment based therapies against aggressive and metastatic breast cancer.

Macromolecular contrast media. A new approach for characterising breast tumors with MR-mammography

International Nuclear Information System (INIS)

Daldrup, H.E.; Gossmann, A.; Koeln Univ.; Wendland, M.; Brasch, R.C.; Rosenau, W.

1997-01-01

The value of macromolecular contrast agents (MMCM) for the characterization of benign and malignant breast tumors will be demonstrated in this review. Animal studies suggest a high potential of MMCM to increase the specificity of MR-mammography. The concept of tumor differentiation is based on the pathological hyperpermeability of microvessels in malignant tumors. MMCM show a leak into the interstitium of carcinomas, whereas they are confined to the intravascular space in benign tumors. Capabilities and limitations of the MMCM-prototype. Albumin-Gd-DTPA, for breast tumor characterization will be summarized and compared to the standard low molecular weight contrast agent Gd-DTPA. Initial experience with new MMCM, such as Dendrimers, Gd-DTPA-Polylysine and MS-325 will be outlined. The potential of 'blood-pool'-iron oxides, such as AMI-227 for the evaluation of tumor microvascular permeabilities will be discussed. (orig.) [de

The usefulness of [sup 201]TlCl scintigraphy for the diagnosis of breast tumor

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Takahashi, Tamami; Moriya, Etsuo; Miyamoto, Yukio; Kawakami, Kenji; Kubo, Hirotaka; Uchida, Takeshi [Jikei Univ., Tokyo (Japan). School of Medicine

1994-06-01

The usefulness of [sup 201]TlCl SPECT (Tl SPECT) for the diagnosis of breast cancer was evaluated in 14 patients with various breast tumors (9 with invasive ductal carcinoma, 2 with fibroadenoma and 3 with benign process). These tumors ranged in size from 1.5 cm x 1.5 cm to 15.0 cm x 14.0 cm. Tl SPECT was carried out 2 hours after the intravenous injection of [sup 201]TlCl (185 MBq). For quantitative study, ROIs were set in the tumor (T), normal tissue of the opposite breast (B) and myocardium (M). Count ratios of T/B and T/M were calculated. Eight patients with breast cancer and a case of fibroadenoma showed intense accumulation of [sup 201]TlCl in the tumors. The T/B ratio was 1.20[+-]0.68 and the T/M ratio was 0.68[+-]0.31 in the 9 cases. Lymph node metastasis was detected in 2 of 6 cases that were confirmed at operation. No remarkable accumulation of [sup 201]TlCl was seen in 4 patients with benign process. One patient with benign tumor showed a false positive result. The rates of accuracy of mammography and ultrasonography for the same subjects were 82% and 84%, respectively. The results suggest that [sup 201]TlCl SPECT might be useful to assess breast cancer in cases in which the findings of other modalities are equivocal. (author).

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

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Brun, E; Grandl, S; Sztrókay-Gaul, A; Barbone, G; Mittone, A; Gasilov, S; Bravin, A; Coan, P

2014-11-01

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. 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. A correct and precise identification of the tumor boundaries was obtained and confirmed by manual contouring performed independently by four experienced radiologists. 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.

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

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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

Mast Cell, the Neglected Member of the Tumor Microenvironment: Role in Breast Cancer.

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Aponte-López, Angélica; Fuentes-Pananá, Ezequiel M; Cortes-Muñoz, Daniel; Muñoz-Cruz, Samira

2018-01-01

Mast cells are unique tissue-resident immune cells that secrete a diverse array of biologically active compounds that can stimulate, modulate, or suppress the immune response. Although mounting evidence supports that mast cells are consistently infiltrating tumors, their role as either a driving or an opposite force for cancer progression is still controversial. Particularly, in breast cancer, their function is still under discussion. While some studies have shown a protective role, recent evidence indicates that mast cells enhance blood and lymphatic vessel formation. Interestingly, one of the most important components of the mast cell cargo, the serine protease tryptase, is a potent angiogenic factor, and elevated serum tryptase levels correlate with bad prognosis in breast cancer patients. Likewise, histamine is known to induce tumor cell proliferation and tumor growth. In agreement, mast cell depletion reduces the size of mammary tumors and metastasis in murine models that spontaneously develop breast cancer. In this review, we will discuss the evidence supporting protumoral and antitumoral roles of mast cells, emphasizing recent findings placing mast cells as important drivers of tumor progression, as well as the potential use of these cells or their mediators as therapeutic targets.

Mel-18 controls the enrichment of tumor-initiating cells in SP fraction in mouse breast cancer.

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Janakiraman, Harinarayanan; Nobukiyo, Asako; Inoue, Hiroko; Kanno, Masamoto

2011-06-01

Side population (SP) cell analysis has been used to identify and isolate a minor population of cells with stem cell properties in normal tissues and in many cancers including breast cancer cells. However, the molecular mechanisms that operate in tumor-initiating cells (TICs) in SP fraction remain unclear. The Polycomb group genes, including Bmi1 and Mel-18, have been implicated in the maintenance of hematopoietic stem cells (HSCs) and suggested to be oncogenic and tumor suppressive, respectively, in breast cancer. In this study, we determined the critical role of Mel-18 in the enrichment mechanisms of TICs with the SP phenotype in a mouse breast cancer cell line, MMK3, that was established from a breast cancer developed spontaneously in Mel-18+/- mice. The Mel-18 protein expression level significantly correlates to the percentage of SP fraction in the mouse breast cancer cell line MMK3 series. The comparison between MMK3V3 (V3) cells containing one copy of the Mel-18 gene and MMK3S2 (S2) cells having twice the amount of Mel-18 expression clearly demonstrates the above relationship. Similar results obtained with the percentage of ALDH+ cells in V3 and S2 further confirmed the correlation between protein expression level of Mel-18 and the TICs. More importantly, transplantation of SP and non-SP cells of V3 and S2 cells into the NOD/SCID mice clearly showed that the heterozygous level of Mel-18 leads to the disappearance of enrichment of TICs into SP fraction in vivo. Stem cell pathway focused gene expression profiling of V3 and S2 cells revealed that the genes Abcg2, Aldh1a1 and Dhh were highly down-regulated in V3 compared to S2. These results indicate that the precise Mel-18 expression level controls TIC enrichment mechanisms through the regulation of channel molecule of Abcg2 and functional TIC marker of Aldhlal. In conclusion, our findings revealed the significance of fine-tuning mechanisms for Mel-18 protein expression level in the maintenance of TIC into SP

Discrimination of Breast Tumors in Ultrasonic Images by Classifier Ensemble Trained with AdaBoost

Science.gov (United States)

Takemura, Atsushi; Shimizu, Akinobu; Hamamoto, Kazuhiko

In this paper, we propose a novel method for acurate automated discrimination of breast tumors (carcinoma, fibroadenoma, and cyst). We defined 199 features related to diagnositic observations noticed when a doctor judges breast tumors, such as internal echo, shape, and boundary echo. These features included novel features based on a parameter of log-compressed K distribution, which reflect physical characteristics of ultrasonic B-mode imaging. Furthermore, we propose a discrimination method of breast tumors by using an ensemble classifier based on the multi-class AdaBoost algorithm with effective features selection. Verification by analyzing 200 carcinomas, 30 fibroadenomas and 30 cycts showed the usefulness of the newly defined features and the effectiveness of the discrimination by using an ensemble classifier trained by AdaBoost.

The effects and mechanisms of SLC34A2 on maintaining stem cell-like phenotypes in CD147+ breast cancer stem cells.

Science.gov (United States)

Lv, Yonggang; Wang, Ting; Fan, Jing; Zhang, Zhenzhen; Zhang, Juliang; Xu, Cheng; Li, Yongping; Zhao, Ge; He, Chenyang; Meng, Huimin; Yang, Hua; Wang, Zhen; Liu, Jiayun; Chen, Jianghao; Wang, Ling

2017-04-01

The cancer stem cell (CSC) hypothesis has gained significant recognition in describing tumorigenesis. Identification of the factors critical to development of breast cancer stem cells (BCSCs) may provide insight into the improvement of effective therapies against breast cancer. In this study, we aim to investigate the biological function of SLC34A2 in affecting the stem cell-like phenotypes in BCSCs and its underlying mechanisms. We demonstrated that CD147 + cells from breast cancer tissue samples and cell lines possessed BCSC-like features, including the ability of self-renewal in vitro, differentiation, and tumorigenic potential in vivo. Flow cytometry analysis showed the presence of a variable fraction of CD147 + cells in 9 of 10 tumor samples. Significantly, SLC34A2 expression in CD147 + BCSCs was enhanced compared with that in differentiated adherent progeny of CD147 + BCSCs and adherently cultured cell line cells. In breast cancer patient cohorts, SLC34A2 expression was found increased in 9 of 10 tumor samples. By using lentiviral-based approach, si-SLC34A2-transduced CD147 + BCSCs showed decreased ability of sphere formation, cell viability in vitro, and tumorigenicity in vivo, which suggested the essential role of SLC34A2 in CD147 + BCSCs. Furthermore, PI3K/AKT pathway and SOX2 were found necessary to maintain the stemness of CD147 + BCSCs by using LY294002 or lentiviral-si-SOX2. Finally, we indicated that SLC34A2 could regulate SOX2 to maintain the stem cell-like features in CD147 + BCSCs through PI3K/AKT pathway. Therefore, our report identifies a novel role of SLC34A2 in BCSCs' state regulation and establishes a rationale for targeting the SLC34A2/PI3K/AKT/SOX2 signaling pathway for breast cancer therapy.

Endothelial cells provide a notch-dependent pro-tumoral niche for enhancing breast cancer survival, stemness and pro-metastatic properties.

Directory of Open Access Journals (Sweden)

Pegah Ghiabi

Full Text Available Treating metastasis has been challenging due to tumors complexity and heterogeneity. This complexity is partly related to the crosstalk between tumor and its microenvironment. Endothelial cells -the building blocks of tumor vasculature- have been shown to have additional roles in cancer progression than angiogenesis and supplying oxygen and nutrients. Here, we show an alternative role for endothelial cells in supporting breast cancer growth and spreading independent of their vascular functions. Using endothelial cells and breast cancer cell lines MDA-MB231 and MCF-7, we developed co-culture systems to study the influence of tumor endothelium on breast tumor development by both in vitro and in vivo approaches. Our results demonstrated that endothelial cells conferred survival advantage to tumor cells under complete starvation and enriched the CD44HighCD24Low/- stem cell population in tumor cells. Moreover, endothelial cells enhanced the pro-metastatic potential of breast cancer cells. The in vitro and in vivo results concordantly confirmed a role for endothelial Jagged1 to promote breast tumor through notch activation. Here, we propose a role for endothelial cells in enhancing breast cancer progression, stemness, and pro-metastatic traits through a perfusion-independent manner. Our findings may be beneficial in developing novel therapeutic approaches.

Breast Cancer Methylomes Establish an Epigenomic Foundation for Metastasis

Science.gov (United States)

Fang, Fang; Turcan, Sevin; Rimner, Andreas; Kaufman, Andrew; Giri, Dilip; Morris, Luc G. T.; Shen, Ronglai; Seshan, Venkatraman; Mo, Qianxing; Heguy, Adriana; Baylin, Stephen B.; Ahuja, Nita; Viale, Agnes; Massague, Joan; Norton, Larry; Vahdat, Linda T.; Moynahan, Mary Ellen; Chan, Timothy A.

2011-01-01

Cancer-specific alterations in DNA methylation are hallmarks of human malignancies; however, the nature of the breast cancer epigenome and its effects on metastatic behavior remain obscure. To address this issue, we used genome-wide analysis to characterize the methylomes of breast cancers with diverse metastatic behavior. Groups of breast tumors were characterized by the presence or absence of coordinate hypermethylation at a large number of genes, demonstrating a breast CpG island methylator phenotype (B-CIMP). The B-CIMP provided a distinct epigenomic profile and was a strong determinant of metastatic potential. Specifically, the presence of the B-CIMP in tumors was associated with low metastatic risk and survival, and the absence of the B-CIMP was associated with high metastatic risk and death. B-CIMP loci were highly enriched for genes that make up the metastasis transcriptome. Methylation at B-CIMP genes accounted for much of the transcriptomal diversity between breast cancers of varying prognosis, indicating a fundamental epigenomic contribution to metastasis. Comparison of the loci affected by the B-CIMP with those affected by the hypermethylator phenotype in glioma and colon cancer revealed that the CIMP signature was shared by multiple human malignancies. Our data provide a unifying epigenomic framework linking breast cancers with varying outcome and transcriptomic changes underlying metastasis. These findings significantly enhance our understanding of breast cancer oncogenesis and aid the development of new prognostic biomarkers for this common malignancy. PMID:21430268

External Beam Accelerated Partial-Breast Irradiation Using 32 Gy in 8 Twice-Daily Fractions: 5-Year Results of a Prospective Study

International Nuclear Information System (INIS)

Pashtan, Itai M.; Recht, Abram; Ancukiewicz, Marek; Brachtel, Elena; Abi-Raad, Rita F.; D'Alessandro, Helen A.; Levy, Antonin; Wo, Jennifer Y.; Hirsch, Ariel E.; Kachnic, Lisa A.; Goldberg, Saveli; Specht, Michelle; Gadd, Michelle; Smith, Barbara L.; Powell, Simon N.; Taghian, Alphonse G.

2012-01-01

Purpose: External beam accelerated partial breast irradiation (APBI) is an increasingly popular technique for treatment of patients with early stage breast cancer following breast-conserving surgery. Here we present 5-year results of a prospective trial. Methods and Materials: From October 2003 through November 2005, 98 evaluable patients with stage I breast cancer were enrolled in the first dose step (32 Gy delivered in 8 twice-daily fractions) of a prospective, multi-institutional, dose escalation clinical trial of 3-dimensional conformal external beam APBI (3D-APBI). Median age was 61 years; median tumor size was 0.8 cm; 89% of tumors were estrogen receptor positive; 10% had a triple-negative phenotype; and 1% had a HER-2-positive subtype. Median follow-up was 71 months (range, 2-88 months; interquartile range, 64-75 months). Results: Five patients developed ipsilateral breast tumor recurrence (IBTR), for a 5-year actuarial IBTR rate of 5% (95% confidence interval [CI], 1%-10%). Three of these cases occurred in patients with triple-negative disease and 2 in non-triple-negative patients, for 5-year actuarial IBTR rates of 33% (95% CI, 0%-57%) and 2% (95% CI, 0%-6%; P<.0001), respectively. On multivariable analysis, triple-negative phenotype was the only predictor of IBTR, with borderline statistical significance after adjusting for tumor grade (P=.0537). Conclusions: Overall outcomes were excellent, particularly for patients with estrogen receptor-positive disease. Patients in this study with triple-negative breast cancer had a significantly higher IBTR rate than patients with other receptor phenotypes when treated with 3D-APBI. Larger, prospective 3D-APBI clinical trials should continue to evaluate the effect of hormone receptor phenotype on IBTR rates.

