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Sample records for breast cancer tumor

  1. Tumor Heterogeneity in Breast Cancer

    Science.gov (United States)

    Turashvili, Gulisa; Brogi, Edi

    2017-01-01

    Breast cancer is a heterogeneous disease and differs greatly among different patients (intertumor heterogeneity) and even within each individual tumor (intratumor heterogeneity). Clinical and morphologic intertumor heterogeneity is reflected by staging systems and histopathologic classification of breast cancer. Heterogeneity in the expression of established prognostic and predictive biomarkers, hormone receptors, and human epidermal growth factor receptor 2 oncoprotein is the basis for targeted treatment. Molecular classifications are indicators of genetic tumor heterogeneity, which is probed with multigene assays and can lead to improved stratification into low- and high-risk groups for personalized therapy. Intratumor heterogeneity occurs at the morphologic, genomic, transcriptomic, and proteomic levels, creating diagnostic and therapeutic challenges. Understanding the molecular and cellular mechanisms of tumor heterogeneity that are relevant to the development of treatment resistance is a major area of research. Despite the improved knowledge of the complex genetic and phenotypic features underpinning tumor heterogeneity, there has been only limited advancement in diagnostic, prognostic, or predictive strategies for breast cancer. The current guidelines for reporting of biomarkers aim to maximize patient eligibility for targeted therapy, but do not take into account intratumor heterogeneity. The molecular classification of breast cancer is not implemented in routine clinical practice. Additional studies and in-depth analysis are required to understand the clinical significance of rapidly accumulating data. This review highlights inter- and intratumor heterogeneity of breast carcinoma with special emphasis on pathologic findings, and provides insights into the clinical significance of molecular and cellular mechanisms of heterogeneity. PMID:29276709

  2. Breast cancer circulating tumor cells

    Directory of Open Access Journals (Sweden)

    Maria Joao Carvalho

    2011-12-01

    Full Text Available Metastasization of breast cancer involves various mechanisms responsible for progression from invasive lesion to dissemination in distant organs. Regional lymph node metastasization was considered an initial step in this process, but it is now recognized that hematogenous dissemination is a deviation from lymphatic circulation. The detection of circulating tumor cells (CTC is an aim in several oncology areas. For this purpose, several techniques have been used to detect CTC, including the use of antibodies and techniques with nucleic acids. This study reviews the published studies considering the detection of breast cancer CTC. There are focused the difficulties in identifying a CTC in a heterogeneous population, the handling of the sample, criteria of positivity, analytical techniques, and specific markers. There are systematized various specific markers of breast cancer cells also the problems with false positive results. Finally, we hypothesize clinical applications either as a prognostic marker or as a therapeutic response monitor.

  3. Tumor markers of breast cancer: New prospectives

    Directory of Open Access Journals (Sweden)

    Ahmed M. Kabel

    2017-04-01

    Full Text Available Tumor markers are substances produced by the tumors or by other cells of the body in response to cancer or certain benign conditions. Although most of these markers are made by the normal cells as well as by cancer cells, they are produced at much higher levels in cancerous conditions. These markers are used to evaluate the patient's response to treatment and to detect the presence of metastasis or recurrence. Breast cancer is one of the most common malignancies in females worldwide. The CA 27-29, CA 15-3, CA27.29, carcinoembryonic antigen, tissue polypeptide specific antigen, p53, cathepsin D, cyclin E, nestin and HER-2 are tumor markers that are often expressed in people with breast cancer. They play a crucial role in diagnosis, monitoring response to therapy, early detection of metastasis and determination of recurrence in patients with breast cancer.

  4. Breast cancer intra-tumor heterogeneity

    Science.gov (United States)

    2014-01-01

    In recent years it has become clear that cancer cells within a single tumor can display striking morphological, genetic and behavioral variability. Burgeoning genetic, epigenetic and phenomenological data support the existence of intra-tumor genetic heterogeneity in breast cancers; however, its basis is yet to be fully defined. Two of the most widely evoked concepts to explain the origin of heterogeneity within tumors are the cancer stem cell hypothesis and the clonal evolution model. Although the cancer stem cell model appeared to provide an explanation for the variability among the neoplastic cells within a given cancer, advances in massively parallel sequencing have provided several lines of evidence to suggest that intra-tumor genetic heterogeneity likely plays a fundamental role in the phenotypic heterogeneity observed in cancers. Many challenges remain, however, in the interpretation of the next generation sequencing results obtained so far. Here we review the models that explain tumor heterogeneity, the causes of intra-tumor genetic diversity and their impact on our understanding and management of breast cancer, methods to study intra-tumor heterogeneity and the assessment of intra-tumor genetic heterogeneity in the clinic. PMID:25928070

  5. Tumor markers of breast cancer: New prospectives

    OpenAIRE

    Ahmed M. Kabel

    2017-01-01

    Tumor markers are substances produced by the tumors or by other cells of the body in response to cancer or certain benign conditions. Although most of these markers are made by the normal cells as well as by cancer cells, they are produced at much higher levels in cancerous conditions. These markers are used to evaluate the patient's response to treatment and to detect the presence of metastasis or recurrence. Breast cancer is one of the most common malignancies in females worldwide. The CA 2...

  6. Drug Helps Fight Breast Tumors Tied to 'Cancer Genes'

    Science.gov (United States)

    ... Drug Helps Fight Breast Tumors Tied to 'Cancer Genes' Lynparza may offer a new treatment for women ... with breast cancer linked to BRCA1 and BRCA2 gene mutations, according to the study. Olaparib delayed cancer ...

  7. Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium

    National Research Council Canada - National Science Library

    Broeks, A; Schmidt, M.K; Sherman, M.E; Couch, F.J; Hopper, J.L; Dite, G.S; Apicella, C; Smith, L.D; Hammet, F; Southey, M.C; Veer, L.J. van 't; Groot, R. de; Smit, V.T; Fasching, P.A; Beckmann, M.W; Jud, S; Ekici, A.B; Hartmann, A; Hein, A; Schulz-Wendtland, R; Burwinkel, B; Marme, F; Schneeweiss, A; Sinn, H.P; Sohn, C; Tchatchou, S; Bojesen, S.E; Nordestgaard, B.G; Flyger, H; Orsted, D.D; Kaur-Knudsen, D; Milne, R.L; Perez, J.I; Zamora, P; Roiguez, P.M; Benitez, J; Brauch, H; Justenhoven, C; Ko, Y.D; Hamann, U; Fischer, H.P; Bruning, T; Pesch, B; Chang-Claude, J; Wang-Gohrke, S; Bremer, M; Karstens, J.H; Hillemanns, P; Dork, T; Nevanlinna, H.A; Heikkinen, T; Heikkila, P; Blomqvist, C; Aittomaki, K; Aaltonen, K; Lindblom, A; Margolin, S; Mannermaa, A; Kosma, V.M; Kauppinen, J.M; Kataja, V; Auvinen, P; Eskelinen, M; Soini, Y; Chenevix-Trench, G; Spurdle, A.B; Beesley, J; Chen, X; Holland, H; Lambrechts, D; Claes, B; Vandorpe, T; Neven, P; Wildiers, H; Flesch-Janys, D; Hein, R; Loning, T; Kosel, M; Fredericksen, Z.S; Wang, X; Giles, G.G; Baglietto, L; Severi, G; McLean, C; Haiman, C.A; Henderson, B.E; Marchand, L. le; Kolonel, L.N; Alnaes, G.G; Kristensen, V; Borresen-Dale, A.L; Hunter, D.J; Hankinson, S.E; Anulis, I.L; Mulligan, A.M; O'Malley, F.P; Devilee, P; Huijts, P.E; Tollenaar, R.A.E.M; Asperen, C.J. van

    2011-01-01

    .... 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...

  8. Nerve Fibers in Breast Cancer Tissues Indicate Aggressive Tumor Progression

    OpenAIRE

    Huang, Di; Su, Shicheng; Cui, Xiuying; Shen, Ximing; Zeng, Yunjie; Wu, Wei; Chen, Jianing; Chen, Fei; He, Chonghua; Liu, Jiang; Huang, Wei; Liu, Qiang; Su, Fengxi; Song, Erwei; Ouyang, Nengtai

    2014-01-01

    Abstract Emerging evidence has indicated nerve fibers as a marker in the progression of various types of cancers, such as pancreatic cancer and prostate cancer. However, whether nerve fibers are associated with breast cancer progression remains unclear. In this study, we evaluated the presence of nerve fibers in 352 breast cancer specimens and 83 benign breast tissue specimens including 43 cases of cystic fibrosis and 40 cases of fibroadenoma from 2 independent breast tumor center using immun...

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

    National Research Council Canada - National Science Library

    ...; Yang, Xiaohong R; Chang-Claude, Jenny; Goode, Ellen L; Couch, Fergus J; Nevanlinna, Heli; Milne, Roger L; Gaudet, Mia; Schmidt, Marjanka K; Broeks, Annegien; Cox, Angela; Fasching, Peter A; Hein, Rebecca; Spurdle, Amanda B; Blows, Fiona; ver, Kristy; Flesch-Janys, Dieter; Heinz, Judith; Sinn, Peter; Vrieling, Alina; Heikkinen, Tuomas; Aittomaeki, Kristiina; Heikkilae, Paeivi; Blomqvist, Carl; Lissowska, Jolanta; Peplonska, Beata; Chanock, Stephen; Figueroa, Jonine; Brinton, Louise; Hall, Per; Czene, Kamila; Humphreys, Keith; Darabi, Hatef; Liu, Jianjun; Van 't Veer, Laura J; Van Leeuwen, Flora E; Anulis, Irene L; Glendon, Gord; Knight, Julia A; Mulligan, Anna Marie; O'Malley, Frances P; Weerasooriya, Nayana; John, Esther M; Beckmann, Matthias W; Hartmann, Arndt; Weihbrecht, Sebastian B; Wachter, David L; Jud, Sebastian M. S; Loehberg, Christian R; Baglietto, Laura; English, Dallas R; Giles, Graham G; McLean, Catriona A; Severi, Gianluca; Lambrechts, Diether; Vandorpe, Thijs; Weltens, Caroline; Paridaens, Robert; Smeets, Ann; Neven, Patrick; Wildiers, Hans; Wang, Xianshu; Olson, Janet E; Cafourek, Victoria; Fredericksen, Zachary; Kosel, Matthew; Vachon, Celine; Cramp, Helen E; Connley, Daniel; Cross, Simon S; Balasubramanian, Sabapathy P; Reed, Malcolm W. R; Doerk, Thilo; Bremer, Michael; Meyer, Aneas; Karstens, Johann H; Ay, Aysun; Park-Simon, Tjoung-Won; Hillemanns, Peter; Arias Perez, Jose Ignacio; Menendez Roiguez, Primitiva; Zamora, Pilar; Bentez, Javier; Ko, Yon-Dschun; Fischer, Hans-Peter; Hamann, Ute; Pesch, Beate; Bruening, Thomas; Justenhoven, Christina; Brauch, Hiltrud; Eccles, Diana M; Tapper, William J; Gerty, Sue M; Sawyer, Elinor J; Tomlinson, Ian P; Jones, Angela; Kerin, Michael; Miller, Nicola; McInerney, Niall; Anton-Culver, Hoda; Ziogas, Argyrios

    2011-01-01

    ...) and progesterone receptor (PR) expression status of the tumors. Methods We pooled tumor marker and epidemiological risk factor data from 35 568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium...

  10. Nerve fibers in breast cancer tissues indicate aggressive tumor progression.

    Science.gov (United States)

    Huang, Di; Su, Shicheng; Cui, Xiuying; Shen, Ximing; Zeng, Yunjie; Wu, Wei; Chen, Jianing; Chen, Fei; He, Chonghua; Liu, Jiang; Huang, Wei; Liu, Qiang; Su, Fengxi; Song, Erwei; Ouyang, Nengtai

    2014-12-01

    Emerging evidence has indicated nerve fibers as a marker in the progression of various types of cancers, such as pancreatic cancer and prostate cancer. However, whether nerve fibers are associated with breast cancer progression remains unclear. In this study, we evaluated the presence of nerve fibers in 352 breast cancer specimens and 83 benign breast tissue specimens including 43 cases of cystic fibrosis and 40 cases of fibroadenoma from 2 independent breast tumor center using immunohistochemical staining for specific peripheral nerve fiber markers.In all, nerve fibers were present in 130 out of 352 breast cancer tissue specimens, while none were detected in normal breast tissue specimens. Among 352 cases, we defined 239 cases from Sun Yat-Sen Memorial Hospital, Guangzhou, China, as the training set, and 113 cases from the First Affiliated Hospital of Shantou University, Guangdong, China, as the validation set. The thickness of tumor-involving nerve fibers is significantly correlated with poor differentiation, lymph node metastasis, high clinical staging, and triple negative subtype in breast cancer. More importantly, Cox multifactor analysis indicates that the thickness of tumor-involving nerve fibers is a previously unappreciated independent prognostic factors associated with shorter disease-free survival of breast cancer patients. Our findings are further validated by online Oncomine database. In conclusion, our results show that nerve fiber involvement in breast cancer is associated with progression of the malignancy and warrant further studies in the future.

  11. Nerve Fibers in Breast Cancer Tissues Indicate Aggressive Tumor Progression

    Science.gov (United States)

    Huang, Di; Su, Shicheng; Cui, Xiuying; Shen, Ximing; Zeng, Yunjie; Wu, Wei; Chen, Jianing; Chen, Fei; He, Chonghua; Liu, Jiang; Huang, Wei; Liu, Qiang; Su, Fengxi; Song, Erwei; Ouyang, Nengtai

    2014-01-01

    Abstract Emerging evidence has indicated nerve fibers as a marker in the progression of various types of cancers, such as pancreatic cancer and prostate cancer. However, whether nerve fibers are associated with breast cancer progression remains unclear. In this study, we evaluated the presence of nerve fibers in 352 breast cancer specimens and 83 benign breast tissue specimens including 43 cases of cystic fibrosis and 40 cases of fibroadenoma from 2 independent breast tumor center using immunohistochemical staining for specific peripheral nerve fiber markers. In all, nerve fibers were present in 130 out of 352 breast cancer tissue specimens, while none were detected in normal breast tissue specimens. Among 352 cases, we defined 239 cases from Sun Yat-Sen Memorial Hospital, Guangzhou, China, as the training set, and 113 cases from the First Affiliated Hospital of Shantou University, Guangdong, China, as the validation set. The thickness of tumor-involving nerve fibers is significantly correlated with poor differentiation, lymph node metastasis, high clinical staging, and triple negative subtype in breast cancer. More importantly, Cox multifactor analysis indicates that the thickness of tumor-involving nerve fibers is a previously unappreciated independent prognostic factors associated with shorter disease-free survival of breast cancer patients. Our findings are further validated by online Oncomine database. In conclusion, our results show that nerve fiber involvement in breast cancer is associated with progression of the malignancy and warrant further studies in the future. PMID:25501061

  12. Active Roles of Tumor Stroma in Breast Cancer Metastasis

    Directory of Open Access Journals (Sweden)

    Zahraa I. Khamis

    2012-01-01

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

  13. Breast Cancer Risk Prediction with Heterogeneous Risk Profiles According to Breast Cancer Tumor Markers

    OpenAIRE

    Rosner, Bernard; Glynn, Robert J.; Tamimi, Rulla M.; Chen, Wendy Y.; Colditz, Graham A.; Willett, Walter C.; Hankinson, Susan E.

    2013-01-01

    Relationships between some risk factors and breast cancer incidence are known to vary by tumor subtype. However, breast tumors can be classified according to a number of markers, which may be correlated, making it difficult to identify heterogeneity of risk factors with specific tumor markers when using standard competing-risk survival analysis. In this paper, we propose a constrained competing-risk survival model that allows for assessment of heterogeneity of risk factor associations accordi...

  14. Breast Cancer Stem Cells and Tumor Suppressor Genes

    Directory of Open Access Journals (Sweden)

    Wendy W. Hwang-Verslues

    2008-10-01

    Full Text Available Studies of breast cancer stem cells are in their infancy and many fundamental questions have yet to be fully addressed. The molecular distinction between normal and cancerous breast stem cells is not clear. While there have been recent breakthroughs in mouse mammary stem cells and lineage determination in mammary glands, little has been determined in human cells. Microarray analyses have provided molecular categorization of breast cancer. However, the cellular origin of different types of breast cancer is largely unknown. In addition, the relationship between breast cancer stem cells and mammary progenitor cells has yet to be clarified. One of the key questions is how a normal mammary stem cell becomes a breast cancer stem cell. Importantly, the existence of different types of human breast cancers with distinct pathologic and molecular signatures suggests the possibility that different types of breast cancer stem cells may exist. Here, we aim to review the current evidence for the existence of different subtypes of breast cancer stem cells and provide further insight into how tumor suppressors might be involved in the initiation of breast cancer stem cells.

  15. Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy.

    Science.gov (United States)

    Williams, Carly Bess; Yeh, Elizabeth S; Soloff, Adam C

    Deleterious inflammation is a primary feature of breast cancer. Accumulating evidence demonstrates that macrophages, the most abundant leukocyte population in mammary tumors, have a critical role at each stage of cancer progression. Such tumor-associated macrophages facilitate neoplastic transformation, tumor immune evasion and the subsequent metastatic cascade. Herein, we discuss the dynamic process whereby molecular and cellular features of the tumor microenvironment act to license tissue-repair mechanisms of macrophages, fostering angiogenesis, metastasis and the support of cancer stem cells. We illustrate how tumors induce, then exploit trophic macrophages to subvert innate and adaptive immune responses capable of destroying malignant cells. Finally, we discuss compelling evidence from murine models of cancer and early clinical trials in support of macrophage-targeted intervention strategies with the potential to dramatically reduce breast cancer morbidity and mortality.

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

    Directory of Open Access Journals (Sweden)

    Bruna Karina Banin Hirata

    2014-01-01

    Full Text Available Breast cancer is one of the most common cancers with greater than 1,300,000 cases and 450,000 deaths each year worldwide. The development of breast cancer involves a progression through intermediate stages until the invasive carcinoma and finally into metastatic disease. Given the variability in clinical progression, the identification of markers that could predict the tumor behavior is particularly important in breast cancer. The determination of tumor markers is a useful tool for clinical management in cancer patients, assisting in diagnostic, staging, evaluation of therapeutic response, detection of recurrence and metastasis, and development of new treatment modalities. In this context, this review aims to discuss the main tumor markers in breast carcinogenesis. The most well-established breast molecular markers with prognostic and/or therapeutic value like hormone receptors, HER-2 oncogene, Ki-67, and p53 proteins, and the genes for hereditary breast cancer will be presented. Furthermore, this review shows the new molecular targets in breast cancer: CXCR4, caveolin, miRNA, and FOXP3, as promising candidates for future development of effective and targeted therapies, also with lower toxicity.

  17. Breast-Cancer Tumor Size, Overdiagnosis, and Mammography Screening Effectiveness.

    Science.gov (United States)

    Welch, H Gilbert; Prorok, Philip C; O'Malley, A James; Kramer, Barnett S

    2016-10-13

    The goal of screening mammography is to detect small malignant tumors before they grow large enough to cause symptoms. Effective screening should therefore lead to the detection of a greater number of small tumors, followed by fewer large tumors over time. We used data from the Surveillance, Epidemiology, and End Results (SEER) program, 1975 through 2012, to calculate the tumor-size distribution and size-specific incidence of breast cancer among women 40 years of age or older. We then calculated the size-specific cancer case fatality rate for two time periods: a baseline period before the implementation of widespread screening mammography (1975 through 1979) and a period encompassing the most recent years for which 10 years of follow-up data were available (2000 through 2002). After the advent of screening mammography, the proportion of detected breast tumors that were small (invasive tumors measuring <2 cm or in situ carcinomas) increased from 36% to 68%; the proportion of detected tumors that were large (invasive tumors measuring ≥2 cm) decreased from 64% to 32%. However, this trend was less the result of a substantial decrease in the incidence of large tumors (with 30 fewer cases of cancer observed per 100,000 women in the period after the advent of screening than in the period before screening) and more the result of a substantial increase in the detection of small tumors (with 162 more cases of cancer observed per 100,000 women). Assuming that the underlying disease burden was stable, only 30 of the 162 additional small tumors per 100,000 women that were diagnosed were expected to progress to become large, which implied that the remaining 132 cases of cancer per 100,000 women were overdiagnosed (i.e., cases of cancer were detected on screening that never would have led to clinical symptoms). The potential of screening to lower breast cancer mortality is reflected in the declining incidence of larger tumors. However, with respect to only these large tumors

  18. Breast cancer risk prediction with heterogeneous risk profiles according to breast cancer tumor markers.

    Science.gov (United States)

    Rosner, Bernard; Glynn, Robert J; Tamimi, Rulla M; Chen, Wendy Y; Colditz, Graham A; Willett, Walter C; Hankinson, Susan E

    2013-07-15

    Relationships between some risk factors and breast cancer incidence are known to vary by tumor subtype. However, breast tumors can be classified according to a number of markers, which may be correlated, making it difficult to identify heterogeneity of risk factors with specific tumor markers when using standard competing-risk survival analysis. In this paper, we propose a constrained competing-risk survival model that allows for assessment of heterogeneity of risk factor associations according to specific tumor markers while controlling for other markers. These methods are applied to Nurses' Health Study data from 1980-2006, during which 3,398 incident invasive breast cancers occurred over 1.4 million person-years of follow-up. Results suggested that when estrogen receptor (ER) and progesterone receptor (PR) status are mutually considered, some risk factors thought to be characteristic of "estrogen-positive tumors," such as high body mass index during postmenopause and increased height, are actually significantly associated with PR-positive tumors but not ER-positive tumors, while other risk factors thought to be characteristic of "estrogen-negative tumors," such as late age at first birth, are actually significantly associated with PR-negative rather than ER-negative breast cancer. This approach provides a strategy for evaluating heterogeneity of risk factor associations by tumor marker levels while controlling for additional tumor markers.

  19. Stromal cells in tumor microenvironment and breast cancer.

    Science.gov (United States)

    Mao, Yan; Keller, Evan T; Garfield, David H; Shen, Kunwei; Wang, Jianhua

    2013-06-01

    Cancer is a systemic disease encompassing multiple components of both tumor cells themselves and host stromal cells. It is now clear that stromal cells in the tumor microenvironment play an important role in cancer development. Molecular events through which reactive stromal cells affect cancer cells can be defined so that biomarkers and therapeutic targets can be identified. Cancer-associated fibroblasts (CAFs) make up the bulk of cancer stroma and affect the tumor microenvironment such that they promote cancer initiation, angiogenesis, invasion, and metastasis. In breast cancer, CAFs not only promote tumor progression but also induce therapeutic resistance. Accordingly, targeting CAFs provides a novel way to control tumors with therapeutic resistance. This review summarizes the current understandings of tumor stroma in breast cancer with a particular emphasis on the role of CAFs and the therapeutic implications of CAFs. In addition, the effects of other stromal components such as endothelial cells, macrophages, and adipocytes in breast cancer are also discussed. Finally, we describe the biologic markers to categorize patients into a specific and confirmed subtype for personalized treatment.

  20. Stroma Cells in Tumor Microenvironment and Breast Cancer

    Science.gov (United States)

    Mao, Yan; Keller, Evan T.; Garfield, David H.; Shen, Kunwei; Wang, Jianhua

    2015-01-01

    Cancer is a systemic disease, encompassing multiple components of both tumor cells themselves and host stromal cells. It is now clear that stromal cells in the tumor microenvironment play an important role in cancer development. Molecular events through which reactive stromal cells affect cancer cells can be defined so that biomarkers and therapeutic targets can be identified. Cancer-associated fibroblasts (CAFs) make up the bulk of cancer stroma and affect the tumor microenvironment such that they promote cancer initiation, angiogenesis, invasion and metastasis. In breast cancer, CAFs not only promote tumor progression, but also induce therapeutic resistances. Accordingly, targeting CAFs provides a novel way to control tumors with therapeutic resistances. This review summarizes the current understanding of tumor stroma in breast cancer with a particular emphasis on the role of CAFs and the therapeutic implications of CAFs. The effects of other stromal components such as endothelial cells, macrophages and adipocytes in breast cancer are also discussed. Finally, we describe the biologic markers to sort patients into a specific and confirmed subtype for personalized treatment. PMID:23114846

  1. 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. 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......3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor...

  2. 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. 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......3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P = 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor...

  3. 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...

  4. Unusual aggressive breast cancer: metastatic malignant phyllodes tumor.

    Science.gov (United States)

    Singer, Adam; Tresley, Jonathan; Velazquez-Vega, Jose; Yepes, Monica

    2013-02-01

    For the year of 2012, it has been estimated that breast cancer will account for the greatest number of newly diagnosed cancers and the second highest proportion of cancer related deaths among women. Breast cancer, while often lumped together as one disease, represents a diverse group of malignancies with different imaging findings, histological appearances and behavior. While most invasive primary breast cancers are epithelial derived adenocarcinomas, rare neoplasms such as the phyllodes tumor may arise from mesenchymal tissue. Compared to the breast adenocarcinoma, the phyllodes tumor tends to affect a younger population, follows a different clinical course, is associated with different imaging and histological findings and is managed distinctively. There may be difficulty in differentiating the phyllodes tumor from a large fibroadenoma, but the mammographer plays a key role in reviewing the clinical and imaging data in order to arrive at the correct diagnosis. Early diagnosis with proper surgical management can often cure non-metastatic phyllodes tumors. However, in rare cases where metastasis occurs, prognosis tends to be poor. This report describes the presentation, imaging findings and management of a metastatic malignant phyllodes tumor.