External Beam Accelerated Partial-Breast Irradiation Using 32 Gy in 8 Twice-Daily Fractions: 5-Year Results of a Prospective Study

Energy Technology Data Exchange (ETDEWEB)

Pashtan, Itai M. [Harvard Radiation Oncology Program, Boston, Massachusetts (United States); Recht, Abram [Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts (United States); Ancukiewicz, Marek [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Brachtel, Elena [Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts (United States); Abi-Raad, Rita F. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); D' Alessandro, Helen A. [Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts (United States); Levy, Antonin; Wo, Jennifer Y. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Hirsch, Ariel E. [Department of Radiation Oncology, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts (United States); Kachnic, Lisa A. [Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts (United States); Goldberg, Saveli [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Specht, Michelle; Gadd, Michelle; Smith, Barbara L. [Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts (United States); Powell, Simon N. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Taghian, Alphonse G., E-mail: ataghian@partners.org [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States)

2012-11-01

Purpose: External beam accelerated partial breast irradiation (APBI) is an increasingly popular technique for treatment of patients with early stage breast cancer following breast-conserving surgery. Here we present 5-year results of a prospective trial. Methods and Materials: From October 2003 through November 2005, 98 evaluable patients with stage I breast cancer were enrolled in the first dose step (32 Gy delivered in 8 twice-daily fractions) of a prospective, multi-institutional, dose escalation clinical trial of 3-dimensional conformal external beam APBI (3D-APBI). Median age was 61 years; median tumor size was 0.8 cm; 89% of tumors were estrogen receptor positive; 10% had a triple-negative phenotype; and 1% had a HER-2-positive subtype. Median follow-up was 71 months (range, 2-88 months; interquartile range, 64-75 months). Results: Five patients developed ipsilateral breast tumor recurrence (IBTR), for a 5-year actuarial IBTR rate of 5% (95% confidence interval [CI], 1%-10%). Three of these cases occurred in patients with triple-negative disease and 2 in non-triple-negative patients, for 5-year actuarial IBTR rates of 33% (95% CI, 0%-57%) and 2% (95% CI, 0%-6%; P<.0001), respectively. On multivariable analysis, triple-negative phenotype was the only predictor of IBTR, with borderline statistical significance after adjusting for tumor grade (P=.0537). Conclusions: Overall outcomes were excellent, particularly for patients with estrogen receptor-positive disease. Patients in this study with triple-negative breast cancer had a significantly higher IBTR rate than patients with other receptor phenotypes when treated with 3D-APBI. Larger, prospective 3D-APBI clinical trials should continue to evaluate the effect of hormone receptor phenotype on IBTR rates.

Circulating tumor cells, disease recurrence and survival in newly diagnosed breast cancer

NARCIS (Netherlands)

Franken, Bas; De Groot, Marco R.; Mastboom, Walter J.B.; Vermes, I.; van der Palen, Jacobus Adrianus Maria; Tibbe, Arjan G.J.; Terstappen, Leonardus Wendelinus Mathias Marie

2012-01-01

Introduction The presence of circulating tumor cells (CTC) is an independent prognostic factor for progression-free survival and breast cancer-related death (BRD) for patients with metastatic breast cancer beginning a new line of systemic therapy. The current study was undertaken to explore whether

Lentivirus mediated RNA interference of EMMPRIN (CD147) gene inhibits the proliferation, matrigel invasion and tumor formation of breast cancer cells.

Science.gov (United States)

Yang, Jing; Wang, Rong; Li, Hongjiang; Lv, Qing; Meng, Wentong; Yang, Xiaoqin

2016-07-08

Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN) or cluster of differentiation 147 (CD147), a glycoprotein enriched on the plasma membrane of tumor cells, promotes proliferation, invasion, metastasis, and survival of malignant tumor cells. In this study, we sought to examine the expression of EMMPRIN in breast tumors, and to identify the potential roles of EMMPRIN on breast cancer cells. EMMPRIN expression in breast cancer tissues was assessed by immunohistochemistry. We used a lentivirus vector-based RNA interference (RNAi) approach expressing short hairpin RNA (shRNA) to knockdown EMMPRIN gene in breast cancer cell lines MDA-MB-231 and MCF-7. In vitro, Cell proliferative, invasive potential were determined by Cell Counting Kit (CCK-8), cell cycle analysis and matrigel invasion assay, respectively. In vivo, tumorigenicity was monitored by inoculating tumor cells into breast fat pad of female nude mice. EMMPRIN was over-expressed in breast tumors and breast cancer cell lines. Down-regulation of EMMPRIN by lentivirus vector-based RNAi led to decreased cell proliferative, decreased matrigel invasion in vitro, and attenuated tumor formation in vivo. High expression of EMMPRIN plays a crucial role in breast cancer cell proliferation, matrigel invasion and tumor formation.

Pattern of Ipsilateral Breast Tumor Recurrence After Breast-Conserving Therapy

International Nuclear Information System (INIS)

Jobsen, Jan; Palen, Job van der; Riemersma, Sietske; Heijmans, Harald; Ong, Francisca; Struikmans, Henk

2014-01-01

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

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.

Predictive genomics: a cancer hallmark network framework for predicting tumor clinical phenotypes using genome sequencing data.

Science.gov (United States)

Wang, Edwin; Zaman, Naif; Mcgee, Shauna; Milanese, Jean-Sébastien; Masoudi-Nejad, Ali; O'Connor-McCourt, Maureen

2015-02-01

Tumor genome sequencing leads to documenting thousands of DNA mutations and other genomic alterations. At present, these data cannot be analyzed adequately to aid in the understanding of tumorigenesis and its evolution. Moreover, we have little insight into how to use these data to predict clinical phenotypes and tumor progression to better design patient treatment. To meet these challenges, we discuss a cancer hallmark network framework for modeling genome sequencing data to predict cancer clonal evolution and associated clinical phenotypes. The framework includes: (1) cancer hallmarks that can be represented by a few molecular/signaling networks. 'Network operational signatures' which represent gene regulatory logics/strengths enable to quantify state transitions and measures of hallmark traits. Thus, sets of genomic alterations which are associated with network operational signatures could be linked to the state/measure of hallmark traits. The network operational signature transforms genotypic data (i.e., genomic alterations) to regulatory phenotypic profiles (i.e., regulatory logics/strengths), to cellular phenotypic profiles (i.e., hallmark traits) which lead to clinical phenotypic profiles (i.e., a collection of hallmark traits). Furthermore, the framework considers regulatory logics of the hallmark networks under tumor evolutionary dynamics and therefore also includes: (2) a self-promoting positive feedback loop that is dominated by a genomic instability network and a cell survival/proliferation network is the main driver of tumor clonal evolution. Surrounding tumor stroma and its host immune systems shape the evolutionary paths; (3) cell motility initiating metastasis is a byproduct of the above self-promoting loop activity during tumorigenesis; (4) an emerging hallmark network which triggers genome duplication dominates a feed-forward loop which in turn could act as a rate-limiting step for tumor formation; (5) mutations and other genomic alterations have

99mTc-HYNIC-(tricine/EDDA)-FROP peptide for MCF-7 breast tumor targeting and imaging.

Science.gov (United States)

Ahmadpour, Sajjad; Noaparast, Zohreh; Abedi, Seyed Mohammad; Hosseinimehr, Seyed Jalal

2018-02-19

Breast cancer is the most common malignancy among women in the world. Development of novel tumor-specific radiopharmaceuticals for early breast tumor diagnosis is highly desirable. In this study we developed 99m Tc-HYNIC-(tricine/EDDA)-Lys-FROP peptide with the ability of specific binding to MCF-7 breast tumor. The FROP-1 peptide was conjugated with the bifunctional chelator hydrazinonicotinamide (HYNIC) and labeled with 99m Tc using tricine/EDDA co-ligand. The cellular specific binding of 99m Tc-HYNIC-FROP was evaluated on different cell lines as well as with blocking experiment on MCF-7 (human breast adenocarcinoma). The tumor targeting and imaging of this labeled peptide were performed on MCF-7 tumor bearing mice. Radiochemical purity for 99m Tc-HYNIC-(tricine/EDDA)-FROP was 99% which was determined with ITLC method. This radiolabeled peptide showed high stability in normal saline and serum about 98% which was monitored with HPLC method. In saturation binding experiments, the binding constant (K d ) to MCF-7 cells was determined to be 158 nM. Biodistribution results revealed that the 99m Tc-HYNIC-FROP was mainly exerted from urinary route. The maximum tumor uptake was found after 30 min post injection (p.i.); however maximum tumor/muscle ratio was seen at 15 min p.i. The tumor uptake of this labeled peptide was specific and blocked by co-injection of excess FROP. According to the planar gamma imaging result, tumor was clearly visible due to the tumor uptake of 99m Tc-HYNIC-(tricine/EDDA)-FROP in mouse after 15 min p.i. The 99m Tc-HYNIC-(tricine/EDDA)-FROP is considered a promising probe with high specific binding to MCF-7 breast cancer cells.

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

International Nuclear Information System (INIS)

Charpentier, Monica; Martin, Stuart

2013-01-01

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

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.

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...

Sunitinib significantly suppresses the proliferation, migration, apoptosis resistance, tumor angiogenesis and growth of triple-negative breast cancers but increases breast cancer stem cells.

Science.gov (United States)

Chinchar, Edmund; Makey, Kristina L; Gibson, John; Chen, Fang; Cole, Shelby A; Megason, Gail C; Vijayakumar, Srinivassan; Miele, Lucio; Gu, Jian-Wei

2014-01-01

The majority of triple-negative breast cancers (TNBCs) are basal-like breast cancers. However there is no reported study on anti-tumor effects of sunitinib in xenografts of basal-like TNBC (MDA-MB-468) cells. In the present study, MDA-MB-231, MDA-MB-468, MCF-7 cells were cultured using RPMI 1640 media with 10% FBS. Vascular endothelia growth factor (VEGF) protein levels were detected using ELISA (R & D Systams). MDA-MB-468 cells were exposed to sunitinib for 18 hours for measuring proliferation (3H-thymidine incorporation), migration (BD Invasion Chamber), and apoptosis (ApopTag and ApoScreen Anuexin V Kit). The effect of sunitinib on Notch-1 expression was determined by Western blot in cultured MDA-MB-468 cells. 10(6) MDA-MB-468 cells were inoculated into the left fourth mammary gland fat pad in athymic nude-foxn1 mice. When the tumor volume reached 100 mm(3), sunitinib was given by gavage at 80 mg/kg/2 days for 4 weeks. Tumor angiogenesis was determined by CD31 immunohistochemistry. Breast cancer stem cells (CSCs) isolated from the tumors were determined by flow cytometry analysis using CD44(+)/CD24(-) or low. ELISA indicated that VEGF was much more highly expressed in MDA-MB-468 cells than MDA-MB-231 and MCF-7 cells. Sunitinib significantly inhibited the proliferation, invasion, and apoptosis resistance in cultured basal like breast cancer cells. Sunitinib significantly increased the expression of Notch-1 protein in cultured MDA-MB-468 or MDA-MB-231 cells. The xenograft models showed that oral sunitinib significantly reduced the tumor volume of TNBCs in association with the inhibition of tumor angiogeneisis, but increased breast CSCs. These findings support the hypothesis that the possibility should be considered of sunitinib increasing breast CSCs though it inhibits TNBC tumor angiogenesis and growth/progression, and that effects of sunitinib on Notch expression and hypoxia may increase breast cancer stem cells. This work provides the groundwork for an

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.

The Potential of Circulating Tumor Cells in Personalized Management of Breast Cancer: A Systematic Review

Directory of Open Access Journals (Sweden)

Fatemeh Khatami

2017-03-01

Full Text Available Circulating tumor cells (CTCs recognition and characterization in the peripheral blood of patients with breast cancer have proven practical and predictive value in different studies. However, the clinical significance of CTCs enumeration and molecular characterization in thepersonalization of breast cancer diagnosis and treatment remains under the debate. A literature search in PubMed, Web of Science and Scopus was performed from October 1990 to June 2016 for studies which evaluating CTCs and its association with clinical and pathological characteristics and medical outcome in the field of breast cancer personalization for both diagnosis and treatment categories. The treatment outcomes were progression-free survival (PFS and overall survival (OS or relapse in different patients. Sixty-nine studies met the inclusion criteria. The sample size varies from 1 to 2026. Median follow-up was 15 months (range 3-27. Different molecular techniques have been applied toresearch, but they mostly are based on CTCs enrichment and then detection by using FDA-approved Cell SearchTM. By far the most studies define CTCs as cytokeratins (CK positive and CD45 negative cells. Despite the differences in methodology, twenty-eight studies for breast cancer diagnosis and prognosis were mainly focused on CTCs isolation and enumeration.Forty-threeresearches were about CTCs count and exact molecular characterization. In the way of precision treatment, CTCs detection before starting the first-line of therapy or during therapy in breast cancer patients is extremely valuable, but in the way of precision medicine it should be supported with some molecular characteristics of CTCs like CTCs phenotypic changes, gene expression analysis of CTCs and molecular characteristics of CTCs.