  5. Cancer-associated adipocytes promotes breast tumor radioresistance

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-07-22

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

  6. Ovarian granulosa cell tumor and increased risk of breast cancer.

    Science.gov (United States)

    Hammer, Anne; Lauszus, Finn F; Petersen, Astrid C

    2013-12-01

    Granulosa cell tumor of the ovary (GCT) is a rare neoplasm. The tumor often secretes estrogens and then presents at an earlier stage due to hormone-related symptoms. GCT women are at increased risk of endometrial carcinoma, but there is only limited information about GCTs and potential association to other hormone-related neoplasms such as breast cancer. We conducted a retrospective follow-up study on 163 women with GCT. Medical records and histological sections were reviewed and a search in the pathology registry performed. Eight [95% confidence interval (CI); 3.4-15.8] GCT women were diagnosed with a breast neoplasm; one with Paget's disease of the nipple and seven with breast carcinoma. Based on calculations using incidence rates on breast cancer among Danish women, we would have expected 2.5 cases of breast cancer. The odds ratio was 3.3 (95% CI, 1.6-6.6), suggesting an increased risk of breast cancer in GCT women. © 2013 Nordic Federation of Societies of Obstetrics and Gynecology.

  7. 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.

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

    NARCIS (Netherlands)

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

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

  9. 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....

  10. Tumor tissue protein signatures reflect histological grade of breast cancer.

    Science.gov (United States)

    Skoog, Petter; Ohlsson, Mattias; Fernö, Mårten; Rydén, Lisa; Borrebaeck, Carl A K; Wingren, Christer

    2017-01-01

    Histological grade is one of the most commonly used prognostic factors for patients diagnosed with breast cancer. However, conventional grading has proven technically challenging, and up to 60% of the tumors are classified as histological grade 2, which represents a heterogeneous cohort less informative for clinical decision making. In an attempt to study and extend the molecular puzzle of histologically graded breast cancer, we have in this pilot project searched for additional protein biomarkers in a new space of the proteome. To this end, we have for the first time performed protein expression profiling of breast cancer tumor tissue, using recombinant antibody microarrays, targeting mainly immunoregulatory proteins. Thus, we have explored the immune system as a disease-specific sensor (clinical immunoproteomics). Uniquely, the results showed that several biologically relevant proteins reflecting histological grade could be delineated. In more detail, the tentative biomarker panels could be used to i) build a candidate model classifying grade 1 vs. grade 3 tumors, ii) demonstrate the molecular heterogeneity among grade 2 tumors, and iii) potentially re-classify several of the grade 2 tumors to more like grade 1 or grade 3 tumors. This could, in the long-term run, lead to improved prognosis, by which the patients could benefit from improved tailored care.

  11. Background parenchymal enhancement in breast MRIs of breast cancer patients: impact on tumor size estimation.

    Science.gov (United States)

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

    2014-08-01

    To evaluate whether the degree of background parenchymal enhancement affects the accuracy of tumor size estimation based on breast MRI. 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. 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%; penhancement 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. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  12. 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)

  13. ID genes mediate tumor reinitiation during breast cancer lung metastasis

    Science.gov (United States)

    Gupta, Gaorav P.; Perk, Jonathan; Acharyya, Swarnali; de Candia, Paola; Mittal, Vivek; Todorova-Manova, Katia; Gerald, William L.; Brogi, Edi; Benezra, Robert; Massagué, Joan

    2007-01-01

    The establishment of distant metastases depends on the capacity of small numbers of cancer cells to regenerate a tumor after entering a target tissue. The mechanisms that confer this capacity remain to be defined. Here we identify a role for the transcriptional inhibitors of differentiation Id1 and Id3 as selective mediators of lung metastatic colonization in the triple negative [TN, i.e., lacking expression of estrogen receptor and progesterone receptor, and lacking Her2 (human epidermal growth factor receptor 2) amplification] subgroup of human breast cancer. Although broad expression of Id1 has recently been documented in tumors of the rare metaplastic subtype, here we report that rare Id1-expressing cells are also present in the more common TN subset of human breast tumors but not in other subtypes. We also provide evidence that Id1 expression is enriched in clinically obtained hormone receptor negative lung metastases. Functional studies demonstrate that Id1 and its closely related family member Id3 are required for tumor initiating functions, both in the context of primary tumor formation and during metastatic colonization of the lung microenvironment. In vivo characterization of lung metastatic progression reveals that Id1 and Id3 facilitate sustained proliferation during the early stages of metastatic colonization, subsequent to extravasation into the lung parenchyma. These results shed light on the proliferative mechanisms that initiate metastatic colonization, and they implicate Id1 and Id3 as mediators of this malignant function in the TN subgroup of breast cancers. PMID:18048329

  14. Coexistence of malignant phyllodes tumor and her2-positive locally advanced breast cancer in distinct breasts: A case report.

    Science.gov (United States)

    Sato, Tomoi; Muto, Ichiro; Sakai, Takeshi

    2016-01-01

    Phyllodes tumor of the breast is a rare biphasic neoplasm, accounting for less than 1% of all breast tumors. Coexistence of phyllodes tumor and breast cancer in distinct breasts is extremely rare. A 47-year-old Japanese woman presented with bilateral breast lumps. A HER2-positive, unresectable invasive carcinoma in the right breast and fibroadenoma in the left were diagnosed via core needle biopsy. During chemotherapy with anti-HER2 therapy, the breast cancer shrank quickly, while the left breast lump suddenly enlarged. Under a diagnosis of malignant neoplasm of the breast, left mastectomy was performed. Malignant phyllodes tumor was diagnosed by postoperative histological examination and recurred in multiple areas as early as 2 months after surgery. Only 10 cases of coexisting phyllodes tumor and breast cancer in distinct breasts have been reported in the English literature. Phyllodes tumor associated with breast cancer in distinct breasts tends to be malignant. This is the first case of phyllodes tumor rapidly enlarging during anti-HER2 chemotherapy for locally advanced HER2-positive breast cancer. Even during effective treatment of advanced or recurrent breast cancer, attention should also be paid to the contralateral breast for the possible association of a second malignancy such as phyllodes tumor. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. Tumor-Host Interaction in Breast Cancer Bone Metastasis

    Science.gov (United States)

    2006-01-01

    Kallioniemi, O.-P., and Ethier, S. P. Molecular cytogenetic analysis of 11 new breast cancer cell lines. Br J Cancer, 81: 1328-1334, 1999. 26. Harris, A...1.318480186 NM_000546 TP53 Tumor protein p53 (Li-Fraumeni syndrome ) 0.875703301 NM_006670 TPBG Trophoblast glycoprotein 1.130637565 NM_003379 VIL2 Villin...primary tumors was determined according to the Richardson– Bloom grading system [17]. BM assessment BM (10 cc) was aspirated from the sternum and both

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-01-02

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

  17. Comparison of tumor-infiltrating lymphocytes between primary and metastatic tumors in breast cancer patients.

    Science.gov (United States)

    Ogiya, Rin; Niikura, Naoki; Kumaki, Nobue; Bianchini, Giampaolo; Kitano, Shigehisa; Iwamoto, Takayuki; Hayashi, Naoki; Yokoyama, Kozue; Oshitanai, Risa; Terao, Mayako; Morioka, Toru; Tsuda, Banri; Okamura, Takuho; Saito, Yuki; Suzuki, Yasuhiro; Tokuda, Yutaka

    2016-12-01

    The presence of tumor-infiltrating lymphocytes (TILs) is associated with favorable long-term outcome in breast cancer. However, little is known about changes in TILs during metastatic progression. To confirm our hypothesis that malignant tumors escape from the host immune system during metastasis, we evaluated the percentage of TILs in paired samples of primary and metastatic breast tumors. We retrospectively identified 25 patients with human epidermal growth factor receptor-2 (HER2 + , n = 14) and triple negative (TN, n = 11) early breast cancer diagnosed between 1990 and 2009 at Tokai University Hospital (Isehara, Japan) and who subsequently experienced regional or distant recurrence confirmed by tumor biopsy/resection. Hematoxylin-eosin-stained slides of these paired samples were evaluated for stromal TILs. Immunohistochemical staining was carried out using primary antibodies against CD4, CD8, Foxp3, programmed cell death ligand 1 (PD-L1), PD-L2, and HLA class I for characterizing the TILs and breast tumors. The percentage of TILs in the primary tumors was significantly higher (average 34.6%) than that in metastatic tumors (average 15.7%) (paired t-test, P = 0.004) and that of CD8 + and CD4 + T cells significantly decreased from primary to metastatic tumors (paired t-test, P = 0.008 and P = 0.026, respectively). The PD-L1, PD-L2, and HLA class I antibody expression changed from positive to negative and vice versa from the primary to the metastatic tumors. Tumors at first metastatic recurrence in HER2 + and TN breast cancers have a lower percentage of TILs and CD8 + and CD4 + T cells compared to primary tumors, which indicates that immune escape plays a role in tumor progression. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  18. Enhancing Tumor Detection in IR-UWB Breast Cancer System

    Science.gov (United States)

    Ghoname, Reda; Elmahdy, Abd Elmonem; Zekry, Abd Elhalim

    2017-01-01

    An ultra-wideband (UWB) microwave system for breast cancer detection is presented. The proposed system includes monocycle pulse generator, antipodal Vivaldi antenna, breast model, and calibration algorithm for tumor detection. Firstly, our pulse generator employs transmission gate in glitch generator to achieve several advantages such as low power consumption and low ringing level. Secondly, the antipodal Vivaldi antenna is designed assuming FR4 dielectric substrate material, and developed antenna element (80 × 80 mm2) features a −10 dB return loss and bandwidth ranges from 2.3 GHz to more than 11 GHz. Thirdly, the phantom breast can be modeled as a layer of skin, fat, and then tumor is inserted in this layer. Finally, subtract and add algorithm (SAD) is used as a calibration algorithm in tumor detection system. The proposed system suggested that horizontal antenna position with 90° between transmitting and receiving antennas is localized as a suitable antenna position with different rotating location and a 0.5 cm near to phantom. The mean advantages of this localization and tracking position around breast is a high received power signal approximately around mv as a higher recognized signal in tumor detection. Using our proposed system we can detect tumor in 5 mm diameter. PMID:28421208

  19. Enhancing Tumor Detection in IR-UWB Breast Cancer System

    Directory of Open Access Journals (Sweden)

    Sara Fouad

    2017-01-01

    Full Text Available An ultra-wideband (UWB microwave system for breast cancer detection is presented. The proposed system includes monocycle pulse generator, antipodal Vivaldi antenna, breast model, and calibration algorithm for tumor detection. Firstly, our pulse generator employs transmission gate in glitch generator to achieve several advantages such as low power consumption and low ringing level. Secondly, the antipodal Vivaldi antenna is designed assuming FR4 dielectric substrate material, and developed antenna element (80×80 mm2 features a −10 dB return loss and bandwidth ranges from 2.3 GHz to more than 11 GHz. Thirdly, the phantom breast can be modeled as a layer of skin, fat, and then tumor is inserted in this layer. Finally, subtract and add algorithm (SAD is used as a calibration algorithm in tumor detection system. The proposed system suggested that horizontal antenna position with 90° between transmitting and receiving antennas is localized as a suitable antenna position with different rotating location and a 0.5 cm near to phantom. The mean advantages of this localization and tracking position around breast is a high received power signal approximately around mv as a higher recognized signal in tumor detection. Using our proposed system we can detect tumor in 5 mm diameter.

  20. Dissecting Tumor-Stromal Interactions in Breast Cancer Bone Metastasis

    Directory of Open Access Journals (Sweden)

    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.

  1. High tumor budding stratifies breast cancer with metastatic properties.

    Science.gov (United States)

    Salhia, Bodour; Trippel, Mafalda; Pfaltz, Katrin; Cihoric, Nikola; Grogg, André; Lädrach, Claudia; Zlobec, Inti; Tapia, Coya

    2015-04-01

    Tumor budding refers to single or small cluster of tumor cells detached from the main tumor mass. In colon cancer high tumor budding is associated with positive lymph nodes and worse prognosis. Therefore, we investigated the value of tumor budding as a predictive feature of lymph node status in breast cancer (BC). Whole tissue sections from 148 surgical resection specimens (SRS) and 99 matched preoperative core biopsies (CB) with invasive BC of no special type were analyzed on one slide stained with pan-cytokeratin. In SRS, the total number of intratumoral (ITB) and peripheral tumor buds (PTB) in ten high-power fields (HPF) were counted. A bud was defined as a single tumor cell or a cluster of up to five tumor cells. High tumor budding equated to scores averaging >4 tumor buds across 10HPFs. In CB high tumor budding was defined as ≥10 buds/HPF. The results were correlated with pathological parameters. In SRS high PTB stratified BC with lymph node metastases (p ≤ 0.03) and lymphatic invasion (p ≤ 0.015). In CB high tumor budding was significantly (p = 0.0063) associated with venous invasion. Pathologists are able, based on morphology, to categorize BC into a high and low risk groups based in part on lymph node status. This risk assessment can be easily performed during routine diagnostics and it is time and cost effective. These results suggest that high PTB is associated with loco-regional metastasis, highlighting the possibility that this tumor feature may help in therapeutic decision-making.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-08-15

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

  3. Tumor-expressed adrenomedullin accelerates breast cancer bone metastasis.

    Science.gov (United States)

    Siclari, Valerie A; Mohammad, Khalid S; Tompkins, Douglas R; Davis, Holly; McKenna, C Ryan; Peng, Xianghong; Wessner, Lisa L; Niewolna, Maria; Guise, Theresa A; Suvannasankha, Attaya; Chirgwin, John M

    2014-12-02

    Adrenomedullin (AM) is secreted by breast cancer cells and increased by hypoxia. It is a multifunctional peptide that stimulates angiogenesis and proliferation. The peptide is also a potent paracrine stimulator of osteoblasts and bone formation, suggesting a role in skeletal metastases-a major site of treatment-refractory tumor growth in patients with advanced disease. The role of adrenomedullin in bone metastases was tested by stable overexpression in MDA-MB-231 breast cancer cells, which cause osteolytic bone metastases in a standard animal model. Cells with fivefold increased expression of AM were characterized in vitro, inoculated into immunodeficient mice and compared for their ability to form bone metastases versus control subclones. Bone destruction was monitored by X-ray, and tumor burden and osteoclast numbers were determined by quantitative histomorphometry. The effects of AM overexpression on tumor growth and angiogenesis in the mammary fat pad were determined. The effects of AM peptide on osteoclast-like multinucleated cell formation were tested in vitro. A small-molecule AM antagonist was tested for its effects on AM-stimulated ex vivo bone cell cultures and co-cultures with tumor cells, where responses of tumor and bone were distinguished by species-specific real-time PCR. Overexpression of AM mRNA did not alter cell proliferation in vitro, expression of tumor-secreted factors or cell cycle progression. AM-overexpressing cells caused osteolytic bone metastases to develop more rapidly, which was accompanied by decreased survival. In the mammary fat pad, tumors grew more rapidly with unchanged blood vessel formation. Tumor growth in the bone was also more rapid, and osteoclasts were increased. AM peptide potently stimulated bone cultures ex vivo; responses that were blocked by small-molecule adrenomedullin antagonists in the absence of cellular toxicity. Antagonist treatment dramatically suppressed tumor growth in bone and decreased markers of

  4. Tumor associated macrophage × cancer cell hybrids may acquire cancer stem cell properties in breast cancer.

    Directory of Open Access Journals (Sweden)

    Jingxian Ding

    Full Text Available Breast cancer is one of the most frequently diagnosed cancers among women, and metastasis makes it lethal. Tumor-associated macrophages (TAMs that acquire an alternatively activated macrophage (M2 phenotype may promote metastasis. However, the underlying mechanisms are still elusive. Here, we examined how TAMs interact with breast cancer cells to promote metastasis. Immunohistochemistry was used to examine the expression of the M2-specific antigen CD163 in paraffin-embedded mammary carcinoma blocks to explore fusion events in breast cancer patients. U937 cells were used as a substitute for human monocytes, and these cells differentiated into M2 macrophages following phorbol 12-myristate 13-acetate (PMA and M-CSF stimulation. M2 macrophages and the breast cancer cell lines MCF-7 and MDA-MB-231 fused in the presence of 50% polyethylene glycol. Hybrids were isolated by fluorescence-activated cell sorting, and the relevant cell biological properties were compared with their parental counterparts. Breast cancer stem cell (BCSC-related markers were quantified by immunofluorescence staining, RT-PCR, quantitative RT-PCR and/or western blotting. The tumor-initiating and metastatic capacities of the hybrids and their parental counterparts were assessed in NOD/SCID mice. We found that the CD163 expression rate in breast cancer tissues varied significantly and correlated with estrogen receptor status (p0.05. Characterization of the fusion hybrids revealed a more aggressive phenotype, including increased migration, invasion and tumorigenicity, but reduced proliferative ability, compared with the parental lines. The hybrids also gained a CD44(+CD24(-/low phenotype and over-expressed epithelial-mesenchymal transition-associated genes. These results indicate that TAMs may promote breast cancer metastasis through cell fusion, and the hybrids may gain a BCSC phenotype.

  5. Macrophage Polarization: Anti-Cancer Strategies to Target Tumor-Associated Macrophage in Breast Cancer.

    Science.gov (United States)

    Tariq, Muhammad; Zhang, Jieqiong; Liang, Guikai; Ding, Ling; He, Qiaojun; Yang, Bo

    2017-09-01

    Tumor-associated macrophages (TAMs) are the most abundant inflammatory cells and orchestrate different stages of breast cancer development. TAMs participate in the tumor angiogenesis, matrix remodeling, invasion, immunosuppression, metastasis, and chemoresistance in breast cancer. Several clinical studies indicate the association between the high influx of TAMs in tumor with poor prognosis in hepatocellular, ovarian, cervical, and breast cancer. Previously developed hypotheses have proposed that TAMs participate in antitumor responses of the body, while recently many clinical and experimental studies have revealed that TAMs in tumor microenvironment predominantly resemble with M2-like polarized macrophages and produce a high amount of anti-inflammatory factors which are directly responsible for the development of tumor. Various studies have shown that TAMs in tumor either enhance or antagonize the anti-tumor efficacy of cytotoxic agents, antibodies-targeting cancer cells, and therapeutic agents depending on the nature of treatment. Thereby, multiple roles of TAMs suggests that it is very important to develop novel therapeutic strategies to target TAMs in breast tumor. In this review, we have discussed the functional role of TAMs in breast cancer and summarized available recent advances potential therapeutic strategies that effectively target to TAMs cells. J. Cell. Biochem. 118: 2484-2501, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  6. Established breast cancer risk factors and risk of intrinsic tumor subtypes.

    Science.gov (United States)

    Barnard, Mollie E; Boeke, Caroline E; Tamimi, Rulla M

    2015-08-01

    Breast cancer is a heterogeneous disease with multiple intrinsic tumor subtypes. These subtypes vary in tumor gene expression and phenotype, and are most commonly grouped into four major subtypes: luminal A, luminal B, HER2-overexpressing and triple negative (or basal-like). A growing number of studies have evaluated the relationship between established breast cancer risk factors and risk of one or more intrinsic tumor subtypes. We conducted a systematic review of 38 studies to synthesize their results and identify areas requiring more research. Taken together, published studies suggest that most established breast cancer risk factors reflect risk factors for the luminal A subtype of breast cancer, and some breast cancer risk factors may be differentially associated with other intrinsic tumor subtypes. Future breast cancer research will need to consider etiologic differences across subtypes and design studies focused on understanding the etiology and prevention of less common tumor subtypes. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Osteoprotegerin rich tumor microenvironment: implications in breast cancer.

    Science.gov (United States)

    Goswami, Sudeshna; Sharma-Walia, Neelam

    2016-07-05

    Osteoprotegerin (OPG) is a soluble decoy receptor for tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL). It belongs to the tumor necrosis factor receptor superfamily (TNFRSF). OPG was initially discovered to contribute to homeostasis of bone turnover due to its capability of binding to receptor activator of nuclear factor-kappaB (NF-kB). However, apart from bone turnover, OPG plays important and diverse role(s) in many biological functions. Besides having anti-osteoclastic activity, OPG is thought to exert a protective anti-apoptotic action in OPG-expressing tumors by overcoming the physiologic mechanism of tumor surveillance exerted by TRAIL. Along with inhibiting TRAIL induced apoptosis, it can induce proliferation by binding to various cell surface receptors and thus turning on the canonical cell survival and proliferative pathways. OPG also induces angiogenesis, one of the hallmarks of cancer, thus facilitating tumor growth. Recently, the understanding of OPG and its different roles has been augmented substantially. This review is aimed at providing a very informative overview as to how OPG affects cancer progression especially breast cancer.

  8. Osteoprotegerin mediates tumor-promoting effects of Interleukin-1beta in breast cancer cells

    NARCIS (Netherlands)

    Chung, S.T.M. (Stephanie Tsang Mui); D. Geerts (Dirk); Roseman, K. (Kim); Renaud, A. (Ashleigh); Connelly, L. (Linda)

    2017-01-01

    markdownabstract__Background:__ It is widely recognized that inflammation promotes breast cancer invasion and metastasis. Given the complex nature of the breast tumor inflammatory microenvironment, much remains to be understood of the molecular mechanisms that govern these effects. We have

  9. Tumor cell budding from focally disrupted tumor capsules: a common pathway for all breast cancer subtype derived invasion?

    Directory of Open Access Journals (Sweden)

    Yan-gao Man

    2010-01-01

    Full Text Available Human breast cancer represents a group of highly heterogeneous lesions consisting of about 20 morphologically and immnohistochemically distinct subtypes with substantially different prognoses. Our recent studies have suggested that all breast cancer subtypes, however, may share a common pathway, tumor cell budding from focally disrupted tumor capsules, for their invasion. The potential mechanisms and clinical implications of our observations are discussed.

  10. Terahertz Imaging of Three-Dimensional Dehydrated Breast Cancer Tumors

    Science.gov (United States)

    Bowman, Tyler; Wu, Yuhao; Gauch, John; Campbell, Lucas K.; El-Shenawee, Magda

    2017-06-01

    This work presents the application of terahertz imaging to three-dimensional formalin-fixed, paraffin-embedded human breast cancer tumors. The results demonstrate the capability of terahertz for in-depth scanning to produce cross section images without the need to slice the tumor. Samples of tumors excised from women diagnosed with infiltrating ductal carcinoma and lobular carcinoma are investigated using a pulsed terahertz time domain imaging system. A time of flight estimation is used to obtain vertical and horizontal cross section images of tumor tissues embedded in paraffin block. Strong agreement is shown comparing the terahertz images obtained by electronically scanning the tumor in-depth in comparison with histopathology images. The detection of cancer tissue inside the block is found to be accurate to depths over 1 mm. Image processing techniques are applied to provide improved contrast and automation of the obtained terahertz images. In particular, unsharp masking and edge detection methods are found to be most effective for three-dimensional block imaging.

  11. 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 ...

  12. HET is a Novel Tumor Suppressor Gene in Human Breast Cancer

    National Research Council Canada - National Science Library

    Oesterreich, Steffi

    1999-01-01

    .... In the first specific aim we will directly answer whether HET is the tumor suppressor gene by performing additional LOB analysis and mutational analysis of BET in breast cancer cell lines as well as in tumors...

  13. MMP13 is potentially a new tumor marker for breast cancer diagnosis.

    Science.gov (United States)

    Chang, Hui-Jen; Yang, Ming-Je; Yang, Yu-Hsiang; Hou, Ming-Feng; Hsueh, Er-Jung; Lin, Shiu-Ru

    2009-11-01

    Within the past decade, the incidence of breast cancer in Taiwan has been rising year after year. Breast cancer is the first most prevalent cancer and the fourth leading cause of cancer-related deaths among women in Taiwan. The early stage of breast cancer not only have a wider range of therapeutic options, but also obtain a higher success rate of therapy than those with advanced breast cancer. A test for tumor markers is the most convenient method to screen for breast cancer. However, the tumor markers currently available for breast cancer detection include carcinoembryonic antigen (CEA), carbohydrate antigen 15.3 (CA15.3), and carbohydrate antigen 27.29 (CA27.29) exhibited certain limitations. Poor sensitivity and specificity greatly limits the diagnostic accuracy of these markers. This study aims to identify potential tumor markers for breast cancer. At first, we analyzed genes expression in infiltrating lobular carcinoma, metaplastic carcinoma, and infiltrating ductal carcinoma of paired specimens (tumor and normal tissue) from breast cancer patients using microarray technology. We selected 371 overexpressed genes in all of the three cell type. In advanced breast cancer tissue, we detected four genes MMP13, CAMP, COL10A1 and FLJ25416 from 25 overexpressed genes which encoded secretion protein more specifically for breast cancer than other genes. After validation with 15 pairs of breast cancer tissue and paired to normal adjacent tissues by membrane array and quantitative RT-PCR, we found MMP13 was 100% overexpressed and confirmed to be a secreted protein by Western blot analysis of the cell culture medium. The expression level of MMP13 was also measured by immunohistochemical staining. We suggest that MMP13 is a highly overexpressed secretion protein in breast cancer tissue. It has potential to be a new tumor marker for breast cancer diagnosis.

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

    DEFF Research Database (Denmark)

    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...... of ITC in the SN of 414 breast cancer patients with recent surgical excision to a group of 16,960 patients without recent surgical procedure in a multivariate analysis by linking data from the Danish Breast Cancer Cooperative Group database and the Danish National Health Register. Moreover, the incidence...

  15. Loss of Tumor Suppressor Merlin in Advanced Breast Cancer Is due to Post-translational Regulation*

    Science.gov (United States)

    Morrow, K. Adam; Das, Shamik; Metge, Brandon J.; Ye, Keqiang; Mulekar, Madhuri S.; Tucker, J. Allan; Samant, Rajeev S.; Shevde, Lalita A.