Induction of erythropoiesis by hypoxia-inducible factor prolyl hydroxylase inhibitors without promotion of tumor initiation, progression, or metastasis in a VEGF-sensitive model of spontaneous breast cancer

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Seeley TW

2017-03-01

Full Text Available Todd W Seeley, Mark D Sternlicht, Stephen J Klaus, Thomas B Neff, David Y Liu Therapeutics R&D, FibroGen, Inc., San Francisco, CA, USA Abstract: The effects of pharmacological hypoxia-inducible factor (HIF stabilization were investigated in the MMTV-Neundl-YD5 (NeuYD mouse model of breast cancer. This study first confirmed the sensitivity of this model to increased vascular endothelial growth factor (VEGF, using bigenic NeuYD;MMTV-VEGF-25 mice. Tumor initiation was dramatically accelerated in bigenic animals. Bigenic tumors were also more aggressive, with shortened doubling times and increased lung metastasis as compared to NeuYD controls. In separate studies, NeuYD mice were treated three times weekly from 7 weeks of age until study end with two different HIF prolyl hydroxylase inhibitors (HIF-PHIs, FG-4497 or roxadustat (FG-4592. In NeuYD mice, HIF-PHI treatments elevated erythropoiesis markers, but no differences were detected in tumor onset or the phenotypes of established tumors. Keywords: cancer progression, erythropoiesis, hypoxia-inducible factor, hypoxia-inducible factor prolyl hydroxylase inhibitors, vascular endothelial growth factor, MMTV-Neu breast cancer model

Rapid and sensitive phenotypic marker detection on breast cancer cells using surface-enhanced Raman scattering (SERS) imaging.

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Lee, Sangyeop; Chon, Hyangah; Lee, Jiyoung; Ko, Juhui; Chung, Bong Hyun; Lim, Dong Woo; Choo, Jaebum

2014-01-15

We report a surface-enhanced Raman scattering (SERS)-based cellular imaging technique to detect and quantify breast cancer phenotypic markers expressed on cell surfaces. This technique involves the synthesis of SERS nano tags consisting of silica-encapsulated hollow gold nanospheres (SEHGNs) conjugated with specific antibodies. Hollow gold nanospheres (HGNs) enhance SERS signal intensity of individual particles by localizing surface electromagnetic fields through pinholes in the hollow particle structures. This capacity to enhance imaging at the level of single molecules permits the use of HGNs to detect specific biological markers expressed in living cancer cells. In addition, silica encapsulation greatly enhances the stability of nanoparticles. Here we applied a SERS-based imaging technique using SEHGNs in the multiplex imaging of three breast cancer cell phenotypes. Expression of epidermal growth factor (EGF), ErbB2, and insulin-like growth factor-1 (IGF-1) receptors were assessed in the MDA-MB-468, KPL4 and SK-BR-3 human breast cancer cell lines. SERS imaging technology described here can be used to test the phenotype of a cancer cell and quantify proteins expressed on the cell surface simultaneously. Based on results, this technique may enable an earlier diagnosis of breast cancer than is currently possible and offer guidance in treatment. © 2013 Elsevier B.V. All rights reserved.

Primary tumor resection in metastatic breast cancer: A propensity-matched analysis, 1988-2011 SEER data base.

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Vohra, Nasreen A; Brinkley, Jason; Kachare, Swapnil; Muzaffar, Mahvish

2018-03-02

Primary tumor resection (PTR) in metastatic breast cancer is not a standard treatment modality, and its impact on survival is conflicting. The primary objective of this study was to analyze impact of PTR on survival in metastatic patients with breast cancer. A retrospective study of metastatic patients with breast cancer was conducted using the 1988-2011 Surveillance, Epidemiology, and End Results (SEER) data base. Cox proportional hazards regression models were used to evaluate the relationship between PTR and survival and to adjust for the heterogeneity between the groups, and a propensity score-matched analysis was also performed. A total of 29 916 patients with metastatic breast cancer were included in the study, and 15 129 (51%) of patients underwent primary tumor resection, and 14 787 (49%) patients did not undergo surgery. Overall, decreasing trend in PTR for metastatic breast cancer in last decades was noted. Primary tumor resection was associated with a longer median OS (34 vs 18 months). In a propensity score-matched analysis, prognosis was also more favorable in the resected group (P = .0017). Primary tumor resection in metastatic breast cancer was associated with survival improvement, and the improvement persisted in propensity-matched analysis. © 2018 Wiley Periodicals, Inc.

Circulating tumor DNA for triple-negative breast cancer diagnosis and treatment decisions.

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Saliou, Adrien; Bidard, François-Clément; Lantz, Olivier; Stern, Marc-Henri; Vincent-Salomon, Anne; Proudhon, Charlotte; Pierga, Jean-Yves

2016-01-01

Triple-negative breast cancer (TNBC) is a highly aggressive disease characterized by a high number of relapses and poor overall survival. The heterogeneity of the disease and the limited treatment options compared to other breast cancer subtypes mainly explain these clinical outcomes. New biomarkers are urgently needed to improve the management of TNBC. Circulating tumor DNA, identified by tumor-related molecular alterations, could be used in the context of non-invasive "liquid biopsy" and help in TNBC diagnosis and treatment decisions. In this review, we discuss the key issues related to the potential of circulating tumor DNA to improve the management of this disease and the future steps to overcome before its implementation into clinical routine within the next 5 years.

Correlation of primary tumor FDG uptake with clinicopathologic prognostic factors in invasive ductal carcinoma of the breast

International Nuclear Information System (INIS)

Jo, I; Kim, Sung Hoon; Kim, Hae Won; Kang, Sung Hee; Zeon, Seok Kil; Kim, Su Jin

2015-01-01

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 (SUV max ) of the primary breast tumor was measured and compared with hormonal receptor and HER2 overexpression status. The high SUV max 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 SUV max 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

Reduction mammaplasty and radiation therapy can allow breast conservation in patients with breast cancers not initially treatable by tumor-ectomy

International Nuclear Information System (INIS)

Otmezguine, Y.; Calitchi, E.; Cothier, I.; Feuilhade, F.; Le Bourgeois, J.P.; Baruch, J.

1997-01-01

A protocol combining reduction mammaplasty (RM) and radiation therapy was developed as an alternative of mastectomy in patients with breast cancers larger than 3 cm in diameter. This protocol was used in 51 patients between 1983 and 1990. Indications were extensive microcalcifications (n = 17; 33 %) ; residual tumor after neo-adjuvant therapy larger than 4 cm in diameter (n 18 ; 35 %); extensive DCIS (n = 4; 8 %) or tumor located within an area of fibrocystic disease (n = 6; 12 %); presence of a bifocal lesion (n = 12 %. area of fibrocystic disease (n = 6; 12 %); and presence of bifocal lesion (n 6; 12 %). Surgery consisted of tumor-ectomy removing a wide margin of skin and mammary gland, followed by immediate remodeling of the breast, same-side axillary node clearance, and symmetrization of the other breast. A radiation dose of 45 Gy was delivered to the entire mammary gland. Adjuvant therapy was given before and/or after therapy according to the institution's routine breast cancer protocol. During the mean follow-up of 8.1 years, four patients (8 %) developed a local recurrence, which has treated surgically. The five-year disease-free survival rate was 76 %. The cosmetic result was good or very good in 78% of cases. RM plus RT is a reasonable alternative to mastectomy in patients with large breast cancers, although further work is needed to refine its indications. (authors)

Contrast-enhanced color Doppler US in breast cancer: Tumoral vascularity correlated with angiogenesis

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Kim, Eun A; Yoon, Kwon Ha; Yun, Ki Jung; Lee, Kwang Man; Park, Ki Han; Juhng, Seon Kwan; Won, Jong Jin [Wonkwang University School of Medicine, Seoul (Korea, Republic of)

2000-12-15

To evaluate the effects of contrast-enhanced color Doppler ultrasonography (CDUS) on the depiction of vascularity and flow pattern in breast cancer and to determine the relationship between tumoral vascularity and angiogenesis. Twenty-one patients with breast cancer were prospectively evaluated with CDUS before and after injection of the contrast agent (SH U 508A, 2.5g, 300 mg/ml ). The tumoral vascularity was expressed as percentage of color Doppler area, which was measured quantitatively by a computerized program (Ultrasonic Imaging Tool; Soongsil University, Seoul, Korea). The flow pattern (four-patterns; spotty, linear, branching, marginal) of the vascularity was analyzed. After surgery, tumor angiogenesis was assessed by microvessel density. The relationship between the vascularity on CDUS and microvessel density was statistically analyzed. At unenhanced CDUS, tumoral flow signals were detected in 12 lesions (48%); at contrast-enhanced CDUS, 18 lesions (86%). All These 18 lesions showed increased signals, compared with those at unenhanced CDUS. The percentage color Doppler area was 1.86 {+-} 0.48% at unenhanced CDUS and 5.23 {+-} 1.18% at contrast-enhanced CDUS. The flow patterns before contrast injection were spotty pattern in 11 tumors and linear pattern in one; after contrast injection, spotty in 8, linear in 4, branching in 5, and marginal in one. The tumoral vascularity at contrast-enhanced CDUS showed no significant correlation with microvessel density. Contrast-enhanced CDUS seems to be a valuable tool in the depiction of vascularity and characterization of flow pattern in breast cancer. However, tumoral vascularity on CDUS may not reflect tumoral angiogenesis.

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

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Debbie Liao

2009-11-01

Full Text Available 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.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.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.

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

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Liao, Debbie; Luo, Yunping; Markowitz, Dorothy; Xiang, Rong; Reisfeld, Ralph A

2009-11-23

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. 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. 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.

Lactate Transporters Expression in Tumor of Balb/c Mice Bearing Breast Cancer after Endurance Training

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M Aveseh

2014-10-01

Full Text Available Background & aim: Changes in the metabolism of cancer cells plays a major role in the survival and their expansion. The aim of this study was to determine expression of lactate transmitters in Balb/c mice with breast cancer after endurance training. Methods: In this experimental study twenty-five Balb C mice were randomly divided into two groups of breast cancer control (N=13 and breast cancer training (N=12. Breast cancer was induced in mammary fat pad by injection of cancer cells (MC4L2 in mice and endurance training protocol was applied for 7 weeks in the experimental group. Tumor volume and MCT1, MCT4, and CD147 expression were measured by micro digital caliper and western blotting technique respectively. Data were analyzed statistically using Student t and Pearson. Results: Significant decreases was found in weight and CD147 expression of tumor after 7 weeks of endurance training in the exercise group compared to the control group. No significant differences were seen in MCT4 expression and tumor volume between the groups (05 / 0p>0.05. Significant correlation was found between tumor MCT1 and CD147 expression (P < 0.05, while the relationship between MCT4 and CD147 expression in tumors was not statistically significant. Conclusion: Endurance training can reduce lactate metabolism in cancer cells through suppression of lactate transporters expression and provides a useful tool in breast cancer treatment or prevention.

Technical evaluation of Virtual Touch™ tissue quantification and elastography in benign and malignant breast tumors

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JIANG, QUAN; ZHANG, YUAN; CHEN, JIAN; ZHANG, YUN-XIAO; HE, ZHU

2014-01-01

The aim of this study was to investigate the diagnostic value of the Virtual Touch™ tissue quantification (VTQ) and elastosonography technologies in benign and malignant breast tumors. Routine preoperative ultrasound, elastosonography and VTQ examinations were performed on 86 patients with breast lesions. The elastosonography score and VTQ speed grouping of each lesion were measured and compared with the pathological findings. The difference in the elastosonography score between the benign and malignant breast tumors was statistically significant (Pbenign and malignant tumors was also statistically significant (P<0.05). In addition, the diagnostic accuracy of conventional ultrasound, elastosonography, VTQ technology and the combined methods showed statistically significant differences (P<0.05). The use of the three technologies in combination significantly improved the diagnostic accuracy to 91.86%. In conclusion, the combination of conventional ultrasound, elastosonography and VTQ technology can significantly improve accuracy in the diagnosis of breast cancer. PMID:25187797

Effect of Depleting Tumor-Associated Macrophages on Breast Cancer Growth and Response to Chemotherapy

National Research Council Canada - National Science Library

Tsan, Min-Fu; Gao, Baochong

2005-01-01

.... and whether depletion of tumor-associated macrophages has any effect on the tumor growth. The breast cancer model was established in BALB/c mice by subcutaneous injection of estrogen receptor-positive murine mammary tumor cells (4T1...

Post-mastectomy radiation in large node-negative breast tumors: Does size really matter?

International Nuclear Information System (INIS)

Floyd, Scott R.; Taghian, Alphonse G.

2009-01-01

Treatment decisions regarding local control can be particularly challenging for T3N0 breast tumors because of difficulty in estimating rates of local failure after mastectomy. Reports in the literature detailing the rates of local failure vary widely, likely owing to the uncommon incidence of this clinical situation. The literature regarding this clinical scenario is reviewed, including recent reports that specifically address the issue of local failure rates after mastectomy in the absence of radiation for large node-negative breast tumors.

Characterization of estrogen receptor-negative/progesterone receptor-positive breast cancer.

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Shen, Tiansheng; Brandwein-Gensler, Margaret; Hameed, Omar; Siegal, Gene P; Wei, Shi

2015-11-01

Despite the controversies, estrogen receptor-negative/progesterone receptor-positive (ER-/PR+) breast cancers have a reported incidence of 1% to 4%. These tumors are less well defined, and it is unclear whether ER-/PR+ represents a distinct subtype. Thus, we analyzed 5374 consecutive breast cancers to characterize the clinicopathological features of this underrecognized subset of tumors. The ER-/PR+ tumors, constituting 2.3% of the total, were mostly high grade and significantly seen in younger patients and African American women when compared with the ER+/PR+ and ER+/PR- groups, but similar to that of ER-/PR- phenotype (P < .0001). A significantly prolonged relapse-free survival (RFS) was associated with the ER+/PR+ subtype when compared with the ER+/PR- (P = .0002) or ER-/PR+ (P = .0004) tumors, whereas all 3 groups showed a superior outcome to that of the ER-/PR- phenotype. In the subset of patients receiving endocrine therapy, those with ER+/PR+ tumors had a significantly prolonged RFS (P = .001) and disease-specific survival (P = .005) when compared with the group with an ER+/PR- phenotype, but did not significantly differ from those with ER-/PR+ tumors. No significant survival advantage was found between the ER+/PR- and ER-/PR+ tumors in any group of patients analyzed. Furthermore, a higher PR expression was associated with a favorable RFS and disease-specific survival in the patients with ER-/PR+ tumors. Therefore, the ER-/PR+ tumors demonstrate a similar, if not higher than, response rate to endocrine therapy when compared with the ER+/PR- tumors and thus are important to identify. Routine PR testing remains necessary in assisting clinical decision making in the pursuit of precision medicine. Copyright © 2015 Elsevier Inc. All rights reserved.