    2011-01-01

    Unlike malignancies of the nervous system, there have been no mutations identified in Merlin in breast cancer. As such, the role of the tumor suppressor, Merlin, has not been investigated in breast cancer. We assessed Merlin expression in breast cancer tissues by immunohistochemistry and by real-time PCR. The expression of Merlin protein (assessed immunohistochemically) was significantly decreased in breast cancer tissues (although the transcript levels were comparable) simultaneous with increased expression of the tumor-promoting protein, osteopontin (OPN). We further demonstrate that the loss of Merlin in breast cancer is brought about, in part, due to OPN-initiated Akt-mediated phosphorylation of Merlin leading to its proteasomal degradation. Restoring expression of Merlin resulted in reduced malignant attributes of breast cancer, characterized by reduced invasion, migration, motility, and impeded tumor (xenograft) growth in immunocompromised mice. The possibility of developing a model using the relationship between OPN and Merlin was tested with a logistic regression model applied to immunohistochemistry data. This identified consistent loss of immunohistochemical expression of Merlin in breast tumor tissues. Thus, we demonstrate for the first time a role for Merlin in impeding breast malignancy, identify a novel mechanism for the loss of Merlin protein in breast cancer, and have developed a discriminatory model using Merlin and OPN expression in breast tumor tissues. PMID:21965655

  16. Loss of tumor suppressor Merlin in advanced breast cancer is due to post-translational regulation.

    Science.gov (United States)

    Morrow, K Adam; Das, Shamik; Metge, Brandon J; Ye, Keqiang; Mulekar, Madhuri S; Tucker, J Allan; Samant, Rajeev S; Shevde, Lalita A

    2011-11-18

    Unlike malignancies of the nervous system, there have been no mutations identified in Merlin in breast cancer. As such, the role of the tumor suppressor, Merlin, has not been investigated in breast cancer. We assessed Merlin expression in breast cancer tissues by immunohistochemistry and by real-time PCR. The expression of Merlin protein (assessed immunohistochemically) was significantly decreased in breast cancer tissues (although the transcript levels were comparable) simultaneous with increased expression of the tumor-promoting protein, osteopontin (OPN). We further demonstrate that the loss of Merlin in breast cancer is brought about, in part, due to OPN-initiated Akt-mediated phosphorylation of Merlin leading to its proteasomal degradation. Restoring expression of Merlin resulted in reduced malignant attributes of breast cancer, characterized by reduced invasion, migration, motility, and impeded tumor (xenograft) growth in immunocompromised mice. The possibility of developing a model using the relationship between OPN and Merlin was tested with a logistic regression model applied to immunohistochemistry data. This identified consistent loss of immunohistochemical expression of Merlin in breast tumor tissues. Thus, we demonstrate for the first time a role for Merlin in impeding breast malignancy, identify a novel mechanism for the loss of Merlin protein in breast cancer, and have developed a discriminatory model using Merlin and OPN expression in breast tumor tissues.

  17. Incorporating Tumor Characteristics to the American Joint Committee on Cancer Breast Cancer Staging System.

    Science.gov (United States)

    Chavez-MacGregor, Mariana; Mittendorf, Elizabeth A; Clarke, Christina A; Lichtensztajn, Daphne Y; Hunt, Kelly K; Giordano, Sharon H

    2017-11-01

    The American Joint Committee on Cancer (AJCC) breast cancer staging system provides important prognostic information. The recently published eighth edition incorporates biological markers and recommends the use of a complex "prognostic stage." In this study, we assessed the relationship between stage, breast cancer subtype, grade, and outcome in a large population-based cohort and evaluated a risk score system incorporating tumor characteristic to the AJCC anatomic staging system. Patients diagnosed with primary breast cancer stage I-IV between 2005-2008 were identified in the California Cancer Registry. For patients with stage I-III disease, pathologic stage was recorded. For patients with stage IV disease, clinical stage was utilized. Five-year breast cancer specific survival (BCSS) and overall survival (OS) rates were determined for each potential tumor size-node involvement-metastases (TNM) combination according to breast cancer subtype. A risk score point-based system using grade, estrogen receptor, and human epidermal growth factor receptor 2 (HER2) status was designed to complement the anatomic AJCC staging system. Survival probabilities between groups were compared using log-rank test. Cox proportional hazards models were used. Among 43,938 patients, we observed differences in 5-year BCSS and OS for each TNM combination according to breast cancer subtype. The most favorable outcomes were seen for hormone receptor-positive tumors followed closely by HER2-positive tumors, with the worst outcomes observed for triple negative breast cancer. Our risk score system separated patients into four risk groups within each stage category (all p  system incorporates biological factors into the AJCC anatomic staging system, providing accurate prognostic information. This study demonstrates that stage, but also breast cancer subtype and grade, define prognosis in a large population of breast cancer patients. It shows that a point-based risk score system that incorporates

  18. Cadmium, arsenic, selenium and iron- Implications for tumor progression in breast cancer.

    Science.gov (United States)

    Jablonska, E; Socha, K; Reszka, E; Wieczorek, E; Skokowski, J; Kalinowski, L; Fendler, W; Seroczynska, B; Wozniak, M; Borawska, M H; Wasowicz, W

    2017-07-01

    The aim of this study was to determine Cd (cadmium) and As (arsenic) contents in human breast cancer tissues, investigate their interactions with Se (selenium) and Fe (iron), and assess their further implications for tumor progression. Metal contents were determined in 42 tissue sets (tumor and adjacent tissue) collected from 42 women diagnosed with primary breast cancer. Analytical methods included AAS and ICP-MS techniques. Significantly higher contents of Cd (p=0.0003), Se (psupport the role of Cd in breast cancer risk and progression. The possible link between As exposure and breast cancer is still not clear. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2016-04-05

    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.

  20. GT198 Expression Defines Mutant Tumor Stroma in Human Breast Cancer.

    Science.gov (United States)

    Yang, Zheqiong; Peng, Min; Cheng, Liang; Jones, Kimya; Maihle, Nita J; Mivechi, Nahid F; Ko, Lan

    2016-05-01

    Human breast cancer precursor cells remain to be elucidated. Using breast cancer gene product GT198 (PSMC3IP; alias TBPIP or Hop2) as a unique marker, we revealed the cellular identities of GT198 mutant cells in human breast tumor stroma. GT198 is a steroid hormone receptor coactivator and a crucial factor in DNA repair. Germline mutations in GT198 are present in breast and ovarian cancer families. Somatic mutations in GT198 are present in ovarian tumor stromal cells. Herein, we show that human breast tumor stromal cells carry GT198 somatic mutations and express cytoplasmic GT198 protein. GT198(+) stromal cells share vascular smooth muscle cell origin, including myoepithelial cells, adipocytes, capillary pericytes, and stromal fibroblasts. Frequent GT198 mutations are associated with GT198(+) tumor stroma but not with GT198(-) tumor cells. GT198(+) progenitor cells are mostly capillary pericytes. When tested in cultured cells, mutant GT198 induces vascular endothelial growth factor promoter, and potentially promotes angiogenesis and adipogenesis. Our results suggest that multiple lineages of breast tumor stromal cells are mutated in GT198. These findings imply the presence of mutant progenitors, whereas their descendants, carrying the same GT198 mutations, are collectively responsible for forming breast tumor microenvironment. GT198 expression is, therefore, a specific marker of mutant breast tumor stroma and has the potential to facilitate diagnosis and targeted treatment of human breast cancer. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  1. Human breast adipose tissue: characterization of factors that change during tumor progression in human breast cancer.

    Science.gov (United States)

    Fletcher, Sabrina Johanna; Sacca, Paula Alejandra; Pistone-Creydt, Mercedes; Coló, Federico Andrés; Serra, María Florencia; Santino, Flavia Eliana; Sasso, Corina Verónica; Lopez-Fontana, Constanza Matilde; Carón, Rubén Walter; Calvo, Juan Carlos; Pistone-Creydt, Virginia

    2017-02-07

    Adipose microenvironment is involved in signaling pathways that influence breast cancer. We aim to characterize factors that are modified: 1) in tumor and non tumor human breast epithelial cell lines when incubated with conditioned media (CMs) from human breast cancer adipose tissue explants (hATT) or normal breast adipose tissue explants (hATN); 2) in hATN-CMs vs hATT-CMs; 3) in the tumor associated adipocytes vs. non tumor associated adipocytes. We used hATN or hATT- CMs on tumor and non-tumor breast cancer cell lines. We evaluated changes in versican, CD44, ADAMTS1 and Adipo R1 expression on cell lines or in the different CMs. In addition we evaluated changes in the morphology and expression of these factors in slices of the different adipose tissues. The statistical significance between different experimental conditions was evaluated by one-way ANOVA. Tukey's post-hoc tests were performed within each individual treatment. hATT-CMs increase versican, CD44, ADAMTS1 and Adipo R1 expression in breast cancer epithelial cells. Furthermore, hATT-CMs present higher levels of versican expression compared to hATN-CMs. In addition, we observed a loss of effect in cellular migration when we pre-incubated hATT-CMs with chondroitinase ABC, which cleaves GAGs chains bound to the versican core protein, thus losing the ability to bind to CD44. Adipocytes associated with the invasive front are reduced in size compared to adipocytes that are farther away. Also, hATT adipocytes express significantly higher amounts of versican, CD44 and Adipo R1, and significantly lower amounts of adiponectin and perilipin, unlike hATN adipocytes. We conclude that hATT secrete a different set of proteins compared to hATN. Furthermore, versican, a proteoglycan that is overexpressed in hATT-CMs compared to hATN-CMs, might be involved in the tumorogenic behavior observed in both cell lines employed. In addition, we may conclude that adipocytes from the tumor microenvironment show a less differentiated

  2. Tropomyosin-1, A Putative Tumor-Suppressor and a Biomarker of Human Breast Cancer

    Science.gov (United States)

    2004-10-01

    cDNA. Lobular carcinoma - 2 A polyclonal pan-TM antibody that recognizes multiple TM Phyllodes tumor - 1 Not determined from the initial pathology...AD Award Number: DAMD17-98-1-8162 TITLE: Tropomyosin-1, A Putative Tumor -Suppressor and a Biomarker of Human Breast Cancer PRINCIPAL INVESTIGATOR...4. TITLE AND SUBTITLE 5. FUNDING NUMBERS Tropomyosin-l, A Putative Tumor -Suppressor and a Biomarker DAMD17-98-1-8162 of Human Breast Cancer 6. A UTHOR

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

    DEFF Research Database (Denmark)

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

    2013-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Fasching, Peter A. [Department of Gynecology and Obstetrics, Erlangen University Hospital, Universitaetsstrasse 21-23, D-91054 Erlangen (Germany)]. E-mail: peter.fasching@gyn.med.uni-erlangen.de; Heusinger, Katharina [Department of Gynecology and Obstetrics, Erlangen University Hospital, Universitaetsstrasse 21-23, D-91054 Erlangen (Germany); Loehberg, Christian R. [Department of Gynecology and Obstetrics, Erlangen University Hospital, Universitaetsstrasse 21-23, D-91054 Erlangen (Germany); Wenkel, Evelyn [Institute of Diagnostic Radiology, Erlangen University Hospital, Erlangen (Germany); Lux, Michael P. [Department of Gynecology and Obstetrics, Erlangen University Hospital, Universitaetsstrasse 21-23, D-91054 Erlangen (Germany); Schrauder, Michael [Department of Gynecology and Obstetrics, Erlangen University Hospital, Universitaetsstrasse 21-23, D-91054 Erlangen (Germany); Koscheck, Thomas [Institute of Pathology, Friedrich Alexander University, Erlangen-Nuremberg (Germany); Bautz, Werner [Institute of Diagnostic Radiology, Erlangen University Hospital, Erlangen (Germany); Schulz-Wendtland, Ruediger [Institute of Diagnostic Radiology, Erlangen University Hospital, Erlangen (Germany); Beckmann, Matthias W. [Department of Gynecology and Obstetrics, Erlangen University Hospital, Universitaetsstrasse 21-23, D-91054 Erlangen (Germany); Bani, Mayada R. [Department of Gynecology and Obstetrics, Erlangen University Hospital, Universitaetsstrasse 21-23, D-91054 Erlangen (Germany)

    2006-12-15

    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 < 0.001). The clinical examination was not affected by BD. Age and tumor size were the only parameters associated with a denser breast in the multivariate analysis. Older women were less likely to have dense breasts (odds ratio 0.157 for women aged {>=}70 years), and patients with larger tumors were less likely to have dense breasts (adjusted OR 0.36 for tumors > 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.

  5. Breast cancer stem cells, cytokine networks, and the tumor microenvironment

    National Research Council Canada - National Science Library

    Korkaya, Hasan; Liu, Suling; Wicha, Max S

    2011-01-01

    .... These cancer stem cells (CSCs) are regulated by complex interactions with the components of the tumor microenvironment - including mesenchymal stem cells, adipocytes, tumor associated fibroblasts, endothelial cells, and immune...

  6. Expression of Iron-Related Proteins Differentiate Non-Cancerous and Cancerous Breast Tumors

    Directory of Open Access Journals (Sweden)

    Sara Pizzamiglio

    2017-02-01

    Full Text Available We have previously reported hepcidin and ferritin increases in the plasma of breast cancer patients, but not in patients with benign breast disease. We hypothesized that these differences in systemic iron homeostasis may reflect alterations in different iron-related proteins also play a key biochemical and regulatory role in breast cancer. Thus, here we explored the expression of a bundle of molecules involved in both iron homeostasis and tumorigenesis in tissue samples. Enzyme-linked immunosorbent assay (ELISA or reverse-phase protein array (RPPA, were used to measure the expression of 20 proteins linked to iron processes in 24 non-cancerous, and 56 cancerous, breast tumors. We found that cancerous tissues had higher level of hepcidin than benign lesions (p = 0.012. The univariate analysis of RPPA data highlighted the following seven proteins differentially expressed between non-cancerous and cancerous breast tissue: signal transducer and transcriptional activator 5 (STAT5, signal transducer and activator of transcription 3 (STAT3, bone morphogenetic protein 6 (BMP6, cluster of differentiation 74 (CD74, transferrin receptor (TFRC, inhibin alpha (INHA, and STAT5_pY694. These findings were confirmed for STAT5, STAT3, BMP6, CD74 and INHA when adjusting for age. The multivariate statistical analysis indicated an iron-related 10-protein panel effective in separating non-cancerous from cancerous lesions including STAT5, STAT5_pY694, myeloid differentiation factor 88 (MYD88, CD74, iron exporter ferroportin (FPN, high mobility group box 1 (HMGB1, STAT3_pS727, TFRC, ferritin heavy chain (FTH, and ferritin light chain (FTL. Our results showed an association between some iron-related proteins and the type of tumor tissue, which may provide insight in strategies for using iron chelators to treat breast cancer.

  7. E2F-HDAC complexes negatively regulate the tumor suppressor gene ARHI in breast cancer

    DEFF Research Database (Denmark)

    Lu, Z; Luo, R Z; Peng, H

    2006-01-01

    ARHI is a maternally imprinted tumor suppressor gene whose expression is markedly downregulated in breast cancer. Reactivation of ARHI expression in breast cancer cells is associated with increased histone H3 acetylation and decreased lysine 9 methylation of histone H3. An ARHI promoter segment...... of the tumor suppressor gene ARHI in breast cancer cells....... that spanned bases -420 to +58 (designated the P2 region) exhibits significantly higher promoter activity in normal cells than in cancer cells. To better understand the molecular mechanisms contributing to this differential transcriptional activity, we sought to identify transcription factors that bind...

  8. Period-2: a tumor suppressor gene in breast cancer

    Directory of Open Access Journals (Sweden)

    Cheng Qi

    2008-03-01

    Full Text Available Abstract Previous reports have suggested that the ablation of the Period 2 gene (Per 2 leads to enhanced development of lymphoma and leukemia in mice. Employing immunoblot analyses, we have demonstrated that PER 2 is endogenously expressed in human breast epithelial cell lines but is not expressed or is expressed at significantly reduced level in human breast cancer cell lines. Expression of PER 2 in MCF-7 breast cancer cells significantly inhibited the growth of MCF-7 human breast cancer cells, and, when PER 2 was co-expressed with the Crytochrome 2 (Cry 2 gene, an even greater growth-inhibitory effect was observed. The inhibitory effect of PER 2 on breast cancer cells was also demonstrated by its suppression of the anchorage-independent growth of MCF-7 cells as evidenced by the reduced number and size of colonies. A corresponding blockade of MCF-7 cells in the G1 phase of the cell cycle was also observed in response to the expression of PER 2 alone or in combination with CRY 2. Expression of PER 2 also induced apoptosis of MCF-7 breast cancer cells as demonstrated by an increase in PARP [poly (ADP-ribose polymerase] cleavage. Finally, our studies demonstrate that PER 2 expression in MCF-7 breast cancer cells is associated with a significant decrease in the expression of cyclin D1 and an up-regulation of p53 levels.

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

    OpenAIRE

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

    2013-01-01

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

  10. Breast Cancer Surgery

    Science.gov (United States)

    FACTS FOR LIFE Breast Cancer Surgery The goal of breast cancer surgery is to remove the whole tumor from the breast. Some lymph nodes ... might still be in the body. Types of breast cancer surgery There are two types of breast cancer ...

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

    Science.gov (United States)

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

    2014-01-01

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

  12. Serum calcium, tumor size, and hormone receptor status in women with untreated breast cancer.

    Science.gov (United States)

    Thaw, Sunn Sunn H; Sahmoun, Abe; Schwartz, Gary G

    2012-05-01

    Elevated serum levels of calcium are frequently observed in advanced breast cancer, but data on serum calcium and breast cancer characteristics at the time of breast cancer diagnosis are limited. We conducted a cross-sectional study of 555 women with newly-diagnosed, untreated breast cancer in North Dakota. We examined the relationship between tumor size, serum calcium and other clinical characteristics of breast tumors, including age and hormone receptor status, using multiple linear regressions. Tumors that were estrogen receptor negative tended to be associated with higher serum calcium levels (p = 0.07). We observed a significant positive correlation between tumor volume and serum calcium levels (adjusted for patient age, body mass index, hormonal receptors, stage at diagnosis, and grade). The association between tumor volume and serum calcium was limited to post-menopausal women. Our finding that postmenopausal women with larger breast tumors had significantly higher serum calcium levels is consistent with a calciotropic effect of early breast cancer in postmenopausal women.

  13. Interval breast cancers have worse tumor characteristics and survival compared to screen-detected breast cancers

    NARCIS (Netherlands)

    de Munck, L.; Siesling, S.; Pijnappel, R. M.; van der Vegt, B.; de Bock, G. H.

    2016-01-01

    Background There is debate to what extend screen-detected cancers (SDC) differ in tumor characteristics and survival from tumors that are detected not trough screening. These can be divide into three groups. Firstly, tumors who manifest clinically in the period between two screens after a negative

  14. Multifocal and Multicentric Breast Carcinoma: A Significantly More Aggressive Tumor than Unifocal Breast Cancer.

    Science.gov (United States)

    Lang, Zhiqiang; Wu, Yanqiu; Li, Cuiyan; Li, Xinna; Wang, Xuan; Qu, Guimei

    2017-08-01

    There are still many questions that surround multifocal or multicentric breast carcinoma (MMBC). The aim of this study was to analyze the clinicopathological characteristics of MMBC and provide feasible suggestions for therapy. A total of 156 cases of MMBC in 3,597 invasive ductal breast carcinomas were collected and reviewed. Some factors related with prognosis such as tumor size, lymph node metastasis and others were assessed in each tumor focus, and mismatches among foci were recorded. The majority of MMBC had aggregate dimensions over 2 cm (85.90%). The rate of axillary lymph node metastasis was 56.41% (88/156) compared to unifocal tumors of 33.01% (1,136/3,441). Most cases had higher Ki-67 proliferative indices (91/156). Mismatches in ER status were present in 6 cases, PR in 4 cases, proliferative index (Ki-67) in 9 cases and HER2-positive status in 2 cases. The larger aggregate dimension of tumor, the higher metastatic rate of axillary lymph node and the high Ki-67 proliferative index seen in most cases, suggest that MMBC is biologically more aggressive than unifocal breast cancer. In addition, every focus should be tested owing to the existence of different expressions of immunostaining between foci. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  15. Effects of Herceptin on circulating tumor cells in HER2 positive early breast cancer.

    Science.gov (United States)

    Zhang, J-L; Yao, Q; Chen Y Wang, J-H; Wang, H; Fan, Q; Ling, R; Yi, J; Wang, L

    2015-03-20

    The objective of this study was to determine the changes in peripheral blood circulating tumor cells in HER2-positive early breast cancer before and after Herceptin therapy, and to explore the effects of the HER2 gene and Herceptin on circulating tumor cells. CK19 mRNA expression in peripheral blood was evaluated by qRT-PCR as an index of circulating tumor cells in 15 cases of HER-2-positive breast cancer and 18 cases of HER2-negative breast cancer before, and after chemotherapy as well. Ten cases of HER2-positive breast cancer continued on Herceptin therapy for 3 months after chemotherapy, and their peripheral blood was again drawn and assayed for CK-19 mRNA expression. Preoperatively, all cases of HER2-positive cancer were positive for CK19 mRNA in peripheral blood, but 6 cases of HER2-negative breast cancer were positive (33.3%), where there was a substantial difference between the two groups. After 6 cycles of adjuvant chemotherapy, CK19 positive rates in cases of HER2-positive and -negative breast cancer reduced by 93.3 and 11.1%, respectively, with a significant difference still existing. After 3 months of Herceptin therapy, expression of CK19 mRNA declined considerably in 10 cases of HER2 positive breast cancer (113.66 ± 88.65 vs 63.35 ± 49.27, P = 0.025). HER-2 gene expression closely correlated with circulating tumor cells in peripheral blood of early breast cancer patients. Moreover, Herceptin, a monoclonal antibody for HER2, can reduce the number of circulating tumor cells, which can be an early predictive factor for Herceptin therapy effectiveness against breast cancer.

  16. Tumor microenvironment: driving forces and potential therapeutic targets for breast cancer metastasis.

    Science.gov (United States)

    Xie, Hong-Yan; Shao, Zhi-Min; Li, Da-Qiang

    2017-03-29

    Distant metastasis to specific target organs is responsible for over 90% of breast cancer-related deaths, but the underlying molecular mechanism is unclear. Mounting evidence suggests that the interplay between breast cancer cells and the target organ microenvironment is the key determinant of organ-specific metastasis of this lethal disease. Here, we highlight new findings and concepts concerning the emerging role of the tumor microenvironment in breast cancer metastasis; we also discuss potential therapeutic intervention strategies aimed at targeting components of the tumor microenvironment.

  17. Osteoprotegerin mediates tumor-promoting effects of Interleukin-1beta in breast cancer cells.

    Science.gov (United States)

    Chung, Stephanie Tsang Mui; Geerts, Dirk; Roseman, Kim; Renaud, Ashleigh; Connelly, Linda

    2017-02-01

    It is widely recognized that inflammation promotes breast cancer invasion and metastasis. Given the complex nature of the breast tumor inflammatory microenvironment, much remains to be understood of the molecular mechanisms that govern these effects. We have previously shown that osteoprotegerin knockdown in breast cancer cells resulted in reduced invasion and metastasis. Here we present novel insight into the role of osteoprotegerin in inflammation-driven tumor progression in breast cancer by investigating the link between osteoprotegerin, macrophages and the potent pro-inflammatory cytokine Interleukin-1beta. We used human breast cancer cell lines to investigate the effects of Interleukin-1beta treatment on osteoprotegerin secretion as measured by ELISA. We analyzed public datasets containing human breast cancer genome-wide mRNA expression data to reveal a significant and positive correlation between osteoprotegerin mRNA expression and the mRNA expression of Interleukin-1beta and of monocyte chemoattractant protein CC-chemokine ligand 2. Osteoprotegerin, Interleukin-1beta and CC-chemokine ligand 2 mRNA levels were also examined by qPCR on cDNA from normal and cancerous human breast tissue. We determined the effect of Interleukin-1beta-producing macrophages on osteoprotegerin expression by co-culturing breast cancer cells and differentiated THP-1 macrophages. Immunohistochemistry was performed on human breast tumor tissue microarrays to assess macrophage infiltration and osteoprotegerin expression. To demonstrate that osteoprotegerin mediated functional effects of Interleukin-1beta we performed cell invasion studies with control and OPG siRNA knockdown on Interleukin-1beta-treated breast cancer cells. We report that Interleukin-1beta induces osteoprotegerin secretion, independent of breast cancer subtype and basal osteoprotegerin levels. Co-culture of breast cancer cells with Interleukin-1beta-secreting macrophages resulted in a similar increase in osteoprotegerin

  18. The association of inherited variation in the CLOCK gene with breast cancer tumor grade

    Directory of Open Access Journals (Sweden)

    Neha Gupta

    2017-07-01

    Full Text Available Background: Sufficient sleep and maintenance of circadian rhythm are important to health. We have shown that short duration of sleep before diagnosis is associated with higher-grade tumors among breast cancer patients. Earlier studies suggest that genetic variation in the CLOCK gene is associated with risk of cancers, including breast cancer. Studies of the association of genetic variation, including in CLOCK, and tumor grade, a standard marker of tumor aggressiveness, are lacking. Methods: We investigated the relationship between single nucleotide polymorphisms (SNPs in the CLOCK gene and tumor grade and estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status in 293 breast cancer patients. Nine SNPs were determined by standard TaqMan assays. Tumor grade, receptor status, and other clinical variables were abstracted from medical records. Results: Two SNPs were excluded because of poor genotyping performance. None of the remaining seven variants had a statistically significant association with breast cancer tumor grade or with receptor status. Conclusion: As with all novel studies, further work is needed to examine the association of CLOCK and other genes in the circadian rhythm pathway with breast cancer tumor grade in other populations.