Irradiation of the tumor bed alone after lumpectomy in selected patients with early stage breast cancer treated with breast conserving therapy

International Nuclear Information System (INIS)

Vicini, F.; Chen, P; Benitez, P.; Johnson, P.; Gustafson, G.; Horwitz, E.; McCarthy, K.; Lacerna, M.; Goldstein, Neil; Martinez, A.

1997-01-01

Purpose: We present the initial findings of our in-house protocol treating the tumor bed alone after lumpectomy with low dose rate (LDR) interstitial brachytherapy in selected patients with early stage breast cancer treated with breast conserving therapy (BCT). Materials and Methods: Since 1/1/93, 50 women with early stage breast cancer were entered into a protocol of tumor bed irradiation alone using an interstitial LDR implant. Patients were eligible if their tumor was an infiltrating ductal carcinoma ≤ 3 cm in maximum diameter, pathologic margins were clear by at least 2 mm, the tumor did not contain an extensive intraductal component, the axilla was surgically staged with ≤ 3 nodes involved with cancer, and a postoperative mammogram was performed. Implants were positioned using a template guide delivering 50 Gy over 96 hours to the lumpectomy bed plus a 1-2 cm margin. Local control, cosmetic outcome, and complications were assessed. Results: Patients ranged in age from 40 to 84 years (median 65). The median tumor size was 10 mm (range, 1-25). Seventeen patients (34%) had well differentiated tumors, 22 (4%) had moderately differentiated tumors, and in 11 (22%) the tumor was poorly differentiated. Forty-five patients (90%) were node negative while 5 (10%) had 1-3 positive nodes. A total of 23 (46%) patients were placed on tamoxifen and 3 (6%) received adjuvant systemic chemotherapy. No patient was lost to follow-up. The median follow-up is 40 months (range 29-50). No patient has experienced a local, regional, or distant failure. One patient died from colorectal carcinoma with no evidence of recurrent breast cancer. Good-to-excellent cosmetic results have been observed in all 50 patients (median cosmetic follow-up 36 months). No patient has experienced significant sequelae related to their implant. Conclusions: Early results with treatment of the tumor bed alone with a LDR interstitial implant appear promising. Long-term follow-up of these patients will be

Tissue microarrays for testing basal biomarkers in familial breast cancer cases

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Rozany Mucha Dufloth

Full Text Available CONTEXT AND OBJECTIVE: The proteins p63, p-cadherin and CK5 are consistently expressed by the basal and myoepithelial cells of the breast, although their expression in sporadic and familial breast cancer cases has yet to be fully defined. The aim here was to study the basal immunopro-file of a breast cancer case series using tissue microarray technology. DESIGN AND SETTING: This was a cross-sectional study at Universidade Estadual de Campinas, Brazil, and the Institute of Pathology and Mo-lecular Immunology, Porto, Portugal. METHODS: Immunohistochemistry using the antibodies p63, CK5 and p-cadherin, and also estrogen receptor (ER and Human Epidermal Receptor Growth Factor 2 (HER2, was per-formed on 168 samples from a breast cancer case series. The criteria for identifying women at high risk were based on those of the Breast Cancer Linkage Consortium. RESULTS: Familial tumors were more frequently positive for the p-cadherin (p = 0.0004, p63 (p < 0.0001 and CK5 (p < 0.0001 than was sporadic cancer. Moreover, familial tumors had coexpression of the basal biomarkers CK5+/ p63+, grouped two by two (OR = 34.34, while absence of coexpression (OR = 0.13 was associ-ated with the sporadic cancer phenotype. CONCLUSION: Familial breast cancer was found to be associated with basal biomarkers, using tissue microarray technology. Therefore, characterization of the familial breast cancer phenotype will improve the understanding of breast carcinogenesis.

"Mixed germ cell testicular tumor" in an adult female

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Udasimath Shivakumarswamy

2012-01-01

Full Text Available The androgen insensitivity (testicular feminization syndrome was described by Morris in phenotypic females with 46XY karyotype, presenting with primary amenorrhea, adequate breast development, and absent or scanty pubic or axillary hair. Gonads consist usually of seminiferous tubules without spermatogenesis. These patients have a 5-10% risk of developing germ cell tumors, usually after the complete development of secondary female sexual characteristics. We hereby report a case considered as a female with married life of 15 years, who was operated for severe abdominal pain. Phenotype characters were that of female. Microscopic examination of the tumor from the abdomen revealed germinoma and yolk sac tumor with adjacent seminiferous tubules. Karyotyping showed 46XY. Final diagnosis of malignant mixed germ cell tumor in androgen insensitivity syndrome was made. Surveillance may be the most appropriate option when these conditions are initially diagnosed in adulthood to prevent development of germ cell tumors.

Flame-broiled food, NAT2 acetylator phenotype, and breast cancer risk among women with benign breast disease.

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Gallicchio, Lisa; McSorley, Meghan A; Newschaffer, Craig J; Thuita, Lucy W; Argani, Pedram; Hoffman, Sandra C; Helzlsouer, Kathy J

2006-09-01

The objective of this study was to examine the association between flame-broiled food consumption, a source of heterocyclic amine exposure, and the development of breast cancer among cohort of women with benign breast disease (BBD). The variation of the association by acetylation phenotype, as determined by the genotypes of selected N-acetyltransferase 2 (NAT2) enzymes, was also examined. Among participants in an ongoing cohort study, 1187 women reported having a breast biopsy for BBD and completed a food frequency questionnaire. NAT2 G857A, NAT2 T341C, and NAT2 G590A genotypes were determined using DNA extracted from blood specimens collected in 1989. Incident cases of breast cancer were identified through linkage of the cohort participants with the Washington County Cancer Registry and the Maryland State Cancer Registry. Follow-up for the BBD cohort began at study entry in 1989 and ended on April 28, 2003. Of the women in this study, 77 subsequently developed breast cancer. Results showed that, among rapid acetylators, flame-broiled food intake was associated with a statistically significant increase in the risk of breast cancer (odds ratio (OR) 2.62; 95% confidence interval (CI) 1.06, 6.46). No association was observed between flame-broiled food intake and breast cancer among slow acetylators (OR 0.75; 95% CI 0.39, 1.43). These findings suggest that flame-broiled food may be a modifiable risk factor for the progression of BBD to invasive breast cancer among women who have genotypes consistent with rapid acetylation.

Double Feature: Carcinoma and Sarcoma Present in a Single Breast Tumor

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Catherine M. Stefaniuk

2012-01-01

Full Text Available Introduction. Primary breast sarcomas (PBSs are rare nonepithelial breast tumors compromised of mesenchymal mammary tissue. Although its rare nature has made the best mode of PBS treatment difficult to determine, it seems better to treat it more like a sarcoma creating clear negative margins verses breast carcinoma utilizing lumpectomy, partial mastectomy, and total mastectomy. Case. A 47-year-old obese Caucasian postmenopausal female G2P2 presents with a breast lump demonstrating a histological sample with a biphasic pattern consistent with both ductal carcinoma containing typical malignant epithelial cells and sarcomatous differentiation of carcinosarcoma. Conclusion. Carcinosarcoma is a rare breast malignancy. Sarcomas of the breast tend to be negative for estrogen receptor and lack known risk factors. Current recommended treatment is to treat breast sarcomas like other soft tissue sarcomas by performing wide local excision instead of partial mastectomy. Antiestrogens and other chemotherapeutic agents typically used in breast epithelial malignancies are not recommended since these sarcomas tend to be negative with these receptors.

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)

Bayerl, A.

2001-01-01

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

Confocal fluorescence microscopy for rapid evaluation of invasive tumor cellularity of inflammatory breast carcinoma core needle biopsies.

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Dobbs, Jessica; Krishnamurthy, Savitri; Kyrish, Matthew; Benveniste, Ana Paula; Yang, Wei; Richards-Kortum, Rebecca

2015-01-01

Tissue sampling is a problematic issue for inflammatory breast carcinoma, and immediate evaluation following core needle biopsy is needed to evaluate specimen adequacy. We sought to determine if confocal fluorescence microscopy provides sufficient resolution to evaluate specimen adequacy by comparing invasive tumor cellularity estimated from standard histologic images to invasive tumor cellularity estimated from confocal images of breast core needle biopsy specimens. Grayscale confocal fluorescence images of breast core needle biopsy specimens were acquired following proflavine application. A breast-dedicated pathologist evaluated invasive tumor cellularity in histologic images with hematoxylin and eosin staining and in grayscale and false-colored confocal images of cores. Agreement between cellularity estimates was quantified using a kappa coefficient. 23 cores from 23 patients with suspected inflammatory breast carcinoma were imaged. Confocal images were acquired in an average of less than 2 min per core. Invasive tumor cellularity estimated from histologic and grayscale confocal images showed moderate agreement by kappa coefficient: κ = 0.48 ± 0.09 (p confocal images require less than 2 min for acquisition and allow for evaluation of invasive tumor cellularity in breast core needle biopsy specimens with moderate agreement to histologic images. We show that confocal fluorescence microscopy can be performed immediately following specimen acquisition and could indicate the need for additional biopsies at the initial visit.

Predicting local recurrence following breast-conserving treatment: parenchymal signal enhancement ratio (SER) around the tumor on preoperative MRI

International Nuclear Information System (INIS)

Kim, Mi Young; Cho, Nariya; Koo, Hye Ryoung; Yun, Bo La; Bae, Min Sun; Moon, Woo Kyung; Chie, Eui Kyu

2013-01-01

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

Standardized assessment of tumor-infiltrating lymphocytes in breast cancer

DEFF Research Database (Denmark)

Tramm, Trine; Di Caterino, Tina; Jylling, Anne-Marie B

2018-01-01

INTRODUCTION: In breast cancer, there is a growing body of evidence that tumor-infiltrating lymphocytes (TILs) may have clinical utility and may be able to direct clinical decisions for subgroups of patients. Clinical utility is, however, not sufficient for warranting the implementation of a new...

Imaging-genomics reveals driving pathways of MRI derived volumetric tumor phenotype features in Glioblastoma

International Nuclear Information System (INIS)

Grossmann, Patrick; Gutman, David A.; Dunn, William D. Jr; Holder, Chad A.; Aerts, Hugo J. W. L.

2016-01-01

Glioblastoma (GBM) tumors exhibit strong phenotypic differences that can be quantified using magnetic resonance imaging (MRI), but the underlying biological drivers of these imaging phenotypes remain largely unknown. An Imaging-Genomics analysis was performed to reveal the mechanistic associations between MRI derived quantitative volumetric tumor phenotype features and molecular pathways. One hundred fourty one patients with presurgery MRI and survival data were included in our analysis. Volumetric features were defined, including the necrotic core (NE), contrast-enhancement (CE), abnormal tumor volume assessed by post-contrast T1w (tumor bulk or TB), tumor-associated edema based on T2-FLAIR (ED), and total tumor volume (TV), as well as ratios of these tumor components. Based on gene expression where available (n = 91), pathway associations were assessed using a preranked gene set enrichment analysis. These results were put into context of molecular subtypes in GBM and prognostication. Volumetric features were significantly associated with diverse sets of biological processes (FDR < 0.05). While NE and TB were enriched for immune response pathways and apoptosis, CE was associated with signal transduction and protein folding processes. ED was mainly enriched for homeostasis and cell cycling pathways. ED was also the strongest predictor of molecular GBM subtypes (AUC = 0.61). CE was the strongest predictor of overall survival (C-index = 0.6; Noether test, p = 4x10 −4 ). GBM volumetric features extracted from MRI are significantly enriched for information about the biological state of a tumor that impacts patient outcomes. Clinical decision-support systems could exploit this information to develop personalized treatment strategies on the basis of noninvasive imaging. The online version of this article (doi:10.1186/s12885-016-2659-5) contains supplementary material, which is available to authorized users

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

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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.

Lobular breast cancers lack the inverse relationship between ER/PR status and cell growth rate characteristic of ductal cancers in two independent patient cohorts: implications for tumor biology and adjuvant therapy.

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Wong, Hilda; Lau, Silvia; Cheung, Polly; Wong, Ting Ting; Parker, Andrew; Yau, Thomas; Epstein, Richard J

2014-11-10

Although invasive lobular carcinoma (ILC) of the breast differs from invasive ductal carcinoma (IDC) in numerous respects - including its genetics, clinical phenotype, metastatic pattern, and chemosensitivity - most experts continue to manage ILC and IDC identically in the adjuvant setting. Here we address this discrepancy by comparing early-stage ILC and IDC in two breast cancer patient cohorts of differing nationality and ethnicity. The clinicopathologic features of 2029 consecutive breast cancer patients diagnosed in Hong Kong (HK) and Australia (AUS) were compared. Interrelationships between tumor histology and other clinicopathologic variables, including ER/PR and Ki67, were analysed. Two hundred thirty-nine patients were identified with ILC (11.8%) and 1790 patients with IDC. AUS patients were older (p patients. As expected, ILC tumors were lower in grade and proliferative rate, and more often ER-positive and HER2-negative, than IDC (p 0.7). Moreover, whereas IDC tumors exhibited a strongly negative relationship between ER/PR and Ki67 status (p 0.6). These data imply that the primary adhesion defect in ILC underlies a secondary stromal-epithelial disconnect between hormonal signaling and tumor growth, suggesting in turn that this peritumoral feedback defect could reduce both the antimetastatic (adjuvant) and tumorilytic (palliative) efficacy of cytotoxic therapies for such tumors. Hence, we caution against assuming similar adjuvant chemotherapeutic survival benefits for ILC and IDC tumors with similar ER and Ki67, whether based on immunohistochemical or gene expression assays.

No association between Epstein-Barr Virus and Mouse Mammary Tumor Virus with Breast Cancer in Mexican Women

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Morales-Sánchez, Abigail; Molina-Muñoz, Tzindilú; Martínez-López, Juan L. E.; Hernández-Sancén, Paulina; Mantilla, Alejandra; Leal, Yelda A.; Torres, Javier; Fuentes-Pananá, Ezequiel M.