  19. Coexistence of Granular Cell Tumor and Invasive Ductal Breast Cancer in Contralateral Breasts: A Case Report

    Directory of Open Access Journals (Sweden)

    Maurizio Di Bonito

    2014-07-01

    Full Text Available Granular cell tumor (GCT is a benign tumor of the breast that can mimic, on breast imaging, invasive carcinomas. Biological evolution of mammary GCT is unknown, especially if it is associated with an invasive carcinoma in the same or contralateral breast. This report details the morphological features of these synchronous lesions highlighting their biological characteristics and suggesting an appropriate follow up.

  20. Claudin-2 Promotes Breast Cancer Liver Metastasis by Facilitating Tumor Cell Interactions with Hepatocytes

    Science.gov (United States)

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

    2012-01-01

    We previously identified claudin-2 as a functional mediator of breast cancer liver metastasis. We now confirm that claudin-2 levels are elevated in liver metastases, but not in skin metastases, compared to levels in their matched primary tumors in patients with breast cancer. Moreover, claudin-2 is specifically expressed in liver-metastatic breast cancer cells compared to populations derived from bone or lung metastases. The increased liver tropism exhibited by claudin-2-expressing breast cancer cells requires claudin-2-mediated interactions between breast cancer cells and primary hepatocytes. Furthermore, the reduction of the claudin-2 expression level, either in cancer cells or in primary hepatocytes, diminishes these heterotypic cell-cell interactions. Finally, we demonstrate that the first claudin-2 extracellular loop is essential for mediating tumor cell-hepatocyte interactions and the ability of breast cancer cells to form liver metastases in vivo. Thus, during breast cancer liver metastasis, claudin-2 shifts from acting within tight-junctional complexes to functioning as an adhesion molecule between breast cancer cells and hepatocytes. PMID:22645303

  1. Morphine Promotes Tumor Angiogenesis and Increases Breast Cancer Progression

    Directory of Open Access Journals (Sweden)

    Sabrina Bimonte

    2015-01-01

    Full Text Available Morphine is considered a highly potent analgesic agent used to relieve suffering of patients with cancer. Several in vitro and in vivo studies showed that morphine also modulates angiogenesis and regulates tumour cell growth. Unfortunately, the results obtained by these studies are still contradictory. In order to better dissect the role of morphine in cancer cell growth and angiogenesis we performed in vitro studies on ER-negative human breast carcinoma cells, MDA.MB231 and in vivo studies on heterotopic mouse model of human triple negative breast cancer, TNBC. We demonstrated that morphine in vitro enhanced the proliferation and inhibited the apoptosis of MDA.MB231 cells. In vivo studies performed on xenograft mouse model of TNBC revealed that tumours of mice treated with morphine were larger than those observed in other groups. Moreover, morphine was able to enhance the neoangiogenesis. Our data showed that morphine at clinical relevant doses promotes angiogenesis and increases breast cancer progression.

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

    Directory of Open Access Journals (Sweden)

    Malgorzata Banys

    2014-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-01-15

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

  4. Circulating tumor cell clusters-associated gene plakoglobin and breast cancer survival.

    Science.gov (United States)

    Lu, Lingeng; Zeng, Hongmei; Gu, Xinsheng; Ma, Wenxue

    2015-06-01

    Breast cancer recurrence is a major cause of the disease-specific death. Circulating tumor cells (CTCs) are negatively associated with breast cancer survival. Plakoglobin, a cell adhesion protein, was recently reported as a determinant of CTCs types, single or clustered ones. Here, we aim to summarize the studies on the roles of plakoglobin and evaluate the association of plakoglobin and breast cancer survival. Plakoglobin as a key component in both cell adhesion and the signaling pathways was briefly reviewed first. Then the double-edge functions of plakoglobin in tumors and its association with CTCs and breast cancer metastasis were introduced. Finally, based on an open-access database, the association between plakoglobin and breast cancer survival was investigated using univariate and multivariate survival analyses. Plakoglobin may be a molecule functioning as a double-edge sword. Loss of plakoglobin expression leads to increased motility of epithelial cells, thereby promoting epithelial-mesenchymal transition and further metastasis of cancer. However, studies also show that plakoglobin can function as an oncogene. High expression of plakoglobin results in clustered tumor cells in circulation with high metastatic potential in breast cancer and shortened patient survival. Plakoglobin may be a potential prognostic biomarker that can be exploited to develop as a therapeutic target for breast cancer.

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

    Directory of Open Access Journals (Sweden)

    Siddharth P Pathi

    2010-01-01

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

  6. Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression.

    Science.gov (United States)

    Singh, Manjulata; Mukundan, Shilpaa; Jaramillo, Maria; Oesterreich, Steffi; Sant, Shilpa

    2016-07-01

    Tumor size is strongly correlated with breast cancer metastasis and patient survival. Increased tumor size contributes to hypoxic and metabolic gradients in the solid tumor and to an aggressive tumor phenotype. Thus, it is important to develop three-dimensional (3D) breast tumor models that recapitulate size-induced microenvironmental changes and, consequently, natural tumor progression in real time without the use of artificial culture conditions or gene manipulations. Here, we developed size-controlled multicellular aggregates ("microtumors") of subtype-specific breast cancer cells by using non-adhesive polyethylene glycol dimethacrylate hydrogel microwells of defined sizes (150-600 μm). These 3D microtumor models faithfully represent size-induced microenvironmental changes, such as hypoxic gradients, cellular heterogeneity, and spatial distribution of necrotic/proliferating cells. These microtumors acquire hallmarks of tumor progression in the same cell lines within 6 days. Of note, large microtumors of hormone receptor-positive cells exhibited an aggressive phenotype characterized by collective cell migration and upregulation of mesenchymal markers at mRNA and protein level, which was not observed in small microtumors. Interestingly, triple-negative breast cancer (TNBC) cell lines did not show size-dependent upregulation of mesenchymal markers. In conclusion, size-controlled microtumor models successfully recapitulated clinically observed positive association between tumor size and aggressive phenotype in hormone receptor-positive breast cancer while maintaining clinically proven poor correlation of tumor size with aggressive phenotype in TNBC. Such clinically relevant 3D models generated under controlled experimental conditions can serve as precise preclinical models to study mechanisms involved in breast tumor progression as well as antitumor drug effects as a function of tumor progression. Cancer Res; 76(13); 3732-43. ©2016 AACR. ©2016 American

  7. Modeling the Effect of Tumor Size in Early Breast Cancer

    Science.gov (United States)

    Verschraegen, Claire; Vinh-Hung, Vincent; Cserni, Gábor; Gordon, Richard; Royce, Melanie E.; Vlastos, Georges; Tai, Patricia; Storme, Guy

    2005-01-01

    Summary Background Data: The purpose of this study was to determine the type of relationship between tumor size and mortality in early breast carcinoma. Methods: The data was abstracted from 83,686 cases registered in the Surveillance, Epidemiology, and End Results Program of women diagnosed with primary breast carcinoma between 1988 and 1997 presenting with a T1–T2 lesion and no metastasis in whom axillary node dissection was performed: 58,070 women were node-negative (N0) and 25,616 were node-positive (N+). End point was death from any cause. Tumor size was modeled as a continuous variable by proportional hazards using a generalized additive models procedure. Results: Functionally, a Gompertzian expression exp(-exp(-(size-15)/10)) provided a good fit to the effect of tumor size (in millimeters) on mortality, irrespective of nodal status. Quantitatively, for tumor size between 3 and 50 mm, the increase of crude cumulative death rate (number of observed deaths divided by the number of patients at risk) increased with size from 10% to 25% for N0 and from 20% to 40% for N+. Conclusions: The functional relationship of tumor size with mortality is concordant with current knowledge of tumor growth. However, its qualitative and quantitative independence of nodal status is in contradiction with the prevailing concept of sequential disease progression from primary tumor to regional nodes. This argues against the perception that nodal metastases are caused by the primary tumor. PMID:15650642

  8. Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant.

    Science.gov (United States)

    van Roosmalen, Wies; Le Dévédec, Sylvia E; Golani, Ofra; Smid, Marcel; Pulyakhina, Irina; Timmermans, Annemieke M; Look, Maxime P; Zi, Di; Pont, Chantal; de Graauw, Marjo; Naffar-Abu-Amara, Suha; Kirsanova, Catherine; Rustici, Gabriella; Hoen, Peter A C 't; Martens, John W M; Foekens, John A; Geiger, Benjamin; van de Water, Bob

    2015-04-01

    Tumor cell migration is a key process for cancer cell dissemination and metastasis that is controlled by signal-mediated cytoskeletal and cell matrix adhesion remodeling. Using a phagokinetic track assay with migratory H1299 cells, we performed an siRNA screen of almost 1,500 genes encoding kinases/phosphatases and adhesome- and migration-related proteins to identify genes that affect tumor cell migration speed and persistence. Thirty candidate genes that altered cell migration were validated in live tumor cell migration assays. Eight were associated with metastasis-free survival in breast cancer patients, with integrin β3-binding protein (ITGB3BP), MAP3K8, NIMA-related kinase (NEK2), and SHC-transforming protein 1 (SHC1) being the most predictive. Examination of genes that modulate migration indicated that SRPK1, encoding the splicing factor kinase SRSF protein kinase 1, is relevant to breast cancer outcomes, as it was highly expressed in basal breast cancer. Furthermore, high SRPK1 expression correlated with poor breast cancer disease outcome and preferential metastasis to the lungs and brain. In 2 independent murine models of breast tumor metastasis, stable shRNA-based SRPK1 knockdown suppressed metastasis to distant organs, including lung, liver, and spleen, and inhibited focal adhesion reorganization. Our study provides comprehensive information on the molecular determinants of tumor cell migration and suggests that SRPK1 has potential as a drug target for limiting breast cancer metastasis.

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

    Directory of Open Access Journals (Sweden)

    Marilys Corbex

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

  10. Quantitative Analysis of Mitochondrial DNA 4977-bp Deletion in Sporadic Breast Cancer and Benign Breast Tumors

    OpenAIRE

    Ye, Chuanzhong; Shu, Xiao-Ou; Wen, Wanqing; Pierce, Larry; Courtney, Regina; Gao, Yu-Tang; Zheng, Wei; Cai, Qiuyin

    2007-01-01

    The mitochondrial DNA (mtDNA) 4977-bp deletion (ΔmtDNA4977 mutation) is one of the most frequently observed mtDNA mutations in human tissues, and may play a role in carcinogenesis. Only a few studies have evaluated ΔmtDNA4977 mutation in breast cancer tissue, and the findings have been inconsistent, which may be due to methodological differences. In this study, we developed a quantitative real-time PCR assay to assess the level of the ΔmtDNA4977 mutation in tumor tissue samples from 55 primar...

  11. P53 Mutation Analysis to Predict Tumor Response in Patients Undergoing Neoadjuvant Treatment for Locally Advanced Breast Cancer

    National Research Council Canada - National Science Library

    Carey, Lisa A

    2004-01-01

    .... In an ongoing multi-institutional prospective trial that is not supported by this award, breast cancer patients receiving neoadjuvant chemotherapy have serial response assessments and tumor sampling...

  12. Mammographic density and risk of breast cancer by age and tumor characteristics.

    Science.gov (United States)

    Bertrand, Kimberly A; Tamimi, Rulla M; Scott, Christopher G; Jensen, Matthew R; Pankratz, V; Visscher, Daniel; Norman, Aaron; Couch, Fergus; Shepherd, John; Fan, Bo; Chen, Yunn-Yi; Ma, Lin; Beck, Andrew H; Cummings, Steven R; Kerlikowske, Karla; Vachon, Celine M

    2013-11-04

    Understanding whether mammographic density (MD) is associated with all breast tumor subtypes and whether the strength of association varies by age is important for utilizing MD in risk models. Data were pooled from six studies including 3414 women with breast cancer and 7199 without who underwent screening mammography. Percent MD was assessed from digitized film-screen mammograms using a computer-assisted threshold technique. We used polytomous logistic regression to calculate breast cancer odds according to tumor type, histopathological characteristics, and receptor (estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2)) status by age (ages, with a two-fold increased risk for high (>51%) versus average density (11-25%). Women ages ages 55-64 and ≥ 65 years (P(age-interaction) = 0.02). Among all ages, MD had a stronger association with large (>2.1 cm) versus small tumors and positive versus negative lymph node status (P's ages breast cancer than ER-positive tumors compared to women ages 55-64 and ≥ 65 years (P(age-interaction) = 0.04). MD was positively associated with both HER2-negative and HER2-positive tumors within each age group. MD is strongly associated with all breast cancer subtypes, but particularly tumors of large size and positive lymph nodes across all ages, and ER-negative status among women ages <55 years, suggesting high MD may play an important role in tumor aggressiveness, especially in younger women.

  13. Elucidation of altered pathways in tumor-initiating cells of triple-negative breast cancer

    DEFF Research Database (Denmark)

    Christensen, Anne G; Ehmsen, Sidse; Terp, Mikkel G

    2017-01-01

    A limited number of cancer cells within a tumor are thought to have self-renewing and tumor-initiating capabilities that produce the remaining cancer cells in a heterogeneous tumor mass. Elucidation of central pathways preferentially used by tumor-initiating cells/cancer stem cells (CSCs) may allow...... reduction was also observed using patient-derived primary cancer cells. Further, blocking NF-κB signaling in mice transplanted with tumor-initiating cells significantly reduced tumor outgrowth. Our study demonstrates that suppressed apoptosis, activation of pathways associated with cell viability and CSCs...... their exploitation as potential cancer therapy targets. We used single cell cloning to isolate and characterize four isogenic cell clones from a triple-negative breast cancer cell line; two exhibited mesenchymal-like and two epithelial-like characteristics. Within these pairs, one, but not the other, resulted...

  14. RORα, a Potential Tumor Suppressor and Therapeutic Target of Breast Cancer

    Directory of Open Access Journals (Sweden)

    Jun Du

    2012-11-01

    Full Text Available The function of the nuclear receptor (NR in breast cancer progression has been investigated for decades. The majority of the nuclear receptors have well characterized natural ligands, but a few of them are orphan receptors for which no ligand has been identified. RORα, one member of the retinoid orphan nuclear receptor (ROR subfamily of orphan receptors, regulates various cellular and pathological activities. RORα is commonly down-regulated and/or hypoactivated in breast cancer compared to normal mammary tissue. Expression of RORα suppresses malignant phenotypes in breast cancer cells, in vitro and in vivo. Activity of RORα can be categorized into the canonical and non-canonical nuclear receptor pathways, which in turn regulate various breast cancer cellular function, including cell proliferation, apoptosis and invasion. This information suggests that RORα is a potent tumor suppressor and a potential therapeutic target for breast cancer.

  15. Novel methylated biomarkers and a robust assay to detect circulating tumor DNA in metastatic breast cancer.

    Science.gov (United States)

    Fackler, Mary Jo; Lopez Bujanda, Zoila; Umbricht, Christopher; Teo, Wei Wen; Cho, Soonweng; Zhang, Zhe; Visvanathan, Kala; Jeter, Stacie; Argani, Pedram; Wang, Chenguang; Lyman, Jaclyn P; de Brot, Marina; Ingle, James N; Boughey, Judy; McGuire, Kandace; King, Tari A; Carey, Lisa A; Cope, Leslie; Wolff, Antonio C; Sukumar, Saraswati

    2014-04-15

    The ability to consistently detect cell-free tumor-specific DNA in peripheral blood of patients with metastatic breast cancer provides the opportunity to detect changes in tumor burden and to monitor response to treatment. We developed cMethDNA, a quantitative multiplexed methylation-specific PCR assay for a panel of ten genes, consisting of novel and known breast cancer hypermethylated markers identified by mining our previously reported study of DNA methylation patterns in breast tissue (103 cancer, 21 normal on the Illumina HumanMethylation27 Beadchip) and then validating the 10-gene panel in The Cancer Genome Atlas project breast cancer methylome database. For cMethDNA, a fixed physiologic level (50 copies) of artificially constructed, standard nonhuman reference DNA specific for each gene is introduced in a constant volume of serum (300 μL) before purification of the DNA, facilitating a sensitive, specific, robust, and quantitative assay of tumor DNA, with broad dynamic range. Cancer-specific methylated DNA was detected in training (28 normal, 24 cancer) and test (27 normal, 33 cancer) sets of recurrent stage IV patient sera with a sensitivity of 91% and a specificity of 96% in the test set. In a pilot study, cMethDNA assay faithfully reflected patient response to chemotherapy (N = 29). A core methylation signature present in the primary breast cancer was retained in serum and metastatic tissues collected at autopsy two to 11 years after diagnosis of the disease. Together, our data suggest that the cMethDNA assay can detect advanced breast cancer, and monitor tumor burden and treatment response in women with metastatic breast cancer. ©2014 AACR.

  16. CPTAC Releases Largest-Ever Breast Cancer Proteome Dataset from Previously Genome Characterized Tumors | Office of Cancer Clinical Proteomics Research

    Science.gov (United States)

    National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) scientists have released a dataset of proteins and  phosphopeptides identified through deep proteomic and phosphoproteomic analysis of breast tumor samples, previously genomically analyzed by The Cancer Genome Atlas (TCGA).

  17. Dense and nondense mammographic area and risk of breast cancer by age and tumor characteristics.

    Science.gov (United States)

    Bertrand, Kimberly A; Scott, Christopher G; Tamimi, Rulla M; Jensen, Matthew R; Pankratz, V Shane; Norman, Aaron D; Visscher, Daniel W; Couch, Fergus J; Shepherd, John; Chen, Yunn-Yi; Fan, Bo; Wu, Fang-Fang; Ma, Lin; Beck, Andrew H; Cummings, Steven R; Kerlikowske, Karla; Vachon, Celine M

    2015-05-01

    Mammographic density (MD) is a strong breast cancer risk factor. We previously reported associations of percent mammographic density (PMD) with larger and node-positive tumors across all ages, and estrogen receptor (ER)-negative status among women ages breast cancer subtypes. Data were pooled from six studies including 4,095 breast cancers and 8,558 controls. DA and NDA were assessed from digitized film-screen mammograms and standardized across studies. Breast cancer odds by density phenotypes and age according to histopathologic characteristics and receptor status were calculated using polytomous logistic regression. DA was associated with increased breast cancer risk [OR for quartiles: 0.65, 1.00 (Ref), 1.22, 1.55; P(trend) ages and invasive tumor characteristics. There were significant trends in the magnitude of associations of both DA and NDA with breast cancer by increasing tumor size (P(trend) age. DA and NDA are important to consider when developing age- and subtype-specific risk models. ©2015 American Association for Cancer Research.

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

    Science.gov (United States)

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

    2011-01-01

    Background Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. Methods We pooled tumor marker and epidemiological risk factor data from 35 568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case–case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case–control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. Results In case–case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR− than PR+ tumors (P = .001). Nulliparity (P = 3 × 10−6) and increasing age at first birth (P = 2 × 10−9) were less frequent in ER− than in ER+ tumors. Obesity (body mass index [BMI] ≥ 30 kg/m2) in younger women (≤50 years) was more frequent in ER−/PR− than in ER+/PR+ tumors (P = 1 × 10−7), whereas obesity in older women (>50 years) was less frequent in PR− than in PR+ tumors (P = 6 × 10−4). The triple-negative (ER−/PR−/HER2−) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6+ and/or epidermal growth factor receptor [EGFR]+) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case–control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER+ or PR+ tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95

  19. Breast cancer prognosis is inherited independently of patient, tumor and treatment characteristics.

    Science.gov (United States)

    Verkooijen, Helena M; Hartman, Mikael; Usel, Massimo; Benhamou, Simone; Neyroud-Caspar, Isabelle; Czene, Kamila; Vlastos, Georges; Chappuis, Pierre O; Bouchardy, Christine; Rapiti, Elisabetta

    2012-05-01

    Population-based studies have shown a concordance of breast cancer survival among first-degree relatives (FDRs), suggesting a heritable component. Reasons for such heritability remain to be elucidated. We aimed to determine whether association of breast cancer survival among FDRs is linked to shared patient and tumor characteristics or type of treatment. At the population-based Geneva Breast Cancer Registry, we identified 162 FDR pairs diagnosed with breast cancer. We categorized FDRs into poor, medium and good familial survival risk groups according to breast cancer-specific survival of their proband (mother or sister). We compared patient, tumor and treatment characteristics between categories and calculated standardized mortality ratios (SMRs) and adjusted disease-specific mortality for each group. Breast cancer patients in the poor familial survival risk group were more likely to be diagnosed at later stages than those in the good familial survival risk group. Similarly, they had higher SMRs than those in the medium and good survival risk groups (18.7, 95% confidence interval [CI]: 9.4-33.5 vs. 16.5, 95% CI: 7.5-31.3 and 9.4, 95% CI: 3.4-20.4, respectively). After adjustment for patient and tumor characteristics and type of treatment, women in the poor familial survival risk group were almost five times more likely to die of breast cancer than those in the good familial survival risk group (adjusted hazard ratio 4.8, 95% CI: 1.4-16.4). Our study shows that breast cancer prognosis clusters within families and suggests that the hereditary component is independent of patient and tumor characteristics and type of treatment. Copyright © 2011 UICC.

  20. Plasma metabolomic profiles in breast cancer patients and healthy controls: by race and tumor receptor subtypes.

    Science.gov (United States)

    Shen, Jie; Yan, Li; Liu, Song; Ambrosone, Christine B; Zhao, Hua

    2013-12-01

    A few studies in the last several years have shown that metabolomics, the study of metabolites and small intermediate molecules, may help better understand the breast carcinogenesis. However, breast cancer is a heterogeneous disease with different subtypes. Additionally, there is a significant racial difference in terms of breast cancer incidence and mortality. Few, if any, metabolomics studies in breast cancer have considered race and tumor subtypes in the study design. We performed a global metabolomic profiling using mass spectrometry and samples from 60 breast cancer cases and 60 matched controls. A total of 375 named metabolites were observed, with 117 metabolites whose levels were significantly different between African American and Caucasian American women (P racial difference.

  1. Toca-1 is suppressed by p53 to limit breast cancer cell invasion and tumor metastasis.

    Science.gov (United States)

    Chander, Harish; Brien, Colin D; Truesdell, Peter; Watt, Kathleen; Meens, Jalna; Schick, Colleen; Germain, Doris; Craig, Andrew W B

    2014-12-30

    Transducer of Cdc42-dependent actin assembly-1 (Toca-1) recruits actin regulatory proteins to invadopodia, and promotes breast tumor metastasis. Since metastatic breast tumors frequently harbor mutations in the tumor suppressor p53, we tested whether p53 regulates Toca-1 expression. Normal mammary epithelial cells (HBL-100, MCF10A) and breast cancer cell lines expressing wild-type (WT) p53 (DU4475, MTLn3) were treated with camptothecin or Nutlin-3 to stabilize p53 to test effects on Toca-1 mRNA and protein levels. Chromatin immunoprecipitation (ChIP) assays were performed to identify p53 binding site in Toca-1 gene. Stable silencing of p53 and Toca-1 were performed in MTLn3 cells to test effects on invadopodia and cell invasion in vitro, and tumor metastasis in vivo. We observed that breast cancer cell lines with mutant p53 have high levels of Toca-1 compared to those with WT p53. Stabilization of WT p53 led to further reduction in Toca-1 mRNA and protein levels in normal breast epithelial cells and breast cancer cells. ChIP assays revealed p53 binding within intron 2 of toca1, and reduced histone acetylation within its promoter region upon p53 upregulation or activation. Stable silencing of WT p53 in MTLn3 cells led to increased extracellular matrix degradation and cell invasion compared to control cells. Interestingly, the combined silencing of p53 and Toca-1 led to a partial rescue of these effects of p53 silencing in vitro and reduced lung metastases in mice. In human breast tumors, Toca-1 levels were high in subtypes with frequent p53 mutations, and high Toca-1 transcript levels correlated with increased risk of relapse. Based on these findings, we conclude that loss of p53 tumor suppressor function in breast cancers leads to upregulation of Toca-1, and results in enhanced risk of developing metastatic disease.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2015-01-01

    In invasive breast cancer, tumor associated neutrophils (TAN) represent a significant portion of the tumor mass and are associated with increased angiogenesis and metastasis. Identifying the regulatory factors that control TAN behavior will help in developing ideal immunotherapies. Vacuolar ATPases (V-ATPases), multi-subunit proton pumps, are highly expressed in metastatic breast cancer cells. A cleaved peptide from a2 isoform V-ATPase (a2NTD) has immunomodulatory role in tumor microenvironment. Here, we report for the first time the role of V-ATPase in neutrophils modulation. In invasive breast cancer cells, a2NTD was detected and a2V was highly expressed on the surface. Immunohistochemical analysis of invasive breast cancer tissues revealed that increased neutrophil recruitment and blood vessel density correlated with increased a2NTD levels. In order to determine the direct regulatory role of a2NTD on neutrophils, recombinant a2NTD was used for the treatment of neutrophils isolated from the peripheral blood of healthy volunteers. Neutrophils treated with a2NTD (a2Neuɸ) showed increased secretion of IL-1RA, IL-10, CCL-2 and IL-6 that are important mediators in cancer related inflammation. Moreover, a2Neuɸ exhibited an increased production of protumorigenic factors including IL-8, matrix metaloprotinase-9 and vascular endothelial growth factor. Further, functional characterization of a2Neuɸ revealed that a2Neuɸ derived products induce in vitro angiogenesis as well as increase the invasiveness of breast cancer cells. This study establishes the modulatory effect of breast cancer associated a2V on neutrophils, by the action of a2NTD, which has a positive impact on tumor progression, supporting that a2V can be a potential selective target for breast cancer therapy. PMID:26460736

  4. Targeting MUC1 mediated tumor stromal metabolic interaction in Triple negative Breast Cancer

    Science.gov (United States)

    2016-11-01

    AWARD NUMBER: W81XWH-13-1-0315 TITLE: Targeting MUC1-mediated tumor -stromal metabolic interaction in Triple- negative breast cancer PRINCIPAL...2013- 14 Aug 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-13-1-0315 Targeting MUC1-mediated tumor -stromal metabolic...recurrence within 1-3 years and a high mortality rate [3]. Therefore, identifying factors that facilitate tumor growth and metastases have the

  5. Targeting MUC1-Mediated Tumor-Stromal Metabolic Interaction in Triple-Negative Breast Cancer

    Science.gov (United States)

    2016-11-01

    AWARD NUMBER: W81XWH-13-1-0315 TITLE: Targeting MUC1-mediated tumor -stromal metabolic interaction in Triple- negative breast cancer PRINCIPAL...2013- 14 Aug 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-13-1-0315 Targeting MUC1-mediated tumor -stromal metabolic...recurrence within 1-3 years and a high mortality rate [3]. Therefore, identifying factors that facilitate tumor growth and metastases have the

  6. Epigenetic silencing of the tumor suppressor klotho in human breast cancer.

    Science.gov (United States)

    Rubinek, Tami; Shulman, Michal; Israeli, Shira; Bose, Shikha; Avraham, Ayelet; Zundelevich, Adi; Evron, Ella; Gal-Yam, Einav Nili; Kaufman, Bella; Wolf, Ido

    2012-06-01

    Klotho is a single pass transmembrane protein, associated with premature aging. We identified tumor suppressor activities for klotho, associated with reduced expression in breast cancer. We now aimed to analyze klotho expression in early stages of breast tumorigenesis and elucidate mechanisms leading to klotho silencing in breast tumors. We studied klotho expression, using immunohistochemistry, and found high klotho expression in all normal and mild hyperplasia samples, whereas reduced expression was associated with moderate and atypical ductal hyperplasia. Promoter methylation and histone deacetylation were studied as possible mechanisms for klotho silencing. Using bisulfite sequencing, and methylation-specific PCR, we identified KLOTHO promoter methylation in five breast cancer cell lines and in hyperplastic MCF-12A cells, but not in the non-tumorous mammary cell line HB2. Importantly, methylation status inversely correlated with klotho mRNA levels, and treatment of breast caner cells with 5-aza-2-deoxycytidine elevated klotho expression by up to 150-fold. KLOTHO promoter methylation was detected in 8/23 of breast cancer samples but not in normal breast samples. Chromatin immunoprecipitation revealed that in HB2 KLOTHO promoter was enriched with AcH3K9; however, in breast cancer cells, H3K9 was deacetylated, and treatment with the histone deacetylase inhibitor suberoylanilide bishydroxamide (SAHA) restored H3K9 acetylation. Taken together, these data indicate loss of klotho expression as an early event in breast cancer development, and suggest a role for DNA methylation and histone deacetylation in klotho silencing. Klotho expression and methylation may, therefore, serve as early markers for breast tumorigenesis.