2013-10-01

Breast cancer is the most frequent malignancy affecting women worldwide. It has been suggested that infection by Epstein Barr Virus (EBV), Mouse Mammary Tumor Virus or a similar virus, MMTV-like virus (MMTV-LV), play a role in the etiology of the disease. However, studies looking at the presence of these viruses in breast cancer have produced conflicting results, and this possible association remains controversial. Here, we used polymerase chain reaction assay to screen specific sequences of EBV and MMTV-LV in 86 tumor and 65 adjacent tissues from Mexican women with breast cancer. Neither tumor samples nor adjacent tissue were positive for either virus in a first round PCR and only 4 tumor samples were EBV positive by a more sensitive nested PCR. Considering the study's statistical power, these results do not support the involvement of EBV and MMTV-LV in the etiology of breast cancer.

Role of tumor microenvironment in triple-negative breast cancer and its prognostic significance

Institute of Scientific and Technical Information of China (English)

Tianjian Yu; Genhong Di

2017-01-01

Breast cancer has been shown to live in the tumor microenvironment,which consists of not only breast cancer cells themselves but also a significant amount of pathophysiologically altered surrounding stroma and cells.Diverse components of the breast cancer microenvironment,such as suppressive immune cells,re-programmed fibroblast cells,altered extracellular matrix (ECM) and certain soluble factors,synergistically impede an effective anti-tumor response and promote breast cancer progression and metastasis.Among these components,stromal cells in the breast cancer microenvironment are characterized by molecular alterations and aberrant signaling pathways,whereas the ECM features biochemical and biomechanical changes.However,triple-negative breast cancer (TNBC),the most aggressive subtype of this disease that lacks effective therapies available for other subtypes,is considered to feature a unique microenvironment distinct from that of other subtypes,especially compared to Luminal A subtype.Because these changes are now considered to significantly impact breast cancer development and progression,these unique alterations may serve as promising prognostic factors of clinical outcome or potential therapeutic targets for the treatment of TNBC.In this review,we focus on the composition of the TNBC microenvironment,concomitant distinct biological alteration,specific interplay between various cell types and TNBC cells,and the prognostic implications of these findings.

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

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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.

Malignant transformation of breast fibroadenoma to malignant phyllodes tumor: long-term outcome of 36 malignant phyllodes tumors.

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Abe, Makoto; Miyata, Satoshi; Nishimura, Seiichiro; Iijima, Kotaro; Makita, Masujiro; Akiyama, Futoshi; Iwase, Takuji

2011-10-01

Malignant phyllodes tumor of the breast is a rare neoplasm for which clinical findings remain insufficient for determination of optimal management. We examined the clinical behavior of these lesions in an attempt to determine appropriate management. We evaluated long-term outcome and clinical characteristics of malignant phyllodes tumors arising from fibroadenomas of the breast. A total of 173 patients were given a diagnosis of phyllodes tumor and underwent surgery at the Cancer Institute Hospital in Japan between January 1980 and December 1999. Of these patients, 39 (22.5%) were given a diagnosis of malignant phyllodes tumor; in three of these cases, detailed medical records were lost. Malignant phyllodes tumors were classified into two groups based on history of malignant transformation. Of the 36 malignant cases, 11 (30.6%) were primary and were given a diagnosis of fibroadenoma, experienced recurrence during the follow-up period, and were diagnosed with malignant phyllodes tumor (cases with a history of fibroadenoma). The other group was defined as cases without history of fibroadenoma and in whom lesions initially occurred as malignant phyllodes tumors. Based on differences between the two groups, overall survival curves were plotted using the Kaplan–Meier method, and statistical comparisons were performed using the log-rank test and Peto and Peto’s test. The outcome of cases with history of fibroadenoma was significantly better than that of cases without history of fibroadenoma. Patients with malignant phyllodes tumors but without prior history of malignant transformation who exhibit rapid growth within 6 months require aggressive treatment.

Haptoglobin phenotype is not a predictor of recurrence free survival in high-risk primary breast cancer patients

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Harris Nathan

2008-12-01

Full Text Available Abstract Background Better breast cancer prognostication may improve selection of patients for adjuvant therapy. We conducted a retrospective follow-up study in which we investigated sera of high-risk primary breast cancer patients, to search for proteins predictive of recurrence free survival. Methods Two sample sets of high-risk primary breast cancer patients participating in a randomised national trial investigating the effectiveness of high-dose chemotherapy were analysed. Sera in set I (n = 63 were analysed by surface enhanced laser desorption ionisation time-of-flight mass spectrometry (SELDI-TOF MS for biomarker finding. Initial results were validated by analysis of sample set II (n = 371, using one-dimensional gel-electrophoresis. Results In sample set I, the expression of a peak at mass-to-charge ratio 9198 (relative intensity ≤ 20 or > 20, identified as haptoglobin (Hp alpha-1 chain, was strongly associated with recurrence free survival (global Log-rank test; p = 0.0014. Haptoglobin is present in three distinct phenotypes (Hp 1-1, Hp 2-1, and Hp 2-2, of which only individuals with phenotype Hp 1-1 or Hp 2-1 express the haptoglobin alpha-1 chain. As the expression of the haptoglobin alpha-1 chain, determined by SELDI-TOF MS, corresponds to the phenotype, initial results were validated by haptoglobin phenotyping of the independent sample set II by native one-dimensional gel-electrophoresis. With the Hp 1-1 phenotype as the reference category, the univariate hazard ratio for recurrence was 0.87 (95% CI: 0.56 – 1.34, p = 0.5221 and 1.03 (95% CI: 0.65 – 1.64, p = 0.8966 for the Hp 2-1 and Hp 2-2 phenotypes, respectively, in sample set II. Conclusion In contrast to our initial results, the haptoglobin phenotype was not identified as a predictor of recurrence free survival in high-risk primary breast cancer in our validation set. Our initial observation in the discovery set was probably the result of a type I error (i.e. false positive

Mammographic density and risk of breast cancer by tumor characteristics: a case-control study.

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Krishnan, Kavitha; Baglietto, Laura; Stone, Jennifer; McLean, Catriona; Southey, Melissa C; English, Dallas R; Giles, Graham G; Hopper, John L

2017-12-16

In a previous paper, we had assumed that the risk of screen-detected breast cancer mostly reflects inherent risk, and the risk of whether a breast cancer is interval versus screen-detected mostly reflects risk of masking. We found that inherent risk was predicted by body mass index (BMI) and dense area (DA) or percent dense area (PDA), but not by non-dense area (NDA). Masking, however, was best predicted by PDA but not BMI. In this study, we aimed to investigate if these associations vary by tumor characteristics and mode of detection. We conducted a case-control study nested within the Melbourne Collaborative Cohort Study of 244 screen-detected cases matched to 700 controls and 148 interval cases matched to 446 controls. DA, NDA and PDA were measured using the Cumulus software. Tumor characteristics included size, grade, lymph node involvement, and ER, PR, and HER2 status. Conditional and unconditional logistic regression were applied as appropriate to estimate the Odds per Adjusted Standard Deviation (OPERA) adjusted for age and BMI, allowing the association with BMI to be a function of age at diagnosis. For screen-detected cancer, both DA and PDA were associated to an increased risk of tumors of large size (OPERA ~ 1.6) and positive lymph node involvement (OPERA ~ 1.8); no association was observed for BMI and NDA. For risk of interval versus screen-detected breast cancer, the association with risk for any of the three mammographic measures did not vary by tumor characteristics; an association was observed for BMI for positive lymph nodes (OPERA ~ 0.6). No associations were observed for tumor grade and ER, PR and HER2 status of tumor. Both DA and PDA were predictors of inherent risk of larger breast tumors and positive nodal status, whereas for each of the three mammographic density measures the association with risk of masking did not vary by tumor characteristics. This might raise the hypothesis that the risk of breast tumours with poorer prognosis

Distribution of Selenium and Oxidative Stress in Breast Tumor-Bearing Mice

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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.

Neuropsychological profiles of breast cancer and brain tumor cohorts in Northeast Ontario, Canada.

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Mariani, Matias; Collins, Mark William Glister

2018-05-17

As developments in cancer treatment have improved outcomes, research has increasingly focused on the role of cancer-related cognitive impairment (CRCI) in quality of life for cancer survivors. Impairment profiles have been heterogeneous across studies, necessitating the study of these effects across different cohorts. The purpose of this preliminary study is to compare the memory profiles of Northeast Ontario breast and CNS cancer patients, as there is no literature which exists for profiling CRCI within this largely rural region. Sixty-three outpatients with breast cancer (n = 32) or CNS tumors (n = 30) at the Northeast Cancer Centre in Sudbury, Canada, were administered a neuropsychological test battery as part of their clinical examination. Domains measured within this study included attention and concentration, processing speed, motor function, language skills, verbal and visual memory, and executive functioning. Participants with brain tumors scored poorer on most neuropsychological measures than participants with breast cancer. Initial verbal memory for individuals with breast cancer was lower than delayed recall and recognition trials. Trial 1 performance for this group was also negatively correlated with self-reported anxiety scores. Consistent with the literature, participants with breast cancer obtained higher scores on most test measures than participants with CNC tumors. Breast cancer participants had lower verbal memory scores on initial trials compared to delayed recall, potentially due to relationships with anxiety and attention. Further research into this cohort will strive to gain greater understanding of the patterns of deficits experienced and how these may inform individuals with cancer in other regions.

Chloroquine Engages the Immune System to Eradicate Irradiated Breast Tumors in Mice

International Nuclear Information System (INIS)

Ratikan, Josephine Anna; Sayre, James William; Schaue, Dörthe

2013-01-01

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

Expression profiling of circulating tumor cells in metastatic breast cancer

Czech Academy of Sciences Publication Activity Database

Lang, J.; Scott, J.H.; Wolf, D.M.; Novák, Petr; Punj, V.; Magbanua, M.J.M.; Zhu, W.Z.; Mineyev, N.; Haqq, CH.; Crothers, J.

2015-01-01

Roč. 149, č. 1 (2015), s. 121-131 ISSN 0167-6806 Institutional support: RVO:60077344 Keywords : Circulating tumor cells * Micrometastases * Breast cancer * EpCAM Subject RIV: FD - Oncology ; Hematology Impact factor: 4.085, year: 2015

Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer.

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Ibrahim Tekedereli

Full Text Available Eukaryotic elongation factor 2 kinase (eEF-2K, through its phosphorylation of elongation factor 2 (eEF2, provides a mechanism by which cells can control the rate of the elongation phase of protein synthesis. The activity of eEF-2K is increased in rapidly proliferating malignant cells, is inhibited during mitosis, and may contribute to the promotion of autophagy in response to anti-cancer therapies. The purpose of this study was to examine the therapeutic potential of targeting eEF-2K in breast cancer tumors. Through the systemic administration of liposomal eEF-2K siRNA (twice a week, i.v. 150 µg/kg, the expression of eEF-2K was down-regulated in vivo in an orthotopic xenograft mouse model of a highly aggressive triple negative MDA-MB-231 tumor. This targeting resulted in a substantial decrease in eEF2 phosphorylation in the tumors, and led to the inhibition of tumor growth, the induction of apoptosis and the sensitization of tumors to the chemotherapy agent doxorubicin. eEF-2K down-modulation in vitro resulted in a decrease in the expression of c-Myc and cyclin D1 with a concomitant increase in the expression of p27(Kip1. A decrease in the basal activity of c-Src (phospho-Tyr-416, focal adhesion kinase (phospho-Tyr-397, and Akt (phospho-Ser-473 was also detected following eEF-2K down-regulation in MDA-MB-231 cells, as determined by Western blotting. Where tested, similar results were seen in ER-positive MCF-7 cells. These effects were also accompanied by a decrease in the observed invasive phenotype of the MDA-MB-231 cells. These data support the notion that the disruption of eEF-2K expression in breast cancer cells results in the down-regulation of signaling pathways affecting growth, survival and resistance and has potential as a therapeutic approach for the treatment of breast cancer.

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

International Nuclear Information System (INIS)

Fabre-Lafay, Stéphanie; Geneix, Jeannine; Lecocq, Eric; Popovici, Cornel; Dubreuil, Patrice; Viens, Patrice; Gonçalves, Anthony; Charafe-Jauffret, Emmanuelle; Jacquemier, Jocelyne; Birnbaum, Daniel; Lopez, Marc; Monville, Florence; Garrido-Urbani, Sarah; Berruyer-Pouyet, Carole; Ginestier, Christophe; Reymond, Nicolas; Finetti, Pascal; Sauvan, Richard; Adélaïde, José

2007-01-01

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. 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. 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 correlate with the number of metastases (P = 0.038). Serum

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

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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

Phenotypic high-throughput screening elucidates target pathway in breast cancer stem cell-like cells.

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Carmody, Leigh C; Germain, Andrew R; VerPlank, Lynn; Nag, Partha P; Muñoz, Benito; Perez, Jose R; Palmer, Michelle A J

2012-10-01

Cancer stem cells (CSCs) are resistant to standard cancer treatments and are likely responsible for cancer recurrence, but few therapies target this subpopulation. Due to the difficulty in propagating CSCs outside of the tumor environment, previous work identified CSC-like cells by inducing human breast epithelial cells into an epithelial-to-mesenchymal transdifferentiated state (HMLE_sh_ECad). A phenotypic screen was conducted against HMLE_sh_ECad with 300 718 compounds from the Molecular Libraries Small Molecule Repository to identify selective inhibitors of CSC growth. The screen yielded 2244 hits that were evaluated for toxicity and selectivity toward an isogenic control cell line. An acyl hydrazone scaffold emerged as a potent and selective scaffold targeting HMLE_sh_ECad. Fifty-three analogues were acquired and tested; compounds ranged in potency from 790 nM to inactive against HMLE_sh_ECad. Of the analogues, ML239 was best-in-class with an IC(50)= 1.18 µM against HMLE_sh_ECad, demonstrated a >23-fold selectivity over the control line, and was toxic to another CSC-like line, HMLE_shTwist, and a breast carcinoma cell line, MDA-MB-231. Gene expression studies conducted with ML239-treated cells showed altered gene expression in the NF-κB pathway in the HMLE_sh_ECad line but not in the isogenic control line. Future studies will be directed toward the identification of ML239 target(s).

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

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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.

Breast tumor targeting with 99mTc-HYNIC-PR81 complex as a new biologic radiopharmaceutical

International Nuclear Information System (INIS)

Salouti, Mojtaba; Rajabi, Hossein; Babaei, Mohammad Hossein; Rasaee, Mohammad Javad

2008-01-01

Human epithelial mucin, MUC1, is commonly overexpressed in adenocarcinoma that includes more than 80% of breast cancers. The PR81 is a murine anti-MUC1 monoclonal antibody (MAb) that was prepared against the human breast cancer. We developed an indirect method for labeling of this antibody with 99m Tc in order to use the new preparation in immunoscintigraphy studies of BALB/c mice bearing breast tumors. The 99m Tc-PR81 complex was prepared using the HYNIC as a chelator and tricine as a coligand. The labeling efficiency determined by instant thin-layer chromatography (ITLC) was 89.2%±4.7%, and radiocolloides measured by cellulose nitrate electrophoresis were 3.4%±0.9%. The in vitro stability of labeled product was determined at room temperature by ITLC and in human serum by gel filtration chromatography - 88.3%±4.6% and 79.8%±5.7% over 24 h, respectively. The integrity of labeled MAb was checked by means of sodium dodecyl sulfate polyacrylamide gel electrophoresis, and no significant fragmentation was seen. The results of cell binding studies showed that both labeled and unlabeled PR81 were able to compete for binding to MCF 7 cells. Biodistribution studies performed in female BALB/c mice with breast tumor xenografts at 4, 16 and 24 h after the 99m Tc-HYNIC-PR81 injection demonstrated a specific localization of the compound at the site of tumors and minimum accumulation in non target organs. The tumor imaging was performed in BALB/c mice with breast xenograft tumors at 4, 8, 12, 16, 20, 24, 28, 32 and 36 h after the complex injection. The tumors were visualized with high sensitivity after 8 h. The findings showed that the new radiopharmaceutical is a promising candidate for radioimmunoscintigraphy of the human breast cancer

Macrophage Polarization Contributes to the Anti-Tumoral Efficacy of Mesoporous Nanovectors Loaded with Albumin-Bound Paclitaxel

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Fransisca Leonard

2017-06-01

Full Text Available Therapies targeted to the immune system, such as immunotherapy, are currently shaping a new, rapidly developing branch of promising cancer treatments, offering the potential to change the prognosis of previously non-responding patients. Macrophages comprise the most abundant population of immune cells in the tumor microenvironment (TME and can undergo differentiation into functional phenotypes depending on the local tissue environment. Based on these functional phenotypes, tumor-associated macrophages (TAMs can either aid tumor progression (M2 phenotype or inhibit it (M1 phenotype. Presence of M2 macrophages and a high ratio of M2/M1 macrophages in the TME are clinically associated with poor prognosis in many types of cancers. Herein, we evaluate the effect of macrophage phenotype on the transport and anti-cancer efficacy of albumin-bound paclitaxel (nAb-PTX loaded into porous silicon multistage nanovectors (MSV. Studies in a coculture of breast cancer cells (3D-spheroid with macrophages and in vivo models were conducted to evaluate the therapeutic efficacy of MSV-nAb-PTX as a function of macrophage phenotype. Association with MSV increased drug accumulation within the macrophages and the tumor spheroids, shifting the inflammation state of the TME toward the pro-inflammatory, anti-tumorigenic milieu. Additionally, the treatment increased macrophage motility toward cancer cells, promoting the active transport of therapeutic nanovectors into the tumor lesion. Consequently, apoptosis of cancer cells was increased and proliferation decreased in the MSV-nAb-PTX-treated group as compared to controls. The results also confirmed that the tested system shifts the macrophage differentiation toward an M1 phenotype, possessing an anti-proliferative effect toward the breast cancer cells. These factors were further incorporated into a mathematical model to help analyze the synergistic effect of the macrophage polarization state on the efficacy of MSV

Human breast tumor imaging using 111In labeled monoclonal antibody: Anthymic mouse model

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Ban An Khaw; Massachusetts General Hospital, Boston; Bailes, J.S.; Schneider, S.L.; Lancaster, J.; Lasher, J.C.; McGuire, W.L.; Powers, J.; Strauss, H.W.

1988-01-01

The monoclonal antibody (MoAb) 323/A3, an IgG1, was raised against the human breast tumor cell line MCF-7 and recognized a 43 Kd membrane associated glycoprotein. Histochemical studies with the antibody detected 75% of metastatic lymph nodes, 59% of primary breast tumors, and showed some staining in 20% of benign breast lesions. For radionuclide imaging, the MoAb 323/A3 was labeled with both 125 I and 111 In, via covalently coupled diethylenetriaminepentaacetic acid (DTPA) by the mixed anhydride method. The antibody activity of the DTPA modified 323/A3 was assessed by an immunoassay using viable and fixed MCF-7 target cells. Male athymic nude mice bearing BT-20 human mammary tumors were injected with dual 125 I/ 111 In labeled DTPA 323/A3 via the tail veins. The animals were imaged with a gamma camera equipped with a pinhole collimator at 1-3 h, 1, 2, 3, 4 and 5 days after the tracer administration. On day 5 or 6, the animals were killed, and the biodistribution of the radiotracers was determined for the blood, thyroid, heart, lungs, liver, spleen, kidneys, gastro-intestinal tract and tumor. Target to blood ratio at 6 days for the 111 In tracer was 24:1 in the group with a mean tumor weight of 0.492 g, and 13:1 in another group with a mean tumor weight of 0.1906 g (day 5). However, the 125 I activity showed only 3.6:1 and 5.4:1 target to blood ratios in the corresponding groups. The larger tumors localized less 111 I tracer (27.13%±7.57% injected dose/g, Mean±SD) than the smaller tumors (52.75%±22.25% ID/g). Analysis of the gamma images showed that the maximum tracer concentration occurred in the tumors at about 2 to 3 days after intravenous tracer administration. The excellent tumor resolution observed with BT-20 tumors may be due to increased 43 Kd glycoprotein antigen density in this tumor cell line. (orig.)

Somatic Cell Fusions Reveal Extensive Heterogeneity in Basal-like Breast Cancer

DEFF Research Database (Denmark)

Su, Ying; Subedee, Ashim; Bloushtain-Qimron, Noga

2015-01-01

Basal-like and luminal breast tumors have distinct clinical behavior and molecular profiles, yet the underlying mechanisms are poorly defined. To interrogate processes that determine these distinct phenotypes and their inheritance pattern, we generated somatic cell fusions and performed integrate...

The role of tumor marker CA 15-3 in detection of breast cancer relapse after curative mastectomy

International Nuclear Information System (INIS)

Hyun, In Young; Kim, In Ho; Lee, Moon Hee; Kim, Chul Soo

2004-01-01

The purpose of this study was to determine the utility of tumor marker CA 15-3 in the following: the diagnosis of breast cancer relapse after curative mastectomy, and the differentiation of the value of tumor marker by site of metastases. Two hundred two patients (median age 48 years) with breast cancer included in the follow-up after curative mastectomy. The tumor marker CA 15-3 was determined by IRMA (CIS BIO INTERNATIONAl, France). Test values > 30 U/ml were considered elevated (positive). Among 202 patients, recurrent diseases were found in 16 patients. CA 15-3 was elevated in 5 of 16 patients with recurrences. There was no false-positive patients who had elevated CA 15-3. Sensitivity and specificity of CA 15-3 for detection of breast cancer recurrence were 31%, and 100%. CA 15-3 was elevated in all of the 4 patients with liver metastases. CA 15-3 was elevated in none of the patients who relapsed with metastasis to bone-only or contralateral breast-only. The tumor marker CA 15-3 in the detection of breast cancer relapse after curative mastectomy is specific, but not sensitive. However, it is useful to rule out liver metastases of breast cancer, which indicates bad prognosis

New Approaches for Early Detection of Breast Tumor Invasion or Progression

National Research Council Canada - National Science Library

Man, Yan-Gao

2003-01-01

To assess interactions between epithelial (EP) and myoepithelial (ME) cells in association with breast tumor progression and invasion, a double immunostaining technique with antibodies to smooth muscle actin (SMA...

Interobserver variability in identification of breast tumors in MRI and its implications for prognostic biomarkers and radiogenomics

Energy Technology Data Exchange (ETDEWEB)

Saha, Ashirbani, E-mail: as698@duke.edu; Grimm, Lars J., E-mail: lars.grimm@duke.edu; Harowicz, Michael, E-mail: michael.harowicz@duke.edu; Ghate, Sujata V., E-mail: sujata.ghate@duke.edu; Kim, Connie, E-mail: connie.kim@duke.edu; Walsh, Ruth, E-mail: ruth.walsh@duke.edu; Mazurowski, Maciej A., E-mail: maciej.mazurowski@duke.edu [Department of Radiology, Duke University Medical Center, 2424 Erwin Road, Suite 302, Durham, North Carolina 27705 (United States)

2016-08-15

Purpose: To assess the interobserver variability of readers when outlining breast tumors in MRI, study the reasons behind the variability, and quantify the effect of the variability on algorithmic imaging features extracted from breast MRI. Methods: Four readers annotated breast tumors from the MRI examinations of 50 patients from one institution using a bounding box to indicate a tumor. All of the annotated tumors were biopsy proven cancers. The similarity of bounding boxes was analyzed using Dice coefficients. An automatic tumor segmentation algorithm was used to segment tumors from the readers’ annotations. The segmented tumors were then compared between readers using Dice coefficients as the similarity metric. Cases showing high interobserver variability (average Dice coefficient <0.8) after segmentation were analyzed by a panel of radiologists to identify the reasons causing the low level of agreement. Furthermore, an imaging feature, quantifying tumor and breast tissue enhancement dynamics, was extracted from each segmented tumor for a patient. Pearson’s correlation coefficients were computed between the features for each pair of readers to assess the effect of the annotation on the feature values. Finally, the authors quantified the extent of variation in feature values caused by each of the individual reasons for low agreement. Results: The average agreement between readers in terms of the overlap (Dice coefficient) of the bounding box was 0.60. Automatic segmentation of tumor improved the average Dice coefficient for 92% of the cases to the average value of 0.77. The mean agreement between readers expressed by the correlation coefficient for the imaging feature was 0.96. Conclusions: There is a moderate variability between readers when identifying the rectangular outline of breast tumors on MRI. This variability is alleviated by the automatic segmentation of the tumors. Furthermore, the moderate interobserver variability in terms of the bounding box

Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers

DEFF Research Database (Denmark)

Schmidt, Marjanka K; Hogervorst, Frans; van Hien, Richard R

2016-01-01

PURPOSE: CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor...... subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. PATIENTS AND METHODS: CHEK2*1100delC genotyping was mostly done by a custom Taqman assay....... Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. RESULTS: Proportions...

Early impact of social isolation and breast tumor progression in mice.

Science.gov (United States)

Madden, Kelley S; Szpunar, Mercedes J; Brown, Edward B

2013-03-01

Evidence from cancer patients and animal models of cancer indicates that exposure to psychosocial stress can promote tumor growth and metastasis, but the pathways underlying stress-induced cancer pathogenesis are not fully understood. Social isolation has been shown to promote tumor progression. We examined the impact of social isolation on breast cancer pathogenesis in adult female severe combined immunodeficiency (SCID) mice using the human breast cancer cell line, MDA-MB-231, a high β-adrenergic receptor (AR) expressing line. When group-adapted mice were transferred into single housing (social isolation) one week prior to MB-231 tumor cell injection into a mammary fat pad (orthotopic), no alterations in tumor growth or metastasis were detected compared to group-housed mice. When social isolation was delayed until tumors were palpable, tumor growth was transiently increased in singly-housed mice. To determine if sympathetic nervous system activation was associated with increased tumor growth, spleen and tumor norepinephrine (NE) was measured after social isolation, in conjunction with tumor-promoting macrophage populations. Three days after transfer to single housing, spleen weight was transiently increased in tumor-bearing and non-tumor-bearing mice in conjunction with reduced splenic NE concentration and elevated CD11b+Gr-1+ macrophages. At day 10 after social isolation, no changes in spleen CD11b+ populations or NE were detected in singly-housed mice. In the tumors, social isolation increased CD11b+Gr-1+, CD11b+Gr-1-, and F4/80+ macrophage populations, with no change in tumor NE. The results indicate that a psychological stressor, social isolation, elicits dynamic but transient effects on macrophage populations that may facilitate tumor growth. The transiency of the changes in peripheral NE suggest that homeostatic mechanisms may mitigate the impact of social isolation over time. Studies are underway to define the neuroendocrine mechanisms underlying the

Trading in your spindles for blebs: the amoeboid tumor cell phenotype in prostate cancer

Directory of Open Access Journals (Sweden)

Samantha Morley

2014-08-01

Full Text Available Prostate cancer (PCa remains a principal cause of mortality in developed countries. Because no clinical interventions overcome resistance to androgen ablation therapy, management of castration resistance and metastatic disease remains largely untreatable. Metastasis is a multistep process in which tumor cells lose cell-cell contacts, egress from the primary tumor, intravasate, survive shear stress within the vasculature and extravasate into tissues to colonize ectopic sites. Tumor cells reestablish migratory behaviors employed during nonneoplastic processes such as embryonic development, leukocyte trafficking and wound healing. While mesenchymal motility is an established paradigm of dissemination, an alternate, 'amoeboid' phenotype is increasingly appreciated as relevant to human cancer. Here we discuss characteristics and pathways underlying the phenotype, and highlight our findings that the cytoskeletal regulator DIAPH3 governs the mesenchymal-amoeboid transition. We also describe our identification of a new class of tumor-derived microvesicles, large oncosomes, produced by amoeboid cells and with potential clinical utility in prostate and other cancers.

Ultrasound Shear Wave Simulation of Breast Tumor Using Nonlinear Tissue Elasticity

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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.

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

Science.gov (United States)

Park, Dae Woo

2015-01-01

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.

Depletion of tumor-associated macrophages switches the epigenetic profile of pancreatic cancer infiltrating T cells and restores their anti-tumor phenotype.