  7. Protective Effect of Perindopril on Tumor Progression and Angiogenesis in Animal Model of Breast Cancer.

    Science.gov (United States)

    Patel, Snehal S; Nakka, Surender

    2017-01-01

    Studies have shown that the renin angiotensin system via angiogenesis is involved in tumor development. Therefore, objective of the present study was to examine the effect of perindopril on tumor growth and angiogenesis in animal models of breast cancer. In the present study, the effect of perindopril on tumor development of mammary gland cancer induced by 7,12-dimethylbenz[a]anthracene, mouse tumor xenograft and corneal micropocket model has been investigated. Anti-angiogenic effect by chick yolk sac membrane assay has also been studied. In the present study, it has been found that perindopril produced a significant inhibition of tumor growth, in DMBA induced breast cancer. Treatment also produced significant suppression of cancer biomarkers such as lactate dehydrogenase, gamma glutamyl transferase and inflammatory markers such as C-reactive protein, erythrocyte sedimentation rate. Histopathological analysis also showed that perindopril was able to inhibit tumor development by the inhibition of hyperplastic lesions. Perindopril produced significant inhibition of tumor growth, in a mouse xenograft model and caused inhibition of neovascularization in the corneal micropocket model. In chick yolk sac membrane assay, perindopril showed inhibition of vascular growth and reduced blood vessel formation. Therefore, perindopril is widely used in clinical practice, may represent a neo-adjuvant therapy for treatment of breast cancer. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  8. Associations of Breast Cancer Risk Prediction Tools With Tumor Characteristics and Metastasis.

    Science.gov (United States)

    Holm, Johanna; Li, Jingmei; Darabi, Hatef; Eklund, Martin; Eriksson, Mikael; Humphreys, Keith; Hall, Per; Czene, Kamila

    2016-01-20

    The association between established risk factors for breast cancer and subtypes or prognosis of the disease is not well known. We analyzed whether the Tyrer-Cuzick-predicted 10-year breast cancer risk score (TCRS), mammographic density (MD), and a 77-single nucleotide polymorphism polygenic risk score (PRS) were associated with breast cancer tumor prognosticators and risk of distant metastasis. We used a case-only design in a population-based cohort of 5,500 Swedish patients with breast cancer. Logistic and multinomial logistic regression of outcomes, estrogen receptor (ER) status, lymph node involvement, tumor size, and grade was performed with TCRS, PRS, and percent MD as exposures. Cox proportional hazard models were used to estimate hazard ratios (HRs) of distant metastasis. Women at high risk for breast cancer based on PRS and/or TCRS were significantly more likely to be diagnosed with favorable prognosticators, such as ER-positive and low-grade tumors. In contrast, PRS weighted on ER-negative disease was associated with ER-negative tumors. When stratifying by age, the associations of TCRS with favorable prognosticators were restricted to women younger than age 50. Women scoring high in both TCRS and PRS had a lower risk of distant metastasis (HR, 0.69; 95% CI, 0.49 to 0.98). MD was not associated with any of the examined prognosticators. Women at high risk for breast cancer based on genetic and lifestyle factors were significantly more likely to be diagnosed with breast cancers with a favorable prognosis. Better knowledge of subtype-specific risk factors could be vital for the success of prevention programs aimed at lowering mortality. © 2015 by American Society of Clinical Oncology.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-08-02

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

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    with the well-established intrinsic molecular subtypes of breast cancer. METHODS: Global gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published...... gene profiles for the ovarian and breast cancer subtypes. Correlations to gene expression modules representing key biological breast cancer features were also sought. Validation was performed using an independent, publicly available dataset. RESULTS: 5,944 genes were significantly differentially......OBJECTIVE: Transcriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities...

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

    Science.gov (United States)

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

    2003-01-01

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

  12. Imaging breast tumor vascularization for detection and diagnosis of breast cancer

    NARCIS (Netherlands)

    Heijblom, M.; Klaase, J.M.; van den Engh, F.M.; van Leeuwen, Ton; Steenbergen, Wiendelt; Manohar, Srirang

    2011-01-01

    Breast cancer is one of the major causes of morbidity and mortality in western women. Current screening and diagnostic imaging modalities, like x-ray mammography and ultrasonography, focus on morphological changes of breast tissue. However, these techniques still miss some cancers and often falsely

  13. Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery.

    Directory of Open Access Journals (Sweden)

    Jessica Kao

    2009-07-01

    Full Text Available Breast cancer cell lines have been used widely to investigate breast cancer pathobiology and new therapies. Breast cancer is a molecularly heterogeneous disease, and it is important to understand how well and which cell lines best model that diversity. In particular, microarray studies have identified molecular subtypes-luminal A, luminal B, ERBB2-associated, basal-like and normal-like-with characteristic gene-expression patterns and underlying DNA copy number alterations (CNAs. Here, we studied a collection of breast cancer cell lines to catalog molecular profiles and to assess their relation to breast cancer subtypes.Whole-genome DNA microarrays were used to profile gene expression and CNAs in a collection of 52 widely-used breast cancer cell lines, and comparisons were made to existing profiles of primary breast tumors. Hierarchical clustering was used to identify gene-expression subtypes, and Gene Set Enrichment Analysis (GSEA to discover biological features of those subtypes. Genomic and transcriptional profiles were integrated to discover within high-amplitude CNAs candidate cancer genes with coordinately altered gene copy number and expression.Transcriptional profiling of breast cancer cell lines identified one luminal and two basal-like (A and B subtypes. Luminal lines displayed an estrogen receptor (ER signature and resembled luminal-A/B tumors, basal-A lines were associated with ETS-pathway and BRCA1 signatures and resembled basal-like tumors, and basal-B lines displayed mesenchymal and stem/progenitor-cell characteristics. Compared to tumors, cell lines exhibited similar patterns of CNA, but an overall higher complexity of CNA (genetically simple luminal-A tumors were not represented, and only partial conservation of subtype-specific CNAs. We identified 80 high-level DNA amplifications and 13 multi-copy deletions, and the resident genes with concomitantly altered gene-expression, highlighting known and novel candidate breast cancer

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

    Directory of Open Access Journals (Sweden)

    Katharina Galmbacher

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

  15. Breast cancer DNA methylation profiles are associated with tumor size and alcohol and folate intake.

    Directory of Open Access Journals (Sweden)

    Brock C Christensen

    2010-07-01

    Full Text Available Although tumor size and lymph node involvement are the current cornerstones of breast cancer prognosis, they have not been extensively explored in relation to tumor methylation attributes in conjunction with other tumor and patient dietary and hormonal characteristics. Using primary breast tumors from 162 (AJCC stage I-IV women from the Kaiser Division of Research Pathways Study and the Illumina GoldenGate methylation bead-array platform, we measured 1,413 autosomal CpG loci associated with 773 cancer-related genes and validated select CpG loci with Sequenom EpiTYPER. Tumor grade, size, estrogen and progesterone receptor status, and triple negative status were significantly (Q-values <0.05 associated with altered methylation of 209, 74, 183, 69, and 130 loci, respectively. Unsupervised clustering, using a recursively partitioned mixture model (RPMM, of all autosomal CpG loci revealed eight distinct methylation classes. Methylation class membership was significantly associated with patient race (P<0.02 and tumor size (P<0.001 in univariate tests. Using multinomial logistic regression to adjust for potential confounders, patient age and tumor size, as well as known disease risk factors of alcohol intake and total dietary folate, were all significantly (P<0.0001 associated with methylation class membership. Breast cancer prognostic characteristics and risk-related exposures appear to be associated with gene-specific tumor methylation, as well as overall methylation patterns.

  16. Breast cancer cells form primary tumors on ex vivo four-dimensional lung model.

    Science.gov (United States)

    Pence, Kristi A; Mishra, Dhruva K; Thrall, Michael; Dave, Bhuvanesh; Kim, Min P

    2017-04-01

    Breast cancer mortality is most common in cancer in women, and there are no ex vivo models that can capture the primary growth of tumor with fidelity to the in vivo tumor growth. In this study, we grew human breast cancer cell lines in an acellular lung matrix of the ex vivo four-dimensional lung model to determine if they form primary tumor and the extent to which they mimic the histology and characteristics of the human tumors. Rat lungs were harvested, decellularized, and placed in a bioreactor. To study the primary tumor growth, we seeded the lung via the trachea with human breast cancer cells SUM159, MCF7, or MDMB231 and perfused the pulmonary artery with oxygenated media. Lobectomies were performed and processed for hematoxylin and eosin, Ki-67, caspase-3, estrogen receptor, and progesterone receptor antibodies. All three cell lines grew in the ex vivo four-dimensional model and formed perfusable tumor nodules with similar histology and morphology as the primary tumors. SUM159 and MDAMB231 showed higher proliferation and apoptotic indices than MCF7. In addition, MCF7 retained its estrogen receptor and progesterone receptor positivity, whereas SUM159 and MDAMB 231 did not have any staining. Overall, our study showed that human breast cancer cells can be grown on the ex vivo four-dimensional lung model, which then form primary tumor nodules that mimic the morphology and histology of the original tumor. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. 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

  18. Usefulness of preoperative breast MRI in breast cancer patients diagnosed with tumor removal using a US-guided mammotome

    Energy Technology Data Exchange (ETDEWEB)

    Noh, Hyun Woo; Kang, Doo Kyung; Yim, Hyun Ee [Ajou University, School of Medicine, Suwon (Korea, Republic of); Park, Hee Boong [Park Breast Clinic, Suwon (Korea, Republic of)

    2007-10-15

    We evaluated the MRI findings that suggested the presence of a residual cancer after a mammotome biopsy in pathologically proven breast cancer patients and the usefulness of MRI to diagnose a residual cancer and additional lesions. We reviewed 41 breast cancer patients that underwent an ultrasonography-guided mammotome biopsy for complete resection of a breast lesion. MRI was performed for preoperative assessment and MRI findings suggestive of a residual cancer at the procedure site were analyzed and correlated to the pathological findings. Additional enhancements on breast MRI were analyzed, and the diagnostic accuracy of MRI for occult additional lesions was calculated. A total of 32 (78.0%) patients had a residual tumor. A mass was the most common MRI finding that suggested a residual cancer. Thick rim enhancement or a mass with a non-mass like enhancement were the most suspicious findings that suggested the presence of a residual cancer. The sensitivity, specificity and accuracy of MRI for the detection of a residual cancer were 81.3%, 66.7% and 78.0%, respectively. Additional malignant lesions were found in 7 cases. The sensitivity, specificity and accuracy of MRI for the detection of additional lesions were 100%, 60.0% and 76.5%, respectively. Further complete surgery should be performed, as residual tumors are found in 50% of the negative MRI examinations, whereas preoperative MRI is helpful to evaluate occult additional lesions.

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

    Directory of Open Access Journals (Sweden)

    Damali N Martin

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

  20. High MicroRNA-370 Expression Correlates with Tumor Progression and Poor Prognosis in Breast Cancer

    OpenAIRE

    Sim, Jongmin; Ahn, Hyein; Abdul, Rehman; Kim, Hyunsung; Yi, Ki-jong; Chung, Yu-Min; Chung, Min Sung; Paik, Seung Sam; Song, Young Soo; Jang, Kiseok

    2015-01-01

    Purpose Deregulation of microRNA-370 (miR-370) has been reported in various cancers, in which it can act as either an oncogene or a tumor suppressor gene. However, the clinicopathologic significance of miR-370 expression in breast cancer has not been studied. Methods The expression of miR-370 was determined with quantitative real-time polymerase chain reaction in 60 formalin-fixed, paraffin-embedded primary breast cancer tissues. Additionally, the protein expression levels of previously known...

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

    Science.gov (United States)

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

    2010-01-01

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

  2. HMGA1: a master regulator of tumor progression in triple-negative breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Sandeep N Shah

    Full Text Available Emerging evidence suggests that tumor cells metastasize by co-opting stem cell transcriptional networks, although the molecular underpinnings of this process are poorly understood. Here, we show for the first time that the high mobility group A1 (HMGA1 gene drives metastatic progression in triple negative breast cancer cells (MDA-MB-231, Hs578T by reprogramming cancer cells to a stem-like state. Silencing HMGA1 expression in invasive, aggressive breast cancer cells dramatically halts cell growth and results in striking morphologic changes from mesenchymal-like, spindle-shaped cells to cuboidal, epithelial-like cells. Mesenchymal genes (Vimentin, Snail are repressed, while E-cadherin is induced in the knock-down cells. Silencing HMGA1 also blocks oncogenic properties, including proliferation, migration, invasion, and orthotopic tumorigenesis. Metastatic progression following mammary implantation is almost completely abrogated in the HMGA1 knock-down cells. Moreover, silencing HMGA1 inhibits the stem cell property of three-dimensional mammosphere formation, including primary, secondary, and tertiary spheres. In addition, knock-down of HMGA1 depletes cancer initiator/cancer stem cells and prevents tumorigenesis at limiting dilutions. We also discovered an HMGA1 signature in triple negative breast cancer cells that is highly enriched in embryonic stem cells. Together, these findings indicate that HMGA1 is a master regulator of tumor progression in breast cancer by reprogramming cancer cells through stem cell transcriptional networks. Future studies are needed to determine how to target HMGA1 in therapy.

  3. Expression Patterns of Biomarkers in Primary Tumors and Corresponding Metastases in Breast Cancer

    DEFF Research Database (Denmark)

    Kümler, Iben; Balslev, Eva; Knop, Ann S

    2016-01-01

    Tumor heterogeneity has been shown for several cancers including breast cancer (BC). Despite the fact that expression of tumor markers may change throughout the metastatic process, rebiopsies at the time of recurrence are still not performed routinely at all institutions. The aims of the study were......, and Ki-67 in 110 paired samples of primary BC and corresponding asynchronous metastases. We found discordant expressions in primary tumor and metastasis for all biomarkers, although only significant for Ki-67. Changes in the expression profile of the metastatic lesions would have altered treatment...

  4. TIMP-1 as a tumor marker in breast cancer - an update

    DEFF Research Database (Denmark)

    Würtz, Sidse Ørnbjerg; Rasmussen, Anne-Sofie Schrohl; Mouridsen, Henning

    2008-01-01

    . This review gives an update on the ongoing investigation of the potential role of TIMP-1 as a tumor marker in breast cancer. Furthermore, we link the clinical findings with studies of the molecular actions of the TIMP-1 protein, raising hypotheses that may explain why TIMP-1 could play an important role...

  5. Relevance of Tumor-Infiltrating Immune Cell Composition and Functionality for Disease Outcome in Breast Cancer

    NARCIS (Netherlands)

    Bense, Rico D.; Sotiriou, Christos; Piccart-Gebhart, Martine J.; Haanen, John B. A. G.; van Vugt, Marcel A. T. M.; de Vries, Elisabeth G. E.; Schroeder, Carolien P.; Fehrmann, Rudolf S. N.

    Background: Not all breast cancer patients benefit from neoadjuvant or adjuvant therapy, resulting in considerable undertreatment or overtreatment. New insights into the role of tumor-infiltrating immune cells suggest that their composition, as well as their functionality, might serve as a biomarker

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

    NARCIS (Netherlands)

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

    2015-01-01

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

  7. Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer

    NARCIS (Netherlands)

    Dreijerink, Koen M A; Groner, Anna C.; Vos, Erica S M; Font-Tello, Alba; Gu, Lei; Chi, David; Reyes, Jaime; Cook, Jennifer; Lim, Elgene; Lin, Charles Y.; de Laat, Wouter; Rao, Prakash K.; Long, Henry W.; Brown, Myles

    2017-01-01

    While the multiple endocrine neoplasia type 1 (MEN1) gene functions as a tumor suppressor in a variety of cancer types, we explored its oncogenic role in breast tumorigenesis. The MEN1 gene product menin is involved in H3K4 trimethylation and co-activates transcription. We integrated ChIP-seq and

  8. HPMA-Copolymer Nanocarrier Targets Tumor-Associated Macrophages in Primary and Metastatic Breast Cancer.

    Science.gov (United States)

    Zimel, Melissa N; Horowitz, Chloe B; Rajasekhar, Vinagolu K; Christ, Alexander B; Wei, Xin; Wu, Jianbo; Wojnarowicz, Paulina M; Wang, Dong; Goldring, Steven R; Purdue, P Edward; Healey, John H

    2017-12-01

    Polymeric nanocarriers such as N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers deliver drugs to solid tumors and avoid the systemic toxicity of conventional chemotherapy. Because HPMA copolymers can target sites of inflammation and accumulate within innate immune cells, we hypothesized that HPMA copolymers could target tumor-associated macrophages (TAM) in both primary and metastatic tumor microenvironments. We verified this hypothesis, first in preliminary experiments with isolated bone marrow macrophage cultures in vitro and subsequently in a spontaneously metastatic murine breast cancer model generated from a well-established, cytogenetically characterized 4T1 breast cancer cell line. Using our standardized experimental conditions, we detected primary orthotopic tumor growth at 7 days and metastatic tumors at 28 days after orthotopic transplantation of 4T1 cells into the mammary fat pad. We investigated the uptake of HPMA copolymer conjugated with Alexa Fluor 647 and folic acid (P-Alexa647-FA) and HPMA copolymer conjugated with IRDye 800CW (P-IRDye), following their retroorbital injection into the primary and metastatic tumor-bearing mice. A significant uptake of P-IRDye was observed at all primary and metastatic tumor sites in these mice, and the P-Alexa647-FA signal was found specifically within CD11b+ TAMs costained with pan-macrophage marker CD68. These findings demonstrate, for the first time, a novel capacity of a P-Alexa647-FA conjugate to colocalize to CD11b+CD68+ TAMs in both primary and metastatic breast tumors. This underscores the potential of this HPMA nanocarrier to deliver functional therapeutics that specifically target tumor-promoting macrophage activation and/or polarization during tumor development. Mol Cancer Ther; 16(12); 2701-10. ©2017 AACR. ©2017 American Association for Cancer Research.

  9. Myeloid cells in circulation and tumor microenvironment of breast cancer patients.

    Science.gov (United States)

    Toor, Salman M; Syed Khaja, Azharuddin Sajid; El Salhat, Haytham; Faour, Issam; Kanbar, Jihad; Quadri, Asif A; Albashir, Mohamed; Elkord, Eyad

    2017-06-01

    Pathological conditions including cancers lead to accumulation of a morphological mixture of highly immunosuppressive cells termed as myeloid-derived suppressor cells (MDSC). The lack of conclusive markers to identify human MDSC, due to their heterogeneous nature and close phenotypical and functional proximity with other cell subsets, made it challenging to identify these cells. Nevertheless, expansion of MDSC has been reported in periphery and tumor microenvironment of various cancers. The majority of studies on breast cancers were performed on murine models and hence limited literature is available on the relation of MDSC accumulation with clinical settings in breast cancer patients. The aim of this study was to investigate levels and phenotypes of myeloid cells in peripheral blood (n = 23) and tumor microenvironment of primary breast cancer patients (n = 7), compared with blood from healthy donors (n = 21) and paired non-tumor normal breast tissues from the same patients (n = 7). Using multicolor flow cytometric assays, we found that breast cancer patients had significantly higher levels of tumor-infiltrating myeloid cells, which comprised of granulocytes (P = 0.022) and immature cells that lack the expression of markers for fully differentiated monocytes or granulocytes (P = 0.016). Importantly, this expansion was not reflected in the peripheral blood. The immunosuppressive potential of these cells was confirmed by expression of Arginase 1 (ARG1), which is pivotal for T-cell suppression. These findings are important for developing therapeutic modalities to target mechanisms employed by immunosuppressive cells that generate an immune-permissive environment for the progression of cancer.

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

    Science.gov (United States)

    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.

  11. Androgen receptor expression on circulating tumor cells in metastatic breast cancer.

    Directory of Open Access Journals (Sweden)

    Takeo Fujii

    Full Text Available Androgen receptor (AR is frequently detected in breast cancers, and AR-targeted therapies are showing activity in AR-positive (AR+ breast cancer. However, the role of AR in breast cancers is still not fully elucidated and the biology of AR in breast cancer remains incompletely understood. Circulating tumor cells (CTCs can serve as prognostic and diagnostic tools, prompting us to measure AR protein expression and conduct genomic analyses on CTCs in patients with metastatic breast cancer.Blood samples from patients with metastatic breast cancer were deposited on glass slides, subjected to nuclear staining with DAPI, and reacted with fluorescent-labeled antibodies to detect CD45, cytokeratin (CK, and biomarkers of interest (AR, estrogen receptor [ER], and HER2 on all nucleated cells. The stained slides were scanned and enumerated by non-enrichment-based non-biased approach independent of cell surface epithelial cell adhesion molecule (EpCAM using the Epic Sciences CTC platform. Data were analyzed using established digital pathology algorithms.Of 68 patients, 51 (75% had at least 1 CTC, and 49 of these 51 (96% had hormone-receptor-positive (HR+/HER2-negative primary tumors. AR was expressed in CK+ CTCs in 10 patients. Of these 10 patients, 3 also had ER expression in CK+ CTCs. Single cell genomic analysis of 78 CTCs from 1 of these 3 patients identified three distinct copy number patterns. AR+ cells had a lower frequency of chromosomal changes than ER+ and HER2+ cells.CTC enumeration and analysis using no enrichment or selection provides a non-biased approach to detect AR expression and chromosomal aberrations in CTCs in patients with metastatic breast cancer. The heterogeneity of intrapatient AR expression in CTCs leads to the new hypothesis that patients with AR+ CTCs have heterogeneous disease with multiple drivers. Further studies are warranted to investigate the clinical applicability of AR+ CTCs and their heterogeneity.

  12. Androgen receptor expression on circulating tumor cells in metastatic breast cancer

    Science.gov (United States)

    Fujii, Takeo; Reuben, James M.; Huo, Lei; Espinosa Fernandez, Jose Rodrigo; Gong, Yun; Krupa, Rachel; Suraneni, Mahipal V.; Graf, Ryon P.; Lee, Jerry; Greene, Stephanie; Rodriguez, Angel; Dugan, Lyndsey; Louw, Jessica; Lim, Bora; Barcenas, Carlos H.; Marx, Angela N.; Tripathy, Debu; Wang, Yipeng; Landers, Mark; Dittamore, Ryan

    2017-01-01

    Purpose Androgen receptor (AR) is frequently detected in breast cancers, and AR-targeted therapies are showing activity in AR-positive (AR+) breast cancer. However, the role of AR in breast cancers is still not fully elucidated and the biology of AR in breast cancer remains incompletely understood. Circulating tumor cells (CTCs) can serve as prognostic and diagnostic tools, prompting us to measure AR protein expression and conduct genomic analyses on CTCs in patients with metastatic breast cancer. Methods Blood samples from patients with metastatic breast cancer were deposited on glass slides, subjected to nuclear staining with DAPI, and reacted with fluorescent-labeled antibodies to detect CD45, cytokeratin (CK), and biomarkers of interest (AR, estrogen receptor [ER], and HER2) on all nucleated cells. The stained slides were scanned and enumerated by non-enrichment-based non-biased approach independent of cell surface epithelial cell adhesion molecule (EpCAM) using the Epic Sciences CTC platform. Data were analyzed using established digital pathology algorithms. Results Of 68 patients, 51 (75%) had at least 1 CTC, and 49 of these 51 (96%) had hormone-receptor-positive (HR+)/HER2-negative primary tumors. AR was expressed in CK+ CTCs in 10 patients. Of these 10 patients, 3 also had ER expression in CK+ CTCs. Single cell genomic analysis of 78 CTCs from 1 of these 3 patients identified three distinct copy number patterns. AR+ cells had a lower frequency of chromosomal changes than ER+ and HER2+ cells. Conclusions CTC enumeration and analysis using no enrichment or selection provides a non-biased approach to detect AR expression and chromosomal aberrations in CTCs in patients with metastatic breast cancer. The heterogeneity of intrapatient AR expression in CTCs leads to the new hypothesis that patients with AR+ CTCs have heterogeneous disease with multiple drivers. Further studies are warranted to investigate the clinical applicability of AR+ CTCs and their

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

    Science.gov (United States)

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

    2008-01-01

    Background 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). Methods 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. Results 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. Conclusion Tumor-derived, but not stromal fibroblast-derived, MMP-13 correlated with aggressive tumor phenotypes, and

  14. Tumor markers in metastatic breast cancer subtypes: frequency of elevation and correlation with outcome.

    Science.gov (United States)

    Yerushalmi, R; Tyldesley, S; Kennecke, H; Speers, C; Woods, R; Knight, B; Gelmon, K A

    2012-02-01

    Little is known about the correlations between tumor markers (TMs), breast cancer subtypes, site(s) of metastasis and prognosis. Women diagnosed with metastatic breast cancer were included. Breast cancer subtypes were defined as LuminalA, LuminalB, LuminalHer2, Her2, Basal and non-Basal triple negative (TN). Levels of elevation of TM values [cancer antigen 15-3 (CA 15-3), carcinoembryonic antigen (CEA) and cancer antigen 125 (CA 125)] among the subtypes were analyzed. Site(s) of metastasis and outcomes were captured. Eight hundred and ten patients were included. Luminal subtypes were associated with an elevation in at least one TM: 90.8% of LuminalHer2+, 90% of LuminalB and 88.6% of LuminalA. TMs were less frequently elevated in Basal (74.1%) and non-Basal TN (71.4%) cases (P Breast cancer-specific survival (BCSS) was significantly worse for patients with elevated TMs (P = 0.001). TM elevation of CA 15-3, CEA and/or CA 125 was documented in the majority of patients with metastatic breast cancer with CA 15-3 occurring most commonly. Luminal subtypes expressed elevated TMs significantly more frequently compared with the non-Luminal groups. TM elevation was not different between the different sites of metastasis. Overall, elevated TMs predicted a worse BCSS.

  15. Tumor-targeting Salmonella typhimurium A1-R prevents experimental human breast cancer bone metastasis in nude mice

    OpenAIRE

    Miwa, Shinji; Yano, Shuya; Zhang, Yong; Matsumoto,Yasunori; Uehara, Fuminari; Yamamoto, Mako; Hiroshima, Yukihiko; Kimura, Hiroaki; Hayashi, Katsuhiro; Yamamoto, Norio; Bouvet, Michael; Tsuchiya, Hiroyuki; Hoffman, Robert M.; Zhao, Ming

    2014-01-01

    Bone metastasis is a lethal and morbid late stage of breast cancer that is currently treatment resistant. More effective mouse models and treatment are necessary. High bone-metastatic variants of human breast cancer cells were selected in nude mice by cardiac injection. After cardiac injection of a high bone-metastatic variant of breast cancer, all untreated mice had bone metastases compared to only 20% with parental cells. Treatment with tumor-targeting Salmonella typhimurium A1-R completely...

  16. A novel method for monitoring high-risk breast cancer with tumor markers

    DEFF Research Database (Denmark)

    Sölétormos, G; Nielsen, D; Schiøler, V

    1993-01-01

    BACKGROUND: An early and reliable diagnosis of metastatic spread has increased interest in serum tumor markers. This study investigated the ability of CA 15.3, CEA, and TPA to identify, predict, and exclude metastases in bone/viscera during adjuvant treatment and follow-up of high-risk breast...... cancer. METHODS: Ninety females with high-risk breast cancer were included in the study. Response evaluation was based upon clinical examination, x-rays or histology and elaborated marker criteria. RESULTS: During the marker monitoring period, metastases in four patients were confined to skin or lymph...

  17. Profiling of microRNAs in tumor interstitial fluid of breast tumors – a novel resource to identify biomarkers for prognostic classification and detection of cancer

    DEFF Research Database (Denmark)

    Halvorsen, Ann Rita; Helland, Åslaug; Gromov, Pavel

    2017-01-01

    and to elucidate the cross-talk that exists among cells in a tumor microenvironment. Matched tumor interstitial fluid samples (TIF, n = 60), normal interstitial fluid samples (NIF, n = 51), corresponding tumor tissue specimens (n = 54), and serum samples (n = 27) were collected from patients with breast cancer......, and detectable microRNAs were analyzed and compared. In addition, serum data from 32 patients with breast cancer and 22 healthy controls were obtained for a validation study. To identify potential serum biomarkers of breast cancer, first the microRNA profiles of TIF and NIF samples were compared. A total of 266...

  18. 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.

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

    Directory of Open Access Journals (Sweden)

    Suhail Mahmoud M

    2011-12-01

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

  20. 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

  1. Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer.

    Science.gov (United States)

    Montoya, Alexa; Amaya, Clarissa N; Belmont, Andres; Diab, Nabih; Trevino, Richard; Villanueva, Geri; Rains, Steven; Sanchez, Luis A; Badri, Nabeel; Otoukesh, Salman; Khammanivong, Ali; Liss, Danielle; Baca, Sarah T; Aguilera, Renato J; Dickerson, Erin B; Torabi, Alireza; Dwivedi, Alok K; Abbas, Aamer; Chambers, Karinn; Bryan, Brad A; Nahleh, Zeina

    2017-01-24

    Previous studies suggest beta-adrenergic receptor (β-AR) antagonists (β-blockers) decrease breast cancer progression, tumor metastasis, and patient mortality; however the mechanism for this is unknown. Immunohistochemical analysis of normal and malignant breast tissue revealed overexpression of β1-AR and β3-AR in breast cancer. A retrospective cross-sectional study of 404 breast cancer patients was performed to determine the effect of β-blocker usage on tumor proliferation. Our analysis revealed that non-selective β-blockers, but not selective β-blockers, reduced tumor proliferation by 66% (p cancer compared to non-users. We tested the efficacy of propranolol on an early stage breast cancer patient, and quantified the tumor proliferative index before and after treatment, revealing a propranolol-mediated 23% reduction (p = 0.02) in Ki67 positive tumor cells over a three-week period. The anti-proliferative effects of β-blockers were measured in a panel of breast cancer lines, demonstrating that mammary epithelial cells were resistant to propranolol, and that most breast cancer cell lines displayed dose dependent viability decreases following treatment. Selective β-blockers alone or in combination were not as effective as propranolol at reducing breast cancer cell proliferation. Molecular analysis revealed that propranolol treatment of the SK-BR-3 breast cancer line, which showed high sensitivity to beta blockade, led to a reduction in Ki67 protein expression, decreased phosphorylation of the mitogenic signaling regulators p44/42 MAPK, p38 MAPK, JNK, and CREB, increased phosphorylation of the cell survival/apoptosis regulators AKT, p53, and GSK3β. In conclusion, use of non-selective β-blockers in patients with early stage breast cancer may lead to decreased tumor proliferation.

  2. A mouse mammary tumor virus-like long terminal repeat superantigen in human breast cancer.

    Science.gov (United States)

    Wang, Yue; Jiang, Jian-Dong; Xu, Dongping; Li, Yan; Qu, Chunfeng; Holland, James F; Pogo, Beatriz G-T

    2004-06-15

    We previously reported a 660-bp mouse mammary tumor virus (MMTV)-like env gene sequence in approximately 38% of human breast cancer DNA, but not in normal breasts or other tumors. This MMTV-like env gene sequence was expressed in 66% of the env gene-positive human breast cancers. An entire proviral structure was identified in human breast cancer DNA with high homology to MMTV and low homology to known human endogenous retrovirus. MMTV-like long terminal repeat (LTR) sequences were also detected in 41.5% of human breast cancers. They contain hormone-responsive elements, TEF-1 family elements, and the open reading frame for the superantigen (SAg). We have now amplified and sequenced MMTV-like sag sequences from 10 human breast cancers, and we found that they are highly homologous to those of MMTV. However, deletions and insertions at the COOH-terminal of sag were observed. The immune function of the human MMTV-like LTR SAg was also investigated. The sag gene was cloned and expressed in a human B-cell line (Ramos). T-cell proliferation and cytokine releasing assays were performed after cocultivation of T cells with irradiated Ramos SAg-expressing cells. The results indicate that expression of the human SAg stimulates T-cell activation in vitro, as the mouse SAg does. Because the T-cell responses in vitro are considered similar to those in vivo, these results suggest that the human LTR SAg might also play a role in human breast carcinogenesis.

  3. A Role for T-Lymphocytes in Human Breast Cancer and in Canine Mammary Tumors

    Directory of Open Access Journals (Sweden)

    Maria Isabel Carvalho

    2014-01-01

    Full Text Available Chronic inflammation in the tumor microenvironment has a prominent role in carcinogenesis and benefits the proliferation and survival of malignant cells, promoting angiogenesis and metastasis. Mammary tumors are frequently infiltrated by a heterogeneous population of immune cells where T-lymphocytes have a great importance. Interestingly, similar inflammatory cell infiltrates, cytokine and chemokine expression in humans and canine mammary tumors were recently described. However, in both species, despite all the scientific evidences that appoint for a significant role of T-lymphocytes, a definitive conclusion concerning the effectiveness of T-cell dependent immune mechanisms has not been achieved yet. In the present review, we describe similarities between human breast cancer and canine mammary tumors regarding tumor T-lymphocyte infiltration, such as relationship of TILs and mammary tumors malignancy, association of ratio CD4+/ CD8+ T-cells with low survival rates, promotion of tumor progression by Th2 cells actions, and association of great amounts of Treg cells with poor prognostic factors. This apparent parallelism together with the fact that dogs develop spontaneous tumors in the context of a natural immune system highlight the dog as a possible useful biological model for studies in human breast cancer immunology.

  4. Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Koen M.A. Dreijerink

    2017-03-01

    Full Text Available While the multiple endocrine neoplasia type 1 (MEN1 gene functions as a tumor suppressor in a variety of cancer types, we explored its oncogenic role in breast tumorigenesis. The MEN1 gene product menin is involved in H3K4 trimethylation and co-activates transcription. We integrated ChIP-seq and RNA-seq data to identify menin target genes. Our analysis revealed that menin-dependent target gene promoters display looping to distal enhancers that are bound by menin, FOXA1 and GATA3. In this fashion, MEN1 co-regulates a proliferative breast cancer-specific gene expression program in ER+ cells. In primary mammary cells, MEN1 exerts an anti-proliferative function by regulating a distinct expression signature. Our findings clarify the cell-type-specific functions of MEN1 and inform the development of menin-directed treatments for breast cancer.

  5. Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer

    Science.gov (United States)

    Qamri, Zahida; Preet, Anju; Nasser, Mohd W.; Bass, Caroline E.; Leone, Gustavo; Barsky, Sanford H.; Ganju, Ramesh K.

    2014-01-01

    Cannabinoids have been reported to possess antitumorogenic activity. Not much is known, however, about the effects and mechanism of action of synthetic nonpsychotic cannabinoids on breast cancer growth and metastasis. We have shown that the cannabinoid receptors CB1 and CB2 are overexpressed in primary human breast tumors compared with normal breast tissue. We have also observed that the breast cancer cell lines MDA-MB231, MDA-MB231-luc, and MDA-MB468 express CB1 and CB2 receptors. Furthermore, we have shown that the CB2 synthetic agonist JWH-133 and the CB1 and CB2 agonist WIN-55,212-2 inhibit cell proliferation and migration under in vitro conditions. These results were confirmed in vivo in various mouse model systems. Mice treated with JWH-133 or WIN-55,212-2 showed a 40% to 50% reduction in tumor growth and a 65% to 80% reduction in lung metastasis. These effects were reversed by CB1 and CB2 antagonists AM 251 and SR144528, respectively, suggesting involvement of CB1 and CB2 receptors. In addition, the CB2 agonist JWH-133 was shown to delay and reduce mammary gland tumors in the polyoma middle T oncoprotein (PyMT) transgenic mouse model system. Upon further elucidation, we observed that JWH-133 and WIN-55,212-2 mediate the breast tumor-suppressive effects via a coordinated regulation of cyclooxygenase-2/ prostaglandin E2 signaling pathways and induction of apoptosis. These results indicate that CB1 and CB2 receptors could be used to develop novel therapeutic strategies against breast cancer growth and metastasis. PMID:19887554

  6. Circulating tumor cells in breast cancer: functional heterogeneity, pathogenetic and clinical aspects.

    Science.gov (United States)

    Cherdyntseva, N V; Litviakov, N V; Denisov, E V; Gervas, P A; Cherdyntsev, E S

    2017-03-01

    Each patient has a unique history of cancer ecosystem development, resulting in intratumor heterogeneity. In order to effectively kill the tumor cells by chemotherapy, dynamic monitoring of driver molecular alterations is necessary to detect the markers for acquired drug resistance and find the new therapeutic targets. To perform the therapeutic monitoring, frequent tumor biopsy is needed, but it is not always possible due to small tumor size or its regression during the therapy or tumor inaccessibility in advanced cancer patients. Liquid biopsy appears to be a promising approach to overcome this problem, providing the testing of circulating tumor cells (CTC) and/or tumor-specific circulating nucleic acids. Their genomic characteristics make it possible to assess the clonal dynamics of tumors, comparing it with the clinical course and identification of driver mutation that confer resistance to therapy. The main attention in this review is paid to CTC. The biological behavior of the tumor is determined by specific cancer-promoting molecular and genetic alterations of tumor cells, and by the peculiarities of their interactions with the microenvironment that can result in the presence of wide spectrum of circulating tumor clones with various properties and potentialities to contribute to tumor progression and response to chemotherapy and prognostic value. Indeed, data on prognostic or predictive value of CTC are rather contradictory, because there is still no standard method of CTC identification, represented by different populations manifesting various biological behavior as well as different potency to metastasis. Circulating clasters of CTC appear to have essentially greater ability to metastasize in comparison with single CTC, as well as strong association with worse prognosis and chemoresistance in breast cancer patients. The Food and Drug Administration (USA) has approved the CTC-based prognostic test for clinical application in patients with advanced breast

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

    Directory of Open Access Journals (Sweden)

    Sara Caceres

    2016-01-01

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

  8. Genomic aberrations in normal tissue adjacent to HER2-amplified breast cancers: field cancerization or contaminating tumor cells?

    Science.gov (United States)

    Sadanandam, Anguraj; Lal, Aseem; Benz, Stephen C; Eppenberger-Castori, Serenella; Scott, Gary; Gray, Joe W; Spellman, Paul; Waldman, Fred; Benz, Christopher C

    2012-12-01

    Field cancerization effects as well as isolated tumor cell foci extending well beyond the invasive tumor margin have been described previously to account for local recurrence rates following breast conserving surgery despite adequate surgical margins and breast radiotherapy. To look for evidence of possible tumor cell contamination or field cancerization by genetic effects, a pilot study (Study 1: 12 sample pairs) followed by a verification study (Study 2: 20 sample pairs) were performed on DNA extracted from HER2-positive breast tumors and matching normal adjacent mammary tissue samples excised 1-3 cm beyond the invasive tumor margin. High-resolution molecular inversion probe (MIP) arrays were used to compare genomic copy number variations, including increased HER2 gene copies, between the paired samples; as well, a detailed histologic and immunohistochemical (IHC) re-evaluation of all Study 2 samples was performed blinded to the genomic results to characterize the adjacent normal tissue composition bracketing the DNA-extracted samples. Overall, 14/32 (44 %) sample pairs from both studies produced genome-wide evidence of genetic aberrations including HER2 copy number gains within the adjacent normal tissue samples. The observed single-parental origin of monoallelic HER2 amplicon haplotypes shared by informative tumor-normal pairs, as well as commonly gained loci elsewhere on 17q, suggested the presence of contaminating tumor cells in the genomically aberrant normal samples. Histologic and IHC analyses identified occult 25-200 μm tumor cell clusters overexpressing HER2 scattered in more than half, but not all, of the genomically aberrant normal samples re-evaluated, but in none of the genomically normal samples. These genomic and microscopic findings support the conclusion that tumor cell contamination rather than genetic field cancerization represents the likeliest cause of local clinical recurrence rates following breast conserving surgery, and mandate caution

  9. ABCG2 is a potential marker of tumor-initiating cells in breast cancer.

    Science.gov (United States)

    Sicchieri, Renata Danielle; da Silveira, Willian Abraham; Mandarano, Larissa Raquel Mouro; de Oliveira, Tatiane Mendes Gonçalves; Carrara, Hélio Humberto Angotti; Muglia, Valdair Francisco; de Andrade, Jurandyr Moreira; Tiezzi, Daniel Guimarães

    2015-12-01

    The existence of tumor-initiating cells (TICs) within solid tumors has been hypothesized to explain tumor heterogeneity and resistance to cancer therapy. In breast cancer, the expression of CD44 and CD24 and the activity of aldehyde dehydrogenase 1 (ALDH1) can be used to selectively isolate a cell population enriched in TICs. However, the ideal marker to identify TICs has not been established. The aim of this study was to evaluate the expression of novel potential markers for TIC in breast carcinoma. We prospectively analyzed the expression of CD44, CD24, ABCG2, and CXCR4, and the activity of ALDH1 by using flow cytometry in 48 invasive ductal carcinomas from locally advanced and metastatic breast cancer patients who were administered primary chemotherapy. A mammosphere assay was employed in 30 samples. The relationship among flow cytometric analyses, ABCG2 gene expression, and clinical and pathological responses to therapy was analyzed. The GSE32646 database was analyzed in silico to identify genes associated with tumors with low and high ABCG2 expression. We observed that the presence of ABCG2(+) cells within the primary tumor was the only marker to predict the formation of mammospheres in vitro (R (2) = 0.15, p = 0.029). Quantitative polymerase chain reaction (qPCR) revealed a positive correlation between ABCG2 expression and the presence of ABCG2(+) cells within the primary tumor. The expression of ABCG2 was predictive of the response to neoadjuvant chemotherapy in our experiments and in the GSE32646 dataset (p = 0.04 and p = 0.002, respectively). The in silico analysis demonstrated that ABCG2(Up) breast cancer samples have a slower cell cycle and a higher expression of membrane proteins but a greater potential for chromosomal instability, metastasis, immune evasion, and resistance to hypoxia. Such genetic characteristics are compatible with highly aggressive and resistant tumors. Our results support the hypothesis that the presence of ABCG2

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

    Directory of Open Access Journals (Sweden)

    Goar Mosoyan

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

  11. Tumor Microvasculature: Endothelial Leakiness and Endothelial Pore Size Distribution in a Breast Cancer Model

    Directory of Open Access Journals (Sweden)

    E.E. Uzgiris

    2008-01-01

    Full Text Available Tumor endothelial leakiness is quantified in a rat mammary adenocarcinoma model using dynamic contrast enhancement MRI and contrast agents of widely varying sizes. The contrast agents were constructed to be of globular configuration and have their uptake rate into tumor interstitium be driven by the same diffusion process and limited only by the availability of endothelial pores of passable size. It was observed that the endothelial pore distribution has a steep power law dependence on size, r−β, with an exponent of −4.1. The model of large pore dominance in tumor leakiness as reported in some earlier investigation with fluorescent probes and optical chamber methods is rejected for this tumor model and a number of other tumor types including chemically induced tumors. This steep power law dependence on size is also consistent with observations on human breast cancer.

  12. Gene Promoter Hypermethylation in Tumors and Plasma of Breast Cancer Patients

    Science.gov (United States)

    Shim, Young Ran; Choi, Joon Hyuk; Kim, Mi Jin; Gabrielson, Edward; Lee, Soo Jung; Hwang, Tae Yoon; Shin, Sei One

    2005-01-01

    Purpose To measure the hypermethylation of four genes in primary tumors and paired plasma samples to determine the feasibility of gene promoter hypermethylation markers for detecting breast cancer in the plasma. Materials and Methods DNA was extracted from the tumor tissues and peripheral blood plasma of 34 patients with invasive breast cancer, and the samples examined for aberrant hypermethylation in cyclin D2, retinoic acid receptor β (RARβ), twist and high in normal-1 (HIN-1) genes using methylation-specific PCR (MSP), and the results correlated with the clinicopathological parameters. Results Promoter hypermethylation was detected at high frequency in the primary tumors for cyclin D2 (53%), RARβ (56%), twist (41%) and HIN-1 (77%). Thirty-three of the 34 (97%) primary tumors displayed promoter hypermethylation in at least one of the genes examined. The corresponding plasma samples showed hyperme thylation of the same genes, although at lower frequencies (6% for cyclin D2, 16% for RARβ, 36% for twist, and 54% for HIN-1). Overall, 22 of the 33 (67%) primary tumors with hypermethylation of at least one of the four genes also had abnormally hypermethylated DNA in their matched plasma samples. No significant relationship was recognized between any of the clinical or pathological parameters (tumor size, axillary lymph node metastasis, stage, or Ki-67 labeling index) with the frequency of hypermethylated DNA in the primary tumor or plasma. Conclusion The detection of aberrant promoter hypermethylation of cancer-related genes in the plasma may be a useful tool for the detection of breast cancer. PMID:19956520

  13. Lignan transformation by gut bacteria lowers tumor burden in a gnotobiotic rat model of breast cancer.

    Science.gov (United States)

    Mabrok, Hoda B; Klopfleisch, Robert; Ghanem, Kadry Z; Clavel, Thomas; Blaut, Michael; Loh, Gunnar

    2012-01-01

    High dietary lignan exposure is implicated in a reduced breast cancer risk in women. The bacterial transformation of plant lignans to enterolignans is thought to be essential for this effect. To provide evidence for this assumption, gnotobiotic rats were colonized with the lignan-converting bacteria Clostridium saccharogumia, Eggerthella lenta, Blautia producta and Lactonifactor longoviformis (LCC rats). Germ-free rats were used as the control. All animals were fed a lignan-rich flaxseed diet and breast cancer was induced with 7,12-dimethylbenz(a)anthracene. The lignan secoisolariciresinol diglucoside was converted into the enterolignans enterodiol and enterolactone in the LCC but not in the germ-free rats. This transformation did not influence cancer incidence at the end of the 13 weeks experimental period but significantly decreased tumor numbers per tumor-bearing rat, tumor size, tumor cell proliferation and increased tumor cell apoptosis in LCC rats. No differences between LCC and control rats were observed in the expression of the genes encoding the estrogen receptors (ERs) α, ERβ and G-coupled protein 30. The same was true for IGF-1 and EGFR involved in tumor growth. The activity of selected enzymes involved in the degradation of oxidants in plasma and liver was significantly increased in the LCC rats. However, plasma and liver concentrations of reduced glutathione and malondialdehyde, considered as oxidative stress markers, did not differ between the groups. In conclusion, our results show that the bacterial conversion of plant lignans to enterolignans beneficially influences their anticancer effects.

  14. Familial breast cancer. Part II: Relationships with histology, staging, steroid receptors and serum tumor markers.

    Science.gov (United States)

    Gavrilov, I; Nacheva, M; Tzingilev, D

    2002-01-01

    To identify differences in clinical characteristics, histological features, hormone receptor status, and tumor marker expression between patients with sporadic and familial breast cancer. As in the previous Part I of this study, two groups of women with breast cancer were compared. The first group (group I) included 504 patients with a family history of breast cancer. The second (control) group (group II) consisted of 300 patients not reporting such a history in their relatives. The examined parameters in this report were stage and axillary lymph node involvement at the time of the initial diagnosis, treatment methods, hormone receptor status, and serum levels of the tumor markers CEA and CA 15.3. The data were processed and analysed using the SPSS statistical package. The statistical significance of differences between groups and subgroups was evaluated by x(2) Pearson's test and Student's paired t-test. Compared to sporadic cases, patients with familial breast cancer were more often diagnosed at an advanced III or IV stage; metastatic involvement of the regional lymph nodes was more frequent in group I patients. In the same group more radical surgical procedures combined with chemotherapy and local irradiation were performed. In group I the percentage of negative hormone receptors was higher (35.3% versus 22.6%; p result of their particular characteristics, these patients require more radical surgical techniques combined with pre- or postoperative local radiotherapy and systemic chemotherapy.

  15. [Surgical treatment of the primary tumor in stage IV breast cancer].