Science.gov (United States)

Borgoni, Simone; Iannello, Andrea; Cutrupi, Santina; Allavena, Paola; D'Incalci, Maurizio; Novelli, Francesco; Cappello, Paola

2018-01-01

Pancreatic Ductal Adenocarcinoma (PDA) is characterized by a complex tumor microenvironment that supports its progression, aggressiveness and resistance to therapies. The delicate interplay between cancer and immune cells creates the conditions for PDA development, particularly due to the functional suppression of T cell anti-tumor effector activity. However, some of the mechanisms involved in this process are still poorly understood. In this study, we analyze whether the functional and epigenetic profile of T cells that infiltrate PDA is modulated by the microenvironment, and in particular by tumor-associated macrophages (TAMs). CD4 and CD8 T cells obtained from mice orthotopically injected with syngeneic PDA cells, and untreated or treated with Trabectedin, a cytotoxic drug that specifically targets TAMs, were sorted and analyzed by flow cytometry and characterized for their epigenetic profile. Assessment of cytokine production and the epigenetic profile of genes coding for IL10, T-bet and PD1 revealed that T cells that infiltrated PDA displayed activated Il10 promoter and repressed T-bet activity, in agreement with their regulatory phenotype (IL10 high /IFNγ low , PD1 high ). By contrast, in Trabectedin-treated mice, PDA-infiltrating T cells displayed repressed Il10 and Pdcd1 and activated T-bet promoter activity, in accordance with their anti-tumor effector phenotype (IL10 low /IFNγ high ), indicating a key role of TAMs in orchestrating functions of PDA-infiltrating T cells by modulating their epigenetic profile towards a pro-tumoral phenotype. These results suggest the targeting of TAMs as an efficient strategy to obtain an appropriate T cell anti-tumor immune response and open new potential combinations for PDA treatment.

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...

A molecular analysis by gene expression profiling reveals Bik/NBK overexpression in sporadic breast tumor samples of Mexican females

International Nuclear Information System (INIS)

García, Normand; Salamanca, Fabio; Astudillo-de la Vega, Horacio; Curiel-Quesada, Everardo; Alvarado, Isabel; Peñaloza, Rosenda; Arenas, Diego

2005-01-01

Breast cancer is one of the most frequent causes of death in Mexican women over 35 years of age. At molecular level, changes in many genetic networks have been reported as associated with this neoplasia. To analyze these changes, we determined gene expression profiles of tumors from Mexican women with breast cancer at different stages and compared these with those of normal breast tissue samples. 32 P-radiolabeled cDNA was synthesized by reverse transcription of mRNA from fresh sporadic breast tumor biopsies, as well as normal breast tissue. cDNA probes were hybridized to microarrays and expression levels registered using a phosphorimager. Expression levels of some genes were validated by real time RT-PCR and immunohistochemical assays. We identified two subgroups of tumors according to their expression profiles, probably related with cancer progression. Ten genes, unexpressed in normal tissue, were turned on in some tumors. We found consistent high expression of Bik gene in 14/15 tumors with predominant cytoplasmic distribution. Recently, the product of the Bik gene has been associated with tumoral reversion in different neoplasic cell lines, and was proposed as therapy to induce apoptosis in cancers, including breast tumors. Even though a relationship among genes, for example those from a particular pathway, can be observed through microarrays, this relationship might not be sufficient to assign a definitive role to Bik in development and progression of the neoplasia. The findings herein reported deserve further investigation

Malignant phyllodes tumor of the breast with heterologous high-grade angiosarcoma

Directory of Open Access Journals (Sweden)

Ghassan Tranesh

2017-03-01

Full Text Available Phyllodes tumors (PTs account for <3% of fibroepithelial breast lesions and for 0.3% to 1.0% of primary breast tumors. They occur predominantly in middle-aged women (mean age range, 40–50 years. PTs can be categorized into benign, borderline, and malignant; the first 2 categories are distinguished only by degree of cellular atypia and mitotic activity. Malignant PTs are more frequent among persons of Hispanic ethnicity, especially those born in Central America or South America. Heterologous sarcomatous elements may be present in malignant PTs, predominantly liposarcoma and rarely fibrosarcoma, rhabdomyosarcoma, leiomyosarcoma, osteosarcoma, and chondrosarcoma. Breast angiosarcoma (BA is a rare heterologous, sarcomatous element that may arise secondary to malignant PT. We report a 47-year-old woman with no history of previous surgery or radiation therapy who presented to the emergency department with a painful right breast mass. She admittedly noticed the right breast mass for many years; however, recently it increased in size. Mammography and ultrasonography identified a partially cystic mass. Core needle biopsy showed dense hyalinized fibrous tissue with old blood clots, suggestive of infarcted fibroadenoma. The patient received antibiotics and analgesics; however, she reported intractable pain and a worsening skin rash of her right breast. Chest computed tomography and magnetic resonance imaging showed a doubling in mass size, with pectoralis major muscle involvement. Incisional biopsy showed malignant PT with heterologous high-grade angiosarcoma. The diagnosis of angiosarcoma was confirmed through immunoreactivity for CD31, FLI1, and ERG immunostains.

Induction of erythropoiesis by hypoxia-inducible factor prolyl hydroxylase inhibitors without promotion of tumor initiation, progression, or metastasis in a VEGF-sensitive model of spontaneous breast cancer

Science.gov (United States)

Seeley, Todd W; Sternlicht, Mark D; Klaus, Stephen J; Neff, Thomas B; Liu, David Y

2017-01-01

The effects of pharmacological hypoxia-inducible factor (HIF) stabilization were investigated in the MMTV-Neundl-YD5 (NeuYD) mouse model of breast cancer. This study first confirmed the sensitivity of this model to increased vascular endothelial growth factor (VEGF), using bigenic NeuYD;MMTV-VEGF-25 mice. Tumor initiation was dramatically accelerated in bigenic animals. Bigenic tumors were also more aggressive, with shortened doubling times and increased lung metastasis as compared to NeuYD controls. In separate studies, NeuYD mice were treated three times weekly from 7 weeks of age until study end with two different HIF prolyl hydroxylase inhibitors (HIF-PHIs), FG-4497 or roxadustat (FG-4592). In NeuYD mice, HIF-PHI treatments elevated erythropoiesis markers, but no differences were detected in tumor onset or the phenotypes of established tumors. PMID:28331872

True Local Recurrences after Breast Conserving Surgery have Poor Prognosis in Patients with Early Breast Cancer

Science.gov (United States)

Sarsenov, Dauren; Ilgun, Serkan; Ordu, Cetin; Alco, Gul; Bozdogan, Atilla; Elbuken, Filiz; Nur Pilanci, Kezban; Agacayak, Filiz; Erdogan, Zeynep; Eralp, Yesim; Dincer, Maktav

2016-01-01

Background: This study was aimed at investigating clinical and histopathologic features of ipsilateral breast tumor recurrences (IBTR) and their effects on survival after breast conservation therapy. Methods: 1,400 patients who were treated between 1998 and 2007 and had breast-conserving surgery (BCS) for early breast cancer (cT1-2/N0-1/M0) were evaluated. Demographic and pathologic parameters, radiologic data, treatment, and follow-up related features of the patients were recorded. Results: 53 patients (3.8%) had IBTR after BCS within a median follow-up of 70 months. The mean age was 45.7 years (range, 27-87 years), and 22 patients (41.5%) were younger than 40 years. 33 patients (62.3%) had true recurrence (TR) and 20 were classified as new primary (NP). The median time to recurrence was shorter in TR group than in NP group (37.0 (6-216) and 47.5 (11-192) months respectively; p = 0.338). Progesterone receptor positivity was significantly higher in the NP group (p = 0.005). The overall 5-year survival rate in the NP group (95.0%) was significantly higher than that of the TR group (74.7%, p 20 mm), high grade tumor and triple-negative molecular phenotype along with developing TR negatively affected overall survival (hazard ratios were 4.2 (CI 0.98-22.76), 4.6 (CI 1.07-13.03), 4.0 (CI 0.68-46.10), 6.5 (CI 0.03-0.68), and 6.5 (CI 0.02- 0.80) respectively, p 2 cm), high grade, triple negative phenotype, and having true recurrence were identified as independent prognostic factors with a negative impact on overall survival in this dataset of patients with recurrent breast cancer. In conjunction with a more intensive follow-up program, the role of adjuvant therapy strategies should be explored further in young patients with large and high-risk tumors to reduce the risk of TR. PMID:27158571

Impact of receptor phenotype on nodal burden in patients with breast cancer who have undergone neoadjuvant chemotherapy

LENUS (Irish Health Repository)

Boland, M. R.

2017-07-31

Optimal evaluation and management of the axilla following neoadjuvant chemotherapy(NAC) in patients with node-positive breast cancer remains controversial. The aim of this study wasto examine the impact of receptor phenotype in patients with nodal metastases who undergo NAC to seewhether this approach can identify those who may be suitable for conservative axillary management.Methods: Between 2009 and 2014, all patients with breast cancer and biopsy-proven nodal diseasewho received NAC were identied from prospectively developed databases. Details of patients who hadaxillary lymph node dissection (ALND) following NAC were recorded and rates of pathological completeresponse (pCR) were evaluated for receptor phenotype.

Downregulation of Smurf2, a tumor-suppressive ubiquitin ligase, in triple-negative breast cancers: Involvement of the RB-microRNA axis

International Nuclear Information System (INIS)

Liu, Xianpeng; Gu, Xin; Sun, Limin; Flowers, Ashley B; Rademaker, Alfred W; Zhou, Yiran; Kiyokawa, Hiroaki

2014-01-01

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

Shear-wave elastography and immunohistochemical profiles in invasive breast cancer: Evaluation of maximum and mean elasticity values

Energy Technology Data Exchange (ETDEWEB)

Ganau, Sergi, E-mail: sganau@tauli.cat [Women' s Imaging Department, UDIAT-Centre Diagnòstic, Institut Universitari Parc Taulí – UAB, Parc Taulí, 1, 08205 Sabadell, Barcelona (Spain); Andreu, Francisco Javier, E-mail: xandreu@tauli.cat [Pathology Department, UDIAT-Centre Diagnòstic, Institut Universitari Parc Taulí – UAB, Parc Taulí, 1, 08205 Sabadell, Barcelona (Spain); Escribano, Fernanda, E-mail: fescribano@tauli.cat [Women' s Imaging Department, UDIAT-Centre Diagnòstic, Institut Universitari Parc Taulí – UAB, Parc Taulí, 1, 08205 Sabadell, Barcelona (Spain); Martín, Amaya, E-mail: amartino@tauli.cat [Women' s Imaging Department, UDIAT-Centre Diagnòstic, Institut Universitari Parc Taulí – UAB, Parc Taulí, 1, 08205 Sabadell, Barcelona (Spain); Tortajada, Lidia, E-mail: ltortajada@tauli.cat [Women' s Imaging Department, UDIAT-Centre Diagnòstic, Institut Universitari Parc Taulí – UAB, Parc Taulí, 1, 08205 Sabadell, Barcelona (Spain); Villajos, Maite, E-mail: mvillajos@tauli.cat [Women' s Imaging Department, UDIAT-Centre Diagnòstic, Institut Universitari Parc Taulí – UAB, Parc Taulí, 1, 08205 Sabadell, Barcelona (Spain); and others

2015-04-15

Highlights: •Shear wave elastography provides a quantitative assessment of the hardness of breast lesions. •The hardness of breast lesions correlates with lesion size: larger lesions are harder than smaller ones. •Histologic type and grade do not correlate clearly with elastography parameters. •HER2, luminal B HER2+, and triple-negative tumors have lower maximum hardness and mean hardness than other tumor types. •Half the tumors classified as BI-RADS 3 were luminal A and half were HER2. -- Abstract: Purpose: To evaluate the correlations of maximum stiffness (Emax) and mean stiffness (Emean) of invasive carcinomas on shear-wave elastography (SWE) with St. Gallen consensus tumor phenotypes. Methods: We used an ultrasound system with SWE capabilities to prospectively study 190 women with 216 histologically confirmed invasive breast cancers. We obtained one elastogram for each lesion. We correlated Emax and Emean with tumor size, histologic type and grade, estrogen and progesterone receptors, HER2 expression, the Ki67 proliferation index, and the five St. Gallen molecular subtypes: luminal A, luminal B without HER2 overexpression (luminal B HER2−), luminal B with HER2 overexpression (luminal B HER2+), HER2, and triple negative. Results: Lesions larger than 20 mm had significantly higher Emax (148.04 kPa) and Emean (118.32 kPa) (P = 0.005) than smaller lesions. We found no statistically significant correlations between elasticity parameters and histologic type and grade or molecular subtypes, although tumors with HER2 overexpression regardless whether they expressed hormone receptors (luminal B HER2+ and HER2 phenotypes) and triple-negative tumors had lower Emax and Emean than the others. We assessed the B-mode ultrasound findings of the lesions with some of the Emax or Emean values less than or equal to 80 kPa; only four of these had ultrasound findings suggestive of a benign lesion (two with luminal A phenotype and two with HER2 phenotype). Conclusions: We

Shear-wave elastography and immunohistochemical profiles in invasive breast cancer: Evaluation of maximum and mean elasticity values

International Nuclear Information System (INIS)

Ganau, Sergi; Andreu, Francisco Javier; Escribano, Fernanda; Martín, Amaya; Tortajada, Lidia; Villajos, Maite

2015-01-01

Highlights: •Shear wave elastography provides a quantitative assessment of the hardness of breast lesions. •The hardness of breast lesions correlates with lesion size: larger lesions are harder than smaller ones. •Histologic type and grade do not correlate clearly with elastography parameters. •HER2, luminal B HER2+, and triple-negative tumors have lower maximum hardness and mean hardness than other tumor types. •Half the tumors classified as BI-RADS 3 were luminal A and half were HER2. -- Abstract: Purpose: To evaluate the correlations of maximum stiffness (Emax) and mean stiffness (Emean) of invasive carcinomas on shear-wave elastography (SWE) with St. Gallen consensus tumor phenotypes. Methods: We used an ultrasound system with SWE capabilities to prospectively study 190 women with 216 histologically confirmed invasive breast cancers. We obtained one elastogram for each lesion. We correlated Emax and Emean with tumor size, histologic type and grade, estrogen and progesterone receptors, HER2 expression, the Ki67 proliferation index, and the five St. Gallen molecular subtypes: luminal A, luminal B without HER2 overexpression (luminal B HER2−), luminal B with HER2 overexpression (luminal B HER2+), HER2, and triple negative. Results: Lesions larger than 20 mm had significantly higher Emax (148.04 kPa) and Emean (118.32 kPa) (P = 0.005) than smaller lesions. We found no statistically significant correlations between elasticity parameters and histologic type and grade or molecular subtypes, although tumors with HER2 overexpression regardless whether they expressed hormone receptors (luminal B HER2+ and HER2 phenotypes) and triple-negative tumors had lower Emax and Emean than the others. We assessed the B-mode ultrasound findings of the lesions with some of the Emax or Emean values less than or equal to 80 kPa; only four of these had ultrasound findings suggestive of a benign lesion (two with luminal A phenotype and two with HER2 phenotype). Conclusions: We