    Science.gov (United States)

    Jiménez Anula, Juan; Sánchez Andújar, Belén; Machuca Chiriboga, Pablo; Navarro Cecilia, Joaquín; Dueñas Rodríguez, Basilio

    2015-01-01

    The aim of the study was to analyze the impact of loco-regional surgery on survival of patients with stage IV breast cancer. Retrospective study that included patients with breast cancer and synchronous metastases. Patients with ECOG above 2 and high-risk patients were excluded. The following variables were evaluated: age, tumor size, nodal involvement, histological type, histological grade, hormone receptor status, HER2 overexpression, number of affected organs, location of metastases and surgical treatment. The impact of surgery and several clinical and pathologic variables on survival was analyzed by Cox regression model. A total of 69 patients, of whom 36 (52.2%) underwent surgery (study group) were included. After a mean follow-up of 34 months, the median survival of the series was 55 months and no significant differences between the study group and the group of patients without surgery (P=0.187) were found. Two factors associated with worse survival were identified: the number of organs with metastases (HR=1.69, IC 95%: 1.05-2.71) and triple negative breast cancer (HR=3.49, IC 95%: 1.39-8.74). Loco-regional surgery, however, was not associated with survival. Loco-regional surgical treatment was not associated with improved survival inpacientes with stage IV breast cancer. The number of organs with metastases and tumors were triple negative prognostic factors for survival. Copyright © 2014 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.

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

    Science.gov (United States)

    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.

  17. Tumor markers in breast cancer- European Group on Tumor Markers recommendations

    DEFF Research Database (Denmark)

    Molina, Rafael; Barak, Vivian; van Dalen, Arie

    2005-01-01

    in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin (trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node...

  18. Exercise-Induced Catecholamines Activate the Hippo Tumor Suppressor Pathway to Reduce Risks of Breast Cancer Development

    DEFF Research Database (Denmark)

    Dethlefsen, Christine; Hansen, Louise S; Lillelund, Christian

    2017-01-01

    Strong epidemiologic evidence documents the protective effect of physical activity on breast cancer risk, recurrence, and mortality, but the underlying mechanisms remain to be identified. Using human exercise-conditioned serum for breast cancer cell incubation studies and murine exercise...... interventions, we aimed to identify exercise factors and signaling pathways involved in the exercise-dependent suppression of breast cancer. Exercise-conditioned serum from both women with breast cancer (n = 20) and healthy women (n = 7) decreased MCF-7 (hormone-sensitive) and MDA-MB-231 (hormone......-insensitive) breast cancer cell viability in vitro by 11% to 19% and reduced tumorigenesis by 50% when preincubated MCF-7 breast cancer cells were inoculated into NMRI-Foxn1(nu) mice. This exercise-mediated suppression of cell viability and tumor formation was completely blunted by blockade of β-adrenergic signaling...

  19. Cytotoxicity and anti-tumor effects of new ruthenium complexes on triple negative breast cancer cells.

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    Cecília P Popolin

    Full Text Available Triple-negative breast cancer (TNBC is a highly aggressive breast cancer subtype. The high rate of metastasis associated to the fact that these cells frequently display multidrug resistance, make the treatment of metastatic disease difficult. Development of antitumor metal-based drugs was started with the discovery of cisplatin, however, the severe side effects represent a limitation for its clinical use. Ruthenium (Ru complexes with different ligands have been successfully studied as prospective antitumor drugs. In this work, we demonstrated the activity of a series of biphosphine bipyridine Ru complexes (1 [Ru(SO4(dppb(bipy], (2 [Ru(CO3(dppb(bipy], (3 [Ru(C2O4(dppb(bipy] and (4 [Ru(CH3CO2(dppb(bipy]PF6 [where dppb = 1,4-bis(diphenylphosphinobutane and bipy = 2,2'-bipyridine], on proliferation of TNBC (MDA-MB-231, estrogen-dependent breast tumor cells (MCF-7 and a non-tumor breast cell line (MCF-10A. Complex (4 was most effective among the complexes and was selected to be further investigated on effects on tumor cell adhesion, migration, invasion and in apoptosis. Moreover, DNA and HSA binding properties of this complex were also investigated. Results show that complex (4 was more efficient inhibiting proliferation of MDA-MB-231 cells over non-tumor cells. In addition, complex (4 was able to inhibit MDA-MB231 cells adhesion, migration and invasion and to induce apoptosis and inhibit MMP-9 secretion in TNBC cells. Complex (4 should be further investigated in vivo in order to stablish its potential to improve breast cancer treatment.

  20. Contralateral breast cancer risk in relation to tumor morphology and age-in which patients is preoperative MRI justified?

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    de Glas, N A; Engels, C C; Bastiaannet, E; van de Water, W; Siesling, S; de Craen, A J M; van de Velde, C J H; Liefers, G J; Merkus, J W S

    2015-02-01

    Identification of patients who are at increased risk for contralateral breast cancer is essential to determine which patients should be routinely screened for contralateral breast cancer using MRI. The aim of this study was to assess the association of age and tumor morphology with contralateral breast cancer incidence in a large, nationwide population-based study in the Netherlands. All patients with breast cancer stage I-III, diagnosed between 1989 and 2009, were selected from the Netherlands Cancer Registry. The association between contralateral breast cancer risk with tumor morphology and age was assessed using competing-risk regression according to Fine & Gray. Overall, 194,898 patients were included. In multivariable analyses, lobular tumors were significantly associated with an increased risk of contralateral breast cancer within 6 months (cumulative incidence 1.9 %, subdistribution hazard ratio (SHR) 1.17, 95 % confidence interval (CI) 1.06-1.30 compared with 1.3 % in ductal tumors, p = 0.002). Age was also associated with an increased risk of contralateral breast cancer within 6 months (SHR 2.34, 95 % CI 2.08-2.62, p age of 75 as compared to patients younger than 50 years). The absolute risk of contralateral breast cancer within 6 months is only slightly increased in patients with a lobular tumor and older patients. In our view, this small increased risk does not justify standard use of preoperative MRI based on tumor morphology or age alone. We propose a more personalized strategy in which additional risk factors (family history, prognosis of primary tumor, and others) may play a role.

  1. Causal Therapy of Breast Cancer Irrelevant of Age, Tumor Stage and ER-Status: Stimulation of Estrogen Signaling Coupled With Breast Conserving Surgery.

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    Suba, Zsuzsanna

    2016-01-01

    Results of long-term studies justify that the rate of breast cancer recurrence and tumor-related mortality remains quite unpredictable, regardless of the use of any current therapeutic measures. Since the application of standard therapies, such as surgery, radiation, chemotherapy and antiestrogen administration does not work as might be expected; our therapeutic practice requires thorough rethinking. Published long-term therapeutic results on breast cancer cases were analyzed in correlation with stage at diagnosis, ER-status of tumors and patients' age. The effectiveness of current therapeutic measures was also compared by estimating the rate of tumor-free survival, breast cancer recurrence and breast cancer-specific mortality. Diagnosis and treatment of breast cancer at an early stage cannot improve the rate of tumor-free survival. Poor differentiation of tumors, ER-negativity in particular, defines poor prognosis even after applying aggressive therapies. In patients treated with in situ breast cancer, the recurrence-rate of invasive tumor increased directly with ageing irrespective of tumor size or ER-status at diagnosis. Women who underwent lumpectomy without adjuvant radiation or chemotherapy exhibited significantly better overall and breast cancer specific survival rates than those receiving mastectomy, regardless of stage and ER-status of tumors. Antiestrogen treatment exhibited unforeseeable effectiveness even on targeted ERpositive tumors. Recent patents propose the detection of ESR1-gene amplification or restoration of ER-alpha expression for prediction of effective antiestrogen treatment, suggesting a crucial inhibitory role of estrogen-signaling against tumorgrowth. Estradiol-induced upregulation of estrogen signaling coupled with sparing of the estrogen-rich mammary fatpad are the most effective strategies against breast cancer.

  2. Differential expression of growth factor receptors and membrane-bound tumor markers for imaging in male and female breast cancer.

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    Jeroen F Vermeulen

    Full Text Available INTRODUCTION: Male breast cancer accounts for 0.5-1% of all breast cancers and is generally diagnosed at higher stage than female breast cancers and therefore might benefit from earlier detection and targeted therapy. Except for HER2 and EGFR, little is known about expression of growth factor receptors in male breast cancer. We therefore investigated expression profiles of growth factor receptors and membrane-bound tumor markers in male breast cancer and gynecomastia, in comparison with female breast cancer. METHODS: Tissue microarrays containing 133 male breast cancer and 32 gynecomastia cases were stained by immunohistochemistry for a panel of membrane-bound targets and compared with data on 266 female breast cancers. RESULTS: Growth factor receptors were variably expressed in 4.5% (MET up to 38.5% (IGF1-R of male breast cancers. Compared to female breast cancer, IGF1-R and carbonic anhydrase 12 (CAXII were more frequently and CD44v6, MET and FGFR2 less frequently expressed in male breast cancer. Expression of EGFR, HER2, CAIX, and GLUT1 was not significantly different between male and female breast cancer. Further, 48.1% of male breast cancers expressed at least one and 18.0% expressed multiple growth factor receptors. Since individual membrane receptors are expressed in only half of male breast cancers, a panel of membrane markers will be required for molecular imaging strategies to reach sensitivity. A potential panel of markers for molecular imaging, consisting of EGFR, IGF1-R, FGFR2, CD44v6, CAXII, GLUT1, and CD44v6 was positive in 77% of male breast cancers, comparable to female breast cancers. CONCLUSIONS: Expression patterns of growth factor receptors and hypoxia membrane proteins in male breast cancer are different from female breast cancer. For molecular imaging strategies, a putative panel consisting of markers for EGFR, IGF1-R, FGFR2, GLUT1, CAXII, CD44v6 was positive in 77% of cases and might be considered for development of

  3. Differential expression of growth factor receptors and membrane-bound tumor markers for imaging in male and female breast cancer.

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

    2013-01-01

    Male breast cancer accounts for 0.5-1% of all breast cancers and is generally diagnosed at higher stage than female breast cancers and therefore might benefit from earlier detection and targeted therapy. Except for HER2 and EGFR, little is known about expression of growth factor receptors in male breast cancer. We therefore investigated expression profiles of growth factor receptors and membrane-bound tumor markers in male breast cancer and gynecomastia, in comparison with female breast cancer. Tissue microarrays containing 133 male breast cancer and 32 gynecomastia cases were stained by immunohistochemistry for a panel of membrane-bound targets and compared with data on 266 female breast cancers. Growth factor receptors were variably expressed in 4.5% (MET) up to 38.5% (IGF1-R) of male breast cancers. Compared to female breast cancer, IGF1-R and carbonic anhydrase 12 (CAXII) were more frequently and CD44v6, MET and FGFR2 less frequently expressed in male breast cancer. Expression of EGFR, HER2, CAIX, and GLUT1 was not significantly different between male and female breast cancer. Further, 48.1% of male breast cancers expressed at least one and 18.0% expressed multiple growth factor receptors. Since individual membrane receptors are expressed in only half of male breast cancers, a panel of membrane markers will be required for molecular imaging strategies to reach sensitivity. A potential panel of markers for molecular imaging, consisting of EGFR, IGF1-R, FGFR2, CD44v6, CAXII, GLUT1, and CD44v6 was positive in 77% of male breast cancers, comparable to female breast cancers. Expression patterns of growth factor receptors and hypoxia membrane proteins in male breast cancer are different from female breast cancer. For molecular imaging strategies, a putative panel consisting of markers for EGFR, IGF1-R, FGFR2, GLUT1, CAXII, CD44v6 was positive in 77% of cases and might be considered for development of molecular tracers for male breast cancer.

  4. 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.

  5. Detection and identification of mouse mammary tumor virus-like DNA sequences in blood and breast tissues of breast cancer patients.

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    Naushad, Wasifa; Bin Rahat, Talha; Gomez, Miriam Kathleen; Ashiq, Muhammad Taimoor; Younas, Muhammad; Sadia, Hajra

    2014-08-01

    Mouse mammary tumor virus (MMTV) is a well-known cause of mammary tumors in mice transmitted as endogenous proviruses or exogenously as infectious virions. The hypothesis that a retrovirus homologous to MMTV is involved in human breast cancers has resulted in renewed interest in the etiology of human breast cancer. Therefore, the detection of MMTV-like exogenous sequences in 30-40 % of invasive breast cancer has increased attention towards this hypothesis. To detect the prevalence of MMTV in Pakistani population, 666-bp-long MMTV envelop and 630-bp LTR sequences were amplified from breast cancer patient samples (tissue biopsies and peripheral blood) using mouse with mammary tumor as control. MMTV-like virus env and LTR DNA sequences were detected in 20 and 26 % of breast tumor samples, respectively, from the total of 80 breast cancer patients' blood and tissue samples. No significant association was observed between age, grade of disease, and lymph node involvement with the prevalence of MMTV-like sequences. Our data add to the growing number of studies implicating MMTV-like virus in human breast cancer, but still clear causal association of MMTV to breast cancer remains to be reputable.

  6. A Case of Recurrent Breast Cancer Identified by Pulmonary Tumor Thrombotic Microangiopathy

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    Tomomi Abe

    2017-07-01

    Full Text Available Pulmonary tumor thrombotic microangiopathy (PTTM is a rare, cancer-related, pulmonary complication that causes hypoxia and pulmonary hypertension. We report on a 42-year-old woman who was diagnosed with recurrent breast cancer that was detected due to the presence of PTTM. Eleven months after surgery for heterochronous bilateral cancer of the left breast, she developed progressive dyspnea but computerized tomography showed no pulmonary thromboembolism, and a transthoracic echocardiography revealed mild pulmonary hypertension. She was diagnosed with PTTM by cytology from pulmonary artery catheterization and perfusion lung scintigraphy. Also, the patients complained of back pain after admission, bone scintigraphy showed multiple bone metastases. Despite the early diagnosis of PTTM, her platelet count decreased, her performance status rapidly deteriorated, and her dyspnea worsened. Thus, we could not treat her with chemotherapy. She died due to respiratory failure 19 days after admission. To the best of our knowledge, this is the first report of recurrent breast cancer identified by the manifestation of PTTM. Although PTTM is a rare phenomenon, it should be considered in the differential diagnosis of acute dyspnea or pulmonary hypertension in patients with breast cancer. Furthermore, upon diagnosis, the patient should be referred to a cardiologist as soon as possible.

  7. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer.

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    Garcia-Murillas, Isaac; Schiavon, Gaia; Weigelt, Britta; Ng, Charlotte; Hrebien, Sarah; Cutts, Rosalind J; Cheang, Maggie; Osin, Peter; Nerurkar, Ashutosh; Kozarewa, Iwanka; Garrido, Javier Armisen; Dowsett, Mitch; Reis-Filho, Jorge S; Smith, Ian E; Turner, Nicholas C

    2015-08-26

    The identification of early-stage breast cancer patients at high risk of relapse would allow tailoring of adjuvant therapy approaches. We assessed whether analysis of circulating tumor DNA (ctDNA) in plasma can be used to monitor for minimal residual disease (MRD) in breast cancer. In a prospective cohort of 55 early breast cancer patients receiving neoadjuvant chemotherapy, detection of ctDNA in plasma after completion of apparently curative treatment-either at a single postsurgical time point or with serial follow-up plasma samples-predicted metastatic relapse with high accuracy [hazard ratio, 25.1 (confidence interval, 4.08 to 130.5; log-rank P Mutation tracking in serial samples increased sensitivity for the prediction of relapse, with a median lead time of 7.9 months over clinical relapse. We further demonstrated that targeted capture sequencing analysis of ctDNA could define the genetic events of MRD, and that MRD sequencing predicted the genetic events of the subsequent metastatic relapse more accurately than sequencing of the primary cancer. Mutation tracking can therefore identify early breast cancer patients at high risk of relapse. Subsequent adjuvant therapeutic interventions could be tailored to the genetic events present in the MRD, a therapeutic approach that could in part combat the challenge posed by intratumor genetic heterogeneity. Copyright © 2015, American Association for the Advancement of Science.

  8. Tumor-extracellular matrix interactions: Identification of tools associated with breast cancer progression.

    Science.gov (United States)

    Giussani, Marta; Merlino, Giuseppe; Cappelletti, Vera; Tagliabue, Elda; Daidone, Maria Grazia

    2015-12-01

    Several evidences support the concept that cancer development and progression are not entirely cancer cell-autonomous processes, but may be influenced, and possibly driven, by cross-talk between cancer cells and the surrounding microenvironment in which, besides immune cells, stromal cells and extracellular matrix (ECM) play a major role in regulating distinct biologic processes. Stroma and ECM-related signatures proved to influence breast cancer progression, and to contribute to the identification of tumor phenotypes resistant to cytotoxic and hormonal treatments. The possible clinical implications of the interplay between tumor cells and the microenvironment, with special reference to ECM remodelling, will be discussed in this review. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  9. Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal A breast cancer.

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    Prat, Aleix; Cheang, Maggie Chon U; Martín, Miguel; Parker, Joel S; Carrasco, Eva; Caballero, Rosalía; Tyldesley, Scott; Gelmon, Karen; Bernard, Philip S; Nielsen, Torsten O; Perou, Charles M

    2013-01-10

    Current immunohistochemical (IHC)-based definitions of luminal A and B breast cancers are imperfect when compared with multigene expression-based assays. In this study, we sought to improve the IHC subtyping by examining the pathologic and gene expression characteristics of genomically defined luminal A and B subtypes. Gene expression and pathologic features were collected from primary tumors across five independent cohorts: British Columbia Cancer Agency (BCCA) tamoxifen-treated only, Grupo Español de Investigación en Cáncer de Mama 9906 trial, BCCA no systemic treatment cohort, PAM50 microarray training data set, and a combined publicly available microarray data set. Optimal cutoffs of percentage of progesterone receptor (PR) -positive tumor cells to predict survival were derived and independently tested. Multivariable Cox models were used to test the prognostic significance. Clinicopathologic comparisons among luminal A and B subtypes consistently identified higher rates of PR positivity, human epidermal growth factor receptor 2 (HER2) negativity, and histologic grade 1 in luminal A tumors. Quantitative PR gene and protein expression were also found to be significantly higher in luminal A tumors. An empiric cutoff of more than 20% of PR-positive tumor cells was statistically chosen and proved significant for predicting survival differences within IHC-defined luminal A tumors independently of endocrine therapy administration. Finally, no additional prognostic value within hormonal receptor (HR) -positive/HER2-negative disease was observed with the use of the IHC4 score when intrinsic IHC-based subtypes were used that included the more than 20% PR-positive tumor cells and vice versa. Semiquantitative IHC expression of PR adds prognostic value within the current IHC-based luminal A definition by improving the identification of good outcome breast cancers. The new proposed IHC-based definition of luminal A tumors is HR positive/HER2 negative/Ki-67 less than 14

  10. Identification of Differentially Expressed IGFBP5-Related Genes in Breast Cancer Tumor Tissues Using cDNA Microarray Experiments

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    Mustafa Akkiprik

    2015-11-01

    Full Text Available IGFBP5 is an important regulatory protein in breast cancer progression. We tried to identify differentially expressed genes (DEGs between breast tumor tissues with IGFBP5 overexpression and their adjacent normal tissues. In this study, thirty-eight breast cancer and adjacent normal breast tissue samples were used to determine IGFBP5 expression by qPCR. cDNA microarrays were applied to the highest IGFBP5 overexpressed tumor samples compared to their adjacent normal breast tissue. Microarray analysis revealed that a total of 186 genes were differentially expressed in breast cancer compared with normal breast tissues. Of the 186 genes, 169 genes were downregulated and 17 genes were upregulated in the tumor samples. KEGG pathway analyses showed that protein digestion and absorption, focal adhesion, salivary secretion, drug metabolism-cytochrome P450, and phenylalanine metabolism pathways are involved. Among these DEGs, the prominent top two genes (MMP11 and COL1A1 which potentially correlated with IGFBP5 were selected for validation using real time RT-qPCR. Only COL1A1 expression showed a consistent upregulation with IGFBP5 expression and COL1A1 and MMP11 were significantly positively correlated. We concluded that the discovery of coordinately expressed genes related with IGFBP5 might contribute to understanding of the molecular mechanism of the function of IGFBP5 in breast cancer. Further functional studies on DEGs and association with IGFBP5 may identify novel biomarkers for clinical applications in breast cancer.

  11. Circadian disruption and biomarkers of tumor progression in breast cancer patients awaiting surgery.

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    Cash, E; Sephton, S E; Chagpar, A B; Spiegel, D; Rebholz, W N; Zimmaro, L A; Tillie, J M; Dhabhar, F S

    2015-08-01

    Psychological distress, which can begin with cancer diagnosis and continue with treatment, is linked with circadian and endocrine disruption. In turn, circadian/endocrine factors are potent modulators of cancer progression. We hypothesized that circadian rest-activity rhythm disruption, distress, and diurnal cortisol rhythms would be associated with biomarkers of tumor progression in the peripheral blood of women awaiting breast cancer surgery. Breast cancer patients (n=43) provided actigraphic data on rest-activity rhythm, cancer-specific distress (IES, POMS), saliva samples for assessment of diurnal cortisol rhythm, cortisol awakening response (CAR), and diurnal mean. Ten potential markers of tumor progression were quantified in serum samples and grouped by exploratory factor analysis. Analyses yielded three factors, which appear to include biomarkers reflecting different aspects of tumor progression. Elevated factor scores indicate both high levels and strong clustering among serum signals. Factor 1 included VEGF, MMP-9, and TGF-β; suggesting tumor invasion/immunosuppression. Factor 2 included IL-1β, TNF-α, IL-6R, MCP-1; suggesting inflammation/chemotaxis. Factor 3 included IL-6, IL-12, IFN-γ; suggesting inflammation/TH1-type immunity. Hierarchical regressions adjusting age, stage and socioeconomic status examined associations of circadian, distress, and endocrine variables with these three factor scores. Patients with poor circadian coordination as measured by rest-activity rhythms had higher Factor 1 scores (R(2)=.160, p=.038). Patients with elevated CAR also had higher Factor 1 scores (R(2)=.293, p=.020). These relationships appeared to be driven largely by VEGF concentrations. Distress was not related to tumor-relevant biomarkers, and no other significant relationships emerged. Women with strong circadian activity rhythms showed less evidence of tumor promotion and/or progression as indicated by peripheral blood biomarkers. The study was not equipped to

  12. Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer

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    Yu, Wei [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Li, Ying; Zhao, Haixia; Xie, Xianfei; Zheng, Hao; Wang, Chenlong; Wang, Xue [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Yang, Guifang [Department of Pathology, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Cai, Xiaojun [Department of Ophthalmology, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Falck, John R. [Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 (United States); Yang, Jing, E-mail: yangjingliu@yahoo.com.cn [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China)

    2012-10-01

    Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressing cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1-expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9-fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation. -- Highlights: ► CYP4Z1 overexpression promotes human breast cancer growth and angiogenesis. ► The pro-angiogenic effects of CYP4Z1 have

  13. The application of estrogen receptor-1 mutations' detection through circulating tumor dna in breast cancer

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    Binliang Liu

    2017-01-01

    Full Text Available Breast cancer is the most common cancer in women worldwide. Endocrine therapy is the cornerstone of treatment for patients with hormone receptor-positive advanced breast cancer. Unfortunately, although most patients initially respond to endocrine treatment, they will eventually acquire resistance to endocrine therapy. The mechanisms of endocrine resistance are complicated. In particular, the estrogen receptor-1 (ESR1 mutation has been recognized as an important topic in recent years. Mutation of ESR1 leads to complete aromatase inhibitor resistance and partial resistance to estrogen receptor agonists and antagonists. Therefore, during clinical treatment, it is of great importance to continuously monitor ESR1 mutations before and after endocrine therapy. Conventional tissue biopsies have unavoidable disadvantages, and therefore, the use of circulating tumor DNA (ctDNA has become more prevalent because it is noninvasive and convenient, has excellent sensitivity, and can quickly assess the overall situation of the tumor. The current methods for detecting ctDNA ESR1 mutations mainly include droplet digital polymerase chain reaction and next-generation sequencing techniques. Based on their advantages and disadvantages, we can establish an initial ESR1 mutation monitoring system. However, developing robust methods to monitor ESR1 mutation, detecting endocrine drug resistance, and evaluating prognoses for guiding clinical treatment strategies require long-term exploration. In this review, we will summarize recent concepts and advancements regarding ESR1 mutation monitoring, ctDNA detection technology, and their application in endocrine therapy of breast cancer.

  14. RAGE mediates S100A7-induced breast cancer growth and metastasis by modulating the tumor microenvironment

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    Nasser, Mohd W.; Wani, Nissar Ahmad; Ahirwar, Dinesh K.; Powell, Catherine A.; Ravi, Janani; Elbaz, Mohamad; Zhao, Helong; Padilla, Laura; Zhang, Xiaoli; Shilo, Konstantin; Ostrowski, Michael; Shapiro, Charles; Carson, William E.; Ganju, Ramesh K.

    2015-01-01

    RAGE is a multi-functional receptor implicated in diverse processes including inflammation and cancer. In this study, we report that RAGE expression is upregulated widely in aggressive triple-negative breast cancer cells, both in primary tumors and lymph node metastases. In evaluating the functional contributions of RAGE in breast cancer, we found RAGE-deficient mice displayed a reduced propensity for breast tumor growth. In an established model of lung metastasis, systemic blockade by injection of a RAGE neutralizing antibody inhibited metastasis development. Mechanistic investigations revealed that RAGE bound to the pro-inflammatory ligand S100A7 and mediated its ability to activate ERK, NF-κB and cell migration. In an S100A7 transgenic mouse model of breast cancer (mS100a7a15 mice), administration of either RAGE neutralizing antibody or soluble RAGE was sufficient to inhibit tumor progression and metastasis. In this model, we found that RAGE/S100A7 conditioned the tumor microenvironment by driving the recruitment of MMP9-positive tumor-associated macrophages. Overall, our results highlight RAGE as a candidate biomarker for triple-negative breast cancers and they reveal a functional role for RAGE/S100A7 signaling in linking inflammation to aggressive breast cancer development. PMID:25572331

  15. Familial Gastrointestinal Stromal Tumor with Germline KIT Mutations Accompanying Hereditary Breast and Ovarian Cancer Syndrome.