High-Dimensional Phenotyping Identifies Age-Emergent Cells in Human Mammary Epithelia

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Fanny A. Pelissier Vatter

2018-04-01

Full Text Available Summary: Aging is associated with tissue-level changes in cellular composition that are correlated with increased susceptibility to disease. Aging human mammary tissue shows skewed progenitor cell potency, resulting in diminished tumor-suppressive cell types and the accumulation of defective epithelial progenitors. Quantitative characterization of these age-emergent human cell subpopulations is lacking, impeding our understanding of the relationship between age and cancer susceptibility. We conducted single-cell resolution proteomic phenotyping of healthy breast epithelia from 57 women, aged 16–91 years, using mass cytometry. Remarkable heterogeneity was quantified within the two mammary epithelial lineages. Population partitioning identified a subset of aberrant basal-like luminal cells that accumulate with age and originate from age-altered progenitors. Quantification of age-emergent phenotypes enabled robust classification of breast tissues by age in healthy women. This high-resolution mapping highlighted specific epithelial subpopulations that change with age in a manner consistent with increased susceptibility to breast cancer. : Vatter et al. find that single-cell mass cytometry of human mammary epithelial cells from 57 women, from 16 to 91 years old, depicts an in-depth phenotyping of aging mammary epithelia. Subpopulations of altered luminal and progenitor cells that accumulate with age may be at increased risk for oncogenic transformation. Keywords: human mammary epithelia, aging, mass cytometry, single-cell analysis, heterogeneity, breast cancer

Chromosomal radiosensitivity in Breast Cancer Patients with Different Tumor size: In vitro and In vivo Assessment

International Nuclear Information System (INIS)

El-Habit, O.H.

2003-01-01

Chromosomal radiosensitivity of normal tissues from breast cancer patients has been used for detection of cancer prone individuals. Interindividual variation among breast cancer patients and cancer-prone individuals is, however, not satisfactorily explained. In this study the type of tumor and its degree of progression is addressed to find out its effect on the variability produced. Three groups of breast cancer patients with different tumor sizes; I, II and III were used in this investigation. The first group of 12 patients with tumor grade I, the second group comprised 15 patients of tumor grade II and a third group of 13 patients of tumor grade III. A fourth control group of 14 normal healthy individuals of the same age group were also used. Blood samples were withdrawn before starting radiotherapy treatment. In vitro irradiation of blood with 2.0, 4.0 or 6.0 Gy, and blood culture was set up at 37 0C for 54 hr. Different types of chromosomal aberrations (dicentrics, rings, breaks, fragments and gaps) were scored. Another set of irradiated cultures were set up for assay of micronucleated binucleate lymphocytes treated with cytochalasin B. Blood samples were also obtained from breast cancer patients 24 hr

Cycling Hypoxia Induces a Specific Amplified Inflammatory Phenotype in Endothelial Cells and Enhances Tumor-Promoting Inflammation In Vivo

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Céline Tellier

2015-01-01

Full Text Available Abnormal architecture of the tumor blood network, as well as heterogeneous erythrocyte flow, leads to temporal fluctuations in tissue oxygen tension exposing tumor and stromal cells to cycling hypoxia. Inflammation is another feature of tumor microenvironment and is considered as a new enabling characteristic of tumor progression. As cycling hypoxia is known to participate in tumor aggressiveness, the purpose of this study was to evaluate its role in tumor-promoting inflammation. Firstly, we assessed the impact of cycling hypoxia in vitro on endothelial inflammatory response induced by tumor necrosis factor α. Results showed that endothelial cells exposed to cycling hypoxia displayed an amplified proinflammatory phenotype, characterized by an increased expression of inflammatory cytokines, namely, interleukin (IL-6 and IL-8; by an increased expression of adhesion molecules, in particular intercellular adhesion molecule–1 (ICAM-1; and consequently by an increase in THP-1 monocyte adhesion. This exacerbation of endothelial inflammatory phenotype occurs through nuclear factor–κB overactivation. Secondly, the role of cycling hypoxia was studied on overall tumor inflammation in vivo in tumor-bearing mice. Results showed that cycling hypoxia led to an enhanced inflammation in tumors as prostaglandin-endoperoxide synthase 2 (PTGS2, IL-6, CXCL1 (C-X-C motif ligand 1, and macrophage inflammatory protein 2 (murine IL-8 functional homologs mRNA expression was increased and as a higher leukocyte infiltration was evidenced. Furthermore, cycling hypoxia–specific inflammatory phenotype, characterized by a simultaneous (baculoviral inhibitor of apoptosis repeat-containing 5low/PTGS2high/ICAM-1high/IL-6high/IL-8high expression, is associated with a poor prognosis in human colon cancer. This new phenotype could thus be used in clinic to more precisely define prognosis for colon cancer patients. In conclusion, our findings evidenced for the first time the

Metastatic Organotropism: An Intrinsic Property of Breast Cancer Molecular Subtypes.

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Wei, Shi; Siegal, Gene P

2017-03-01

It has long been known that some cancers have the propensity to metastasize to certain organs thus creating a nonrandom distribution of sites for distant relapse, a phenomenon known as "metastatic organotropism." Some of these examples include ovary primary to abdominal cavity, prostate primary to bone, and pancreas primary to liver. In contrast, other tumor types, such as mammary and renal cell carcinoma, can relapse in multiple organs although approximately half of advanced breast cancers metastasize to bone. On the other hand gene expression profiling studies have identified various breast cancer classes with prognostic significance. Recent studies have revealed that breast cancer subtypes differ not only in primary tumor characteristics but also in their metastatic behavior. In particular, the luminal tumors are remarkable for their significant bone-seeking phenotype; the HER2 subtype demonstrates a significant liver-homing characteristic; whereas so-called triple-negative breast cancers predispose to lung metastases. These findings suggest that this knowledge could potentially be utilized in the development of effective disease surveillance strategies in the pursuit of precision medicine, thus necessitating further investigation.

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

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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

Tumor-suppressor activity of RRIG1 in breast cancer

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Zhang, Guihong; Brewster, Abenaa; Guan, Baoxiang; Fan, Zhen; Brown, Powel H; Xu, Xiao-Chun

2011-01-01

Retinoid receptor-induced gene-1 (RRIG1) is a novel gene that has been lost in several types of human cancers. The aim of this study was to determine whether RRIG1 plays a role in breast cancer, such as in the suppression of breast cancer cell growth and invasion. Immunohistochemistry was used to detect RRIG1 expression in breast tissue specimens. Gene transfection was used to restore or knock down RRIG1 expression in breast cancer cell lines for analysis of cell viability, colony formation, and migration/invasion potential. Reverse-transcription polymerase chain reaction and western blot assays were used to detect the changes in gene expression. The RhoA activation assay was used to assess RRIG1-induced inhibition of RhoA activity. The immunohistochemical data showed that RRIG1 expression was reduced in breast cancer tissues compared with normal and atypical hyperplastic breast tissues. RRIG1 expression was inversely correlated with lymph node metastasis of breast cancer but was not associated with the status of hormone receptors, such as estrogen receptor, progesterone receptor, or HER2. Furthermore, restoration of RRIG1 expression inhibited proliferation, colony formation, migration, and invasion of breast cancer cells. Expression of RRIG1 also reduced phosphorylated Erk1/2 and Akt levels; c-Jun, MMP9, and Akt expressions; and RhoA activity. In contrast, knockdown of RRIG1 expression promoted breast cancer cell proliferation, colony formation, migration, and invasion potential. The data from the current study indicated that RRIG1 expression was reduced or lost in breast cancer and that restoration of RRIG1 expression suppressed breast cancer cell growth and invasion capacity. Future studies will determine the underlying molecular mechanisms and define RRIG1 as a tumor-suppressor gene in breast cancer

Local iron homeostasis in the breast ductal carcinoma microenvironment

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Marques, Oriana; Porto, Graça; Rêma, Alexandra; Faria, Fátima; Cruz Paula, Arnaud; Gomez-Lazaro, Maria; Silva, Paula; Martins da Silva, Berta; Lopes, Carlos

2016-01-01

While the deregulation of iron homeostasis in breast epithelial cells is acknowledged, iron-related alterations in stromal inflammatory cells from the tumor microenvironment have not been explored. Immunohistochemistry for hepcidin, ferroportin 1 (FPN1), transferrin receptor 1 (TFR1) and ferritin (FT) was performed in primary breast tissues and axillary lymph nodes in order to dissect the iron-profiles of epithelial cells, lymphocytes and macrophages. Furthermore, breast carcinoma core biopsies frozen in optimum cutting temperature (OCT) compound were subjected to imaging flow cytometry to confirm FPN1 expression in the cell types previously evaluated and determine its cellular localization. We confirm previous results by showing that breast cancer epithelial cells present an ‘iron-utilization phenotype’ with an increased expression of hepcidin and TFR1, and decreased expression of FT. On the other hand, lymphocytes and macrophages infiltrating primary tumors and from metastized lymph nodes display an ‘iron-donor’ phenotype, with increased expression of FPN1 and FT, concomitant with an activation profile reflected by a higher expression of TFR1 and hepcidin. A higher percentage of breast carcinomas, compared to control mastectomy samples, present iron accumulation in stromal inflammatory cells, suggesting that these cells may constitute an effective tissue iron reservoir. Additionally, not only the deregulated expression of iron-related proteins in epithelial cells, but also on lymphocytes and macrophages, are associated with clinicopathological markers of breast cancer poor prognosis, such as negative hormone receptor status and tumor size. The present results reinforce the importance of analyzing the tumor microenvironment in breast cancer, extending the contribution of immune cells to local iron homeostasis in the tumor microenvironment context

Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium

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Muranen, Taru A; Blomqvist, Carl; Dörk, Thilo

2016-01-01

BACKGROUND: P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival...... and characteristics of breast tumors of germ line p.I157T carriers. METHODS: We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer...... characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models...

LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast cancer

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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.

Quantitative DNA methylation analyses reveal stage dependent DNA methylation and association to clinico-pathological factors in breast tumors

International Nuclear Information System (INIS)

Klajic, Jovana; Tost, Jörg; Kristensen, Vessela N; Fleischer, Thomas; Dejeux, Emelyne; Edvardsen, Hege; Warnberg, Fredrik; Bukholm, Ida; Lønning, Per Eystein; Solvang, Hiroko; Børresen-Dale, Anne-Lise

2013-01-01

Aberrant DNA methylation of regulatory genes has frequently been found in human breast cancers and correlated to clinical outcome. In the present study we investigate stage specific changes in the DNA methylation patterns in order to identify valuable markers to understand how these changes affect breast cancer progression. Quantitative DNA methylation analyses of 12 candidate genes ABCB1, BRCCA1, CDKN2A, ESR1, GSTP1, IGF2, MGMT, HMLH1, PPP2R2B, PTEN, RASSF1A and FOXC1 was performed by pyrosequencing a series of 238 breast cancer tissue samples from DCIS to invasive tumors stage I to IV. Significant differences in methylation levels between the DCIS and invasive stage II tumors were observed for six genes RASSF1A, CDKN2A, MGMT, ABCB1, GSTP1 and FOXC1. RASSF1A, ABCB1 and GSTP1 showed significantly higher methylation levels in late stage compared to the early stage breast carcinoma. Z-score analysis revealed significantly lower methylation levels in DCIS and stage I tumors compared with stage II, III and IV tumors. Methylation levels of PTEN, PPP2R2B, FOXC1, ABCB1 and BRCA1 were lower in tumors harboring TP53 mutations then in tumors with wild type TP53. Z-score analysis showed that TP53 mutated tumors had significantly lower overall methylation levels compared to tumors with wild type TP53. Methylation levels of RASSF1A, PPP2R2B, GSTP1 and FOXC1 were higher in ER positive vs. ER negative tumors and methylation levels of PTEN and CDKN2A were higher in HER2 positive vs. HER2 negative tumors. Z-score analysis also showed that HER2 positive tumors had significantly higher z-scores of methylation compared to the HER2 negative tumors. Univariate survival analysis identifies methylation status of PPP2R2B as significant predictor of overall survival and breast cancer specific survival. In the present study we report that the level of aberrant DNA methylation is higher in late stage compared with early stage of invasive breast cancers and DCIS for genes mentioned above

LOXL4 knockdown enhances tumor growth and lung metastasis through collagen-dependent extracellular matrix changes in triple-negative breast cancer.

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Choi, Sul Ki; Kim, Hoe Suk; Jin, Tiefeng; Moon, Woo Kyung

2017-02-14

Lysyl oxidase (LOX) family genes catalyze collagen cross-link formation. To determine the effects of lysyl oxidase-like 4 (LOXL4) expression on breast tumor formation and metastasis, we evaluated primary tumor growth and lung metastasis in mice injected with LOXL4-knockdown MDA-MB-231 triple-negative human breast cancer cells. In addition, we analyzed overall survival in breast cancer patients based on LOXL4 expression using a public online database. In the mouse xenograft model, LOXL4 knockdown increased primary tumor growth and lung colonization as well as collagen I and IV, lysine hydroxylase 1 and 2, and prolyl 4-hydroxylase subunit alpha 1 and 2 levels. Second harmonic generation imaging revealed that LOXL4 knockdown resulted in the thickening of collagen bundles within tumors. In addition, weak LOXL4 expression was associated with poor overall survival in breast cancer patients from the BreastMark dataset, and this association was strongest in triple-negative breast cancer patients. These results demonstrate that weak LOXL4 expression leads to remodeling of the extracellular matrix through induction of collagen synthesis, deposition, and structural changes. These alterations in turn promote tumor growth and metastasis and are associated with poor clinical outcomes in triple-negative breast cancer.