    Science.gov (United States)

    Sekido, Yuki; Ohigashi, Seiji; Takahashi, Tsuyoshi; Hayashi, Naoki; Suzuki, Koyu; Hirota, Seiichi

    2017-03-01

    Familial gastrointestinal stromal tumor (GIST) is a rare disease with germline mutations in the c-kit gene (KIT) or platelet-derived growth factor receptor alpha gene (PDGFRA). We had encountered multiple GISTs in the stomach and small intestine during a screening of ovarian cancer for a woman with hereditary breast and ovarian cancer syndrome (HBOC) with breast cancer susceptibility gene II (BRCA2) mutations. The aim of this study was to examine this case in detail. A 65-year-old woman diagnosed with HBOC harboring BRCA2 mutations was found to have multiple tumors in the stomach and small intestine by abdominal screening. All tumors were resected, and KIT gene mutations (p.Trp557Leu and p.Lys558Glu) in exon 11 were detected in all tumors and peripheral blood leukocytes. The patient was diagnosed with familial GIST. This was an extremely rare case in which familial GIST with germline KIT gene mutations co-existed with HBOC. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  16. Autoantibody to tumor antigen, alpha 2-HS glycoprotein: a novel biomarker of breast cancer screening and diagnosis.

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    Yi, Jae Kyo; Chang, Jong Wook; Han, Wonshik; Lee, Jong Won; Ko, Eunyoung; Kim, Dong Hyun; Bae, Ji-Yeon; Yu, Jonghan; Lee, Cheolju; Yu, Myeong-Hee; Noh, Dong-Young

    2009-05-01

    We sought to identify a new serum biomarker for breast cancer screening and diagnosis using stepwise proteomic analysis of sera from breast cancer patients to detect the presence of autoantibodies that react with urinary protein. Two-dimensional immunoblotting was done for screening autoimmunogenic tumor antigens in the urine of breast cancer patients. Reactive spots were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Among urinary proteins separated by two-dimensional electrophoresis, 13 spots showed strong reactivity with pooled sera from breast cancer patients or control sera. By mass spectrometry, we identified alpha 2-HS glycoprotein (AHSG) as a tumor antigen. Peripheral blood was obtained from 81 women diagnosed with breast cancer before surgery and 73 female donors without evidence of any malignancy for the individual analysis. In one-dimensional Western blot analysis, AHSG autoantibody was detected in 64 of 81 breast cancer patients (79.1%) and in 7 of 73 controls (9.6%). The sensitivity of this test in breast cancer patients was 79.0%. Our results suggest that AHSG and anti-AHSG autoantibody may be useful serum biomarkers for breast cancer screening and diagnosis.

  17. Tumor subtype-specific associations of hormone-related reproductive factors on breast cancer survival.

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    Nan Song

    Full Text Available It is inconclusive whether reproductive factors, which are known as risk factors of breast cancer, also influence survival. We investigated overall and subtype-specific associations between reproductive factors and breast cancer survival.Among 3,430 incident breast cancer patients who enrolled in the Seoul Breast Cancer Study, 269 patients (7.8% died and 528 patients (15.4% recurred. The overall and subtype-specific associations of reproductive factors including age at menarche and menopause, duration of estrogen exposure, menstrual cycle, parity, age at first full-term pregnancy, number of children, age at last birth, time since the last birth, and duration of breastfeeding, on overall and disease-free survival (OS and DFS were estimated by hazard ratios (HRs and 95% confidence intervals (95% CIs using a multivariate Cox proportional hazard model.An older age at menarche (HR for OS=1.10, 95% CI=1.03-1.19, a greater number of children (≥ 4 vs. 2, HR for DFS=1.58, 95% CI=1.11-2.26, and a shorter time since last birth (<5 vs. ≥ 20 years, HR for DFS=1.67, 95% CI=1.07-2.62 were associated with worse survival while longer duration of estrogen exposure with better survival (HR for DFS=0.97, 95% CI=0.96-0.99. In the stratified analyses by subtypes, those associations were more pronounced among women with hormone receptor and human epidermal growth factor 2 positive (HR+ HER2+ tumors.It is suggested that reproductive factors, specifically age at menarche, number of children, time since last birth, and duration of estrogen exposure, could influence breast tumor progression, especially in the HR+ HER2+ subtype.

  18. Birth size in the most recent pregnancy and maternal mortality in premenopausal breast cancer by tumor characteristics.

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    Hajiebrahimi, Mohammadhossein; Cnattingius, Sven; Lambe, Mats; Hsieh, Chung-Cheng; Ahlgren, Johan; Adolfsson, Jan; Bahmanyar, Shahram

    2014-06-01

    The main aim of this study was to investigate possible associations between measures of offspring size at birth in the most recent pregnancy before premenopausal breast cancer diagnosis and the risks of maternal breast cancer mortality, taking tumor characteristics into account. We also aimed to investigate if these associations are modified by age at childbirth, time since childbirth, parity, and age at diagnosis. We followed 6,019 women from their date of premenopausal breast cancer (diagnosed from 1992 to 2008) until emigration, death or December 31st, 2009, whichever occurred first. We used Cox proportional hazard regression models, adjusted for parity, age at diagnosis, and education level, to estimate associations between women pregnancy, cancer characteristics and offspring birth characteristics, and mothers' mortality risk. In stratified analyses, mortality risks were estimated by tumor stage, ER or PR status. There was no association between offspring birth weight (HR = 1.00, 95 % CI 0.99-1.01, when used as a continuous variable), birth weight for gestational age or ponderal index, and premenopausal breast cancer mortality. Similarly, in analyses stratified by tumor stage, receptor status, and time difference between last pregnancy and date of diagnosis, we found no associations between birth size and breast cancer mortality. Our findings suggest that the hypothesis that "premenopausal breast cancer mortality is associated with offspring birth characteristics in the most recent pregnancy before the diagnosis" may not be valid. In addition, these associations are not modified by tumor characteristics.

  19. Analysis by MRI of residual tumor after radiofrequency ablation for early stage breast cancer.

    Science.gov (United States)

    Vilar, Vanessa Sales; Goldman, Suzan Menasce; Ricci, Marcos Desidério; Pincerato, Katia; Oliveira, Helio; Abud, Thiago Giansante; Ajzen, Sergio; Baracat, Edmund Chada; Szejnfeld, Jacob

    2012-03-01

    The objective of our study was to evaluate the effectiveness of MRI in the detection of possible residual lesions after radiofrequency ablation (RFA) in the treatment of breast cancer. We prospectively evaluated 14 patients who had undergone ultrasound-guided core biopsies diagnostic of invasive ductal carcinoma (IDC; range of diameters, 1.0-3.0 cm) and then ultrasound-guided percutaneous RFA with sentinel node biopsy as the primary treatment. Breast MRI was performed 1 week before RFA to evaluate tumor extension and again 3 weeks after RFA to verify the presence of possible residual lesions. Conventional surgical resection of the tumors was performed 1 week after RFA. The MRI findings were compared with histopathologic analyses to confirm the presence or absence of residual tumor. There was no residual enhancement in seven lesions on the postablation breast MRI scans. These findings were confirmed by negative histopathologic findings in the surgical specimens. The MRI scans of five patients showed small areas of irregular enhancement that corresponded to residual lesions. In the two remaining patients, we observed enhancement of almost the entire lesion, indicating that RFA had failed. Breast MRI is effective in detecting residual lesions after RFA in patients with IDC.

  20. Loss of CSL Unlocks a Hypoxic Response and Enhanced Tumor Growth Potential in Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Eike-Benjamin Braune

    2016-05-01

    Full Text Available Notch signaling is an important regulator of stem cell differentiation. All canonical Notch signaling is transmitted through the DNA-binding protein CSL, and hyperactivated Notch signaling is associated with tumor development; thus it may be anticipated that CSL deficiency should reduce tumor growth. In contrast, we report that genetic removal of CSL in breast tumor cells caused accelerated growth of xenografted tumors. Loss of CSL unleashed a hypoxic response during normoxic conditions, manifested by stabilization of the HIF1α protein and acquisition of a polyploid giant-cell, cancer stem cell-like, phenotype. At the transcriptome level, loss of CSL upregulated more than 1,750 genes and less than 3% of those genes were part of the Notch transcriptional signature. Collectively, this suggests that CSL exerts functions beyond serving as the central node in the Notch signaling cascade and reveals a role for CSL in tumorigenesis and regulation of the cellular hypoxic response.

  1. Tocotrienol-adjuvanted dendritic cells inhibit tumor growth and metastasis: a murine model of breast cancer.

    Directory of Open Access Journals (Sweden)

    Sitti Rahma Abdul Hafid

    Full Text Available Tocotrienol-rich fraction (TRF from palm oil is reported to possess anti-cancer and immune-enhancing effects. In this study, TRF supplementation was used as an adjuvant to enhance the anti-cancer effects of dendritic cells (DC-based cancer vaccine in a syngeneic mouse model of breast cancer. Female BALB/c mice were inoculated with 4T1 cells in mammary pad to induce tumor. When the tumor was palpable, the mice in the experimental groups were injected subcutaneously with DC-pulsed with tumor lysate (TL from 4T1 cells (DC+TL once a week for three weeks and fed daily with 1 mg TRF or vehicle. Control mice received unpulsed DC and were fed with vehicle. The combined therapy of using DC+TL injections and TRF supplementation (DC+TL+TRF inhibited (p<0.05 tumor growth and metastasis. Splenocytes from the DC+TL+TRF group cultured with mitomycin-C (MMC-treated 4T1 cells produced higher (p<0.05 levels of IFN-γ and IL-12. The cytotoxic T-lymphocyte (CTL assay also showed enhanced tumor-specific killing (p<0.05 by CD8(+ T-lymphocytes isolated from mice in the DC+TL+TRF group. This study shows that TRF has the potential to be used as an adjuvant to enhance effectiveness of DC-based vaccines.

  2. Proteolysis-a characteristic of tumor-initiating cells in murine metastatic breast cancer

    Science.gov (United States)

    Hillebrand, Larissa E.; Bengsch, Fee; Hochrein, Jochen; Hülsdünker, Jan; Bender, Julia; Follo, Marie; Busch, Hauke; Boerries, Melanie; Reinheckel, Thomas

    2016-01-01

    Tumor initiating cells (TICs) have been identified and functionally characterized in hematological malignancies as well as in solid tumors such as breast cancer. In addition to their high tumor-initiating potential, TICs are founder cells for metastasis formation and are involved in chemotherapy resistance. In this study we explored molecular pathways which enable this tumor initiating potential for a cancer cell subset of the transgenic MMTV-PyMT mouse model for metastasizing breast cancer. The cell population, characterized by the marker profile CD24+CD90+CD45−, showed a high tumorigenicity compared to non-CD24+CD90+CD45− cancer cells in colony formation assays, as well as upon orthotopic transplantation into the mammary fat pad of mice. In addition, these orthotopically grown CD24+CD90+CD45− TICs metastasized to the lungs. The transcriptome of TICs freshly isolated from primary tumors by cell sorting was compared with that of sorted non-CD24+CD90+CD45− cancer cells by RNA-seq. In addition to more established TIC signatures, such as epithelial-to-mesenchymal transition or mitogen signaling, an upregulated gene set comprising several classes of proteolytic enzymes was uncovered in the TICs. Accordingly, TICs showed high intra- and extracellular proteolytic activity. Application of a broad range of protease inhibitors to TICs in a colony formation assay reduced anchorage independent growth and had an impact on colony morphology in 3D cell culture assays. We conclude that CD24+CD90+CD45− cells of the MMTV- PyMT mouse model possess an upregulated proteolytic signature which could very well represent a functional hallmark of metastatic TICs from mammary carcinomas. PMID:27542270

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

    Energy Technology Data Exchange (ETDEWEB)

    Ong, Danny C.T.; Rudduck, Christina; Chin, Koei; Kuo, Wen-Lin; Lie, Daniel K.H.; Chua, Constance L.M.; Wong, Chow Yin; Hong, Ga Sze; Gray, Joe; Lee, Ann S.G.

    2008-05-06

    Deletion of 11q23-q24 is frequent in a diverse variety of malignancies, including breast and colorectal carcinoma, implicating the presence of a tumor suppressor gene at that chromosomal region. We show here that LARG, from 11q23, has functional characteristics of a tumor suppressor. We examined a 6-Mb region on 11q23 by high-resolution deletion mapping, utilizing both loss of heterozygosity (LOH) analysis and microarray comparative genomic hybridization (CGH). LARG (also called ARHGEF12), identified from the analyzed region, was underexpressed in 34% of primary breast carcinomas and 80% of breast cancer cell lines including the MCF-7 line. Multiplex ligation-dependent probe amplification on 30 primary breast cancers and six breast cancer cell lines showed that LARG had the highest frequency of deletion compared to the BCSC-1 and TSLC1 genes, two known candidate tumor suppressor genes from 11q. In vitro analysis of breast cancer cell lines that underexpress LARG showed that LARG could be reactivated by trichostatin A, a histone deacetylase inhibitor, but not by 5-Aza-2{prime}-deoxycytidine, a demethylating agent. Bisulfite sequencing and quantitative high-throughput analysis of DNA methylation confirmed the lack of CpG island methylation in LARG in breast cancer. Restoration of LARG expression in MCF-7 cells by stable transfection resulted in reduced proliferation and colony formation, suggesting that LARG has functional characteristics of a tumor suppressor gene.

  4. Simultaneous loss of the DLC1 and PTEN tumor suppressors enhances breast cancer cell migration

    Energy Technology Data Exchange (ETDEWEB)

    Heering, Johanna; Erlmann, Patrik [University of Stuttgart, Institute of Cell Biology and Immunology, Allmandring 31, 70569 Stuttgart (Germany); Olayioye, Monilola A., E-mail: monilola.olayioye@izi.uni-stuttgart.de [University of Stuttgart, Institute of Cell Biology and Immunology, Allmandring 31, 70569 Stuttgart (Germany)

    2009-09-10

    The phosphatase and tensin homolog (PTEN) gene is a tumor suppressor frequently deleted or mutated in sporadic tumors of the breast, prostate, endometrium and brain. The protein acts as a dual specificity phosphatase for lipids and proteins. PTEN loss confers a growth advantage to cells, protects from apoptosis and favors cell migration. The deleted in liver cancer 1 (DLC1) gene has emerged as a novel tumor suppressor downregulated in a variety of tumor types including those of the breast. DLC1 contains a Rho GTPase activating domain that is involved in the inhibition of cell proliferation, migration and invasion. To investigate how simultaneous loss of PTEN and DLC1 contributes to cell transformation, we downregulated both proteins by RNA interference in the non-invasive MCF7 breast carcinoma cell line. Joint depletion of PTEN and DLC1 resulted in enhanced cell migration in wounding and chemotactic transwell assays. Interestingly, both proteins were found to colocalize at the plasma membrane and interacted physically in biochemical pulldowns and coimmunoprecipitations. We therefore postulate that the concerted local inactivation of signaling pathways downstream of PTEN and DLC1, respectively, is required for the tight control of cell migration.

  5. Can Biomarker Assessment on Circulating Tumor Cells Help Direct Therapy in Metastatic Breast Cancer?

    Energy Technology Data Exchange (ETDEWEB)

    Turner, Natalie [Sandro Pitigliani Medical Oncology Department, Prato Hospital, Istituto Toscano Tumori, Via Ugo Foscolo, Prato, PO 59100 (Italy); Pestrin, Marta [Sandro Pitigliani Medical Oncology Department, Prato Hospital, Istituto Toscano Tumori, Via Ugo Foscolo, Prato, PO 59100 (Italy); Translational Research Laboratory, Prato Hospital, Via Ugo Foscolo, Prato, PO 59100 (Italy); Galardi, Francesca; De Luca, Francesca [Translational Research Laboratory, Prato Hospital, Via Ugo Foscolo, Prato, PO 59100 (Italy); Malorni, Luca [Sandro Pitigliani Medical Oncology Department, Prato Hospital, Istituto Toscano Tumori, Via Ugo Foscolo, Prato, PO 59100 (Italy); Translational Research Laboratory, Prato Hospital, Via Ugo Foscolo, Prato, PO 59100 (Italy); Di Leo, Angelo, E-mail: adileo@usl4.toscana.it [Sandro Pitigliani Medical Oncology Department, Prato Hospital, Istituto Toscano Tumori, Via Ugo Foscolo, Prato, PO 59100 (Italy)

    2014-03-25

    Circulating tumor cell (CTC) count has prognostic significance in metastatic breast cancer, but the predictive utility of CTCs is uncertain. Molecular studies on CTCs have often been limited by a low number of CTCs isolated from a high background of leukocytes. Improved enrichment techniques are now allowing molecular characterisation of single CTCs, whereby molecular markers on single CTCs may provide a real-time assessment of tumor biomarker status from a blood test or “liquid biopsy”, potentially negating the need for a more invasive tissue biopsy. The predictive ability of CTC biomarker analysis has predominantly been assessed in relation to HER2, with variable and inconclusive results. Limited data exist for other biomarkers, such as the estrogen receptor. In addition to the need to define and validate the most accurate and reproducible method for CTC molecular analysis, the clinical relevance of biomarkers, including gain of HER2 on CTC after HER2 negative primary breast cancer, remains uncertain. This review summarises the currently available data relating to biomarker evaluation on CTCs and its role in directing management in metastatic breast cancer, discusses limitations, and outlines measures that may enable future development of this approach.

  6. Exercise-Induced Catecholamines Activate the Hippo Tumor Suppressor Pathway to Reduce Risks of Breast Cancer Development.

    Science.gov (United States)

    Dethlefsen, Christine; Hansen, Louise S; Lillelund, Christian; Andersen, Christina; Gehl, Julie; Christensen, Jesper F; Pedersen, Bente K; Hojman, Pernille

    2017-09-15

    Strong epidemiologic evidence documents the protective effect of physical activity on breast cancer risk, recurrence, and mortality, but the underlying mechanisms remain to be identified. Using human exercise-conditioned serum for breast cancer cell incubation studies and murine exercise interventions, we aimed to identify exercise factors and signaling pathways involved in the exercise-dependent suppression of breast cancer. Exercise-conditioned serum from both women with breast cancer ( n = 20) and healthy women ( n = 7) decreased MCF-7 (hormone-sensitive) and MDA-MB-231 (hormone-insensitive) breast cancer cell viability in vitro by 11% to 19% and reduced tumorigenesis by 50% when preincubated MCF-7 breast cancer cells were inoculated into NMRI-Foxn1 nu mice. This exercise-mediated suppression of cell viability and tumor formation was completely blunted by blockade of β-adrenergic signaling in MCF-7 cells, indicating that catecholamines were the responsible exercise factors. Both epinephrine (EPI) and norepinephrine (NE) could directly inhibit breast cancer cell viability, as well as tumor growth in vivo EPI and NE activate the tumor suppressor Hippo signaling pathway, and the suppressive effect of exercise-conditioned serum was found to be mediated through phosphorylation and cytoplasmic retention of YAP and reduced expression of downstream target genes, for example, ANKRD1 and CTGF. In parallel, tumor-bearing mice with access to running wheels showed reduced growth of MCF-7 (-36%, P exercise-dependent suppression of breast cancer cell growth. Cancer Res; 77(18); 4894-904. ©2017 AACR . ©2017 American Association for Cancer Research.

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

    Science.gov (United States)

    Schmidt, Marjanka K; Hogervorst, Frans; van Hien, Richard; Cornelissen, Sten; Broeks, Annegien; Adank, Muriel A; Meijers, Hanne; Waisfisz, Quinten; Hollestelle, Antoinette; Schutte, Mieke; van den Ouweland, Ans; Hooning, Maartje; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Antoniou, Antonis C; Arndt, Volker; Bermisheva, Marina; Bogdanova, Natalia V; Bolla, Manjeet K; Brauch, Hiltrud; Brenner, Hermann; Brüning, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Dunning, Alison M; Fasching, Peter A; Figueroa, Jonine; Fletcher, Olivia; Flyger, Henrik; Galle, Eva; García-Closas, Montserrat; Giles, Graham G; Haeberle, Lothar; Hall, Per; Hillemanns, Peter; Hopper, John L; Jakubowska, Anna; John, Esther M; Jones, Michael; Khusnutdinova, Elza; Knight, Julia A; Kosma, Veli-Matti; Kristensen, Vessela; Lee, Andrew; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Margolin, Sara; Meindl, Alfons; Milne, Roger L; Muranen, Taru A; Newcomb, Polly A; Offit, Kenneth; Park-Simon, Tjoung-Won; Peto, Julian; Pharoah, Paul D P; Robson, Mark; Rudolph, Anja; Sawyer, Elinor J; Schmutzler, Rita K; Seynaeve, Caroline; Soens, Julie; Southey, Melissa C; Spurdle, Amanda B; Surowy, Harald; Swerdlow, Anthony; Tollenaar, Rob A E M; Tomlinson, Ian; Trentham-Dietz, Amy; Vachon, Celine; Wang, Qin; Whittemore, Alice S; Ziogas, Argyrios; van der Kolk, Lizet; Nevanlinna, Heli; Dörk, Thilo; Bojesen, Stig; Easton, Douglas F

    2016-08-10

    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. 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. Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up. © 2016

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

    Science.gov (United States)

    Hogervorst, Frans; van Hien, Richard; Cornelissen, Sten; Broeks, Annegien; Adank, Muriel A.; Meijers, Hanne; Waisfisz, Quinten; Hollestelle, Antoinette; Schutte, Mieke; van den Ouweland, Ans; Hooning, Maartje; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Antoniou, Antonis C.; Arndt, Volker; Bermisheva, Marina; Bogdanova, Natalia V.; Bolla, Manjeet K.; Brauch, Hiltrud; Brenner, Hermann; Brüning, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Dunning, Alison M.; Fasching, Peter A.; Figueroa, Jonine; Fletcher, Olivia; Flyger, Henrik; Galle, Eva; García-Closas, Montserrat; Giles, Graham G.; Haeberle, Lothar; Hall, Per; Hillemanns, Peter; Hopper, John L.; Jakubowska, Anna; John, Esther M.; Jones, Michael; Khusnutdinova, Elza; Knight, Julia A.; Kosma, Veli-Matti; Kristensen, Vessela; Lee, Andrew; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Margolin, Sara; Meindl, Alfons; Milne, Roger L.; Muranen, Taru A.; Newcomb, Polly A.; Offit, Kenneth; Park-Simon, Tjoung-Won; Peto, Julian; Pharoah, Paul D.P.; Robson, Mark; Rudolph, Anja; Sawyer, Elinor J.; Schmutzler, Rita K.; Seynaeve, Caroline; Soens, Julie; Southey, Melissa C.; Spurdle, Amanda B.; Surowy, Harald; Swerdlow, Anthony; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Trentham-Dietz, Amy; Vachon, Celine; Wang, Qin; Whittemore, Alice S.; Ziogas, Argyrios; van der Kolk, Lizet; Nevanlinna, Heli; Dörk, Thilo; Bojesen, Stig; Easton, Douglas F.

    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 of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center–based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10−20). The OR was higher for estrogen receptor (ER)–positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10−21]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10−4). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. Conclusion These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into

  9. Toward a siRNA-containing nanoparticle targeted to breast cancer cells and the tumor microenvironment.

    Science.gov (United States)

    Gomes-da-Silva, Lígia C; Santos, Adriana O; Bimbo, Luís M; Moura, Vera; Ramalho, José S; Pedroso de Lima, Maria C; Simões, Sérgio; Moreira, João N

    2012-09-15

    The present work aimed at designing a lipid-based nanocarrier for siRNA delivery toward two cell sub-populations within breast tumors, the cancer and the endothelial cells from angiogenic tumor blood vessels. To achieve such goal, the F3 peptide, which is specifically internalized by nucleolin overexpressed on both those sub-populations, was used as a targeting moiety. The developed F3-targeted stable nucleic acid lipid particles presented adequate features for systemic administration. In addition, the attachment of the F3 peptide onto the liposomal surface enabled an internalization by both cancer and endothelial cells from angiogenic blood vessels that was significantly higher than the one observed with non-cancer cells. Sequence-specific downregulation of enhanced green fluorescent protein (eGFP) in eGFP-overexpressing human cancer cell lines, both at the protein and mRNA levels, was further observed upon delivery of anti-eGFP siRNA by F3-targeted liposomes, in contrast with the non-targeted counterpart. This effect was highly dependent on the content of poly(ethylene glycol) (PEG), as evidenced by the co-localization studies between the siRNA and the lysosomes. Overall, the present work represents an important contribution toward a nanoparticle with multi-targeting capabilities in breast cancer, both at the cellular and molecular level. Copyright © 2012 Elsevier B.V. All rights reserved.

  10. Interface between breast cancer cells and the tumor microenvironment using platelet-rich plasma to promote tumor angiogenesis - influence of platelets and fibrin bundles on the behavior of breast tumor cells.

    Science.gov (United States)

    Andrade, Sheila Siqueira; Sumikawa, Joana Tomomi; Castro, Eloísa Dognani; Batista, Fabricio Pereira; Paredes-Gamero, Edgar; Oliveira, Lilian Carolina; Guerra, Izabel Monastério; Peres, Giovani Bravin; Cavalheiro, Renan Pelluzzi; Juliano, Luiz; Nazário, Afonso Pinto; Facina, Gil; Tsai, Siu Mui; Oliva, Maria Luiza Vilela; Girão, Manoel João Batista Castello

    2017-03-07

    Cancer progression is associated with an evolving tissue interface of direct epithelial-tumor microenvironment interactions. In biopsies of human breast tumors, extensive alterations in molecular pathways are correlated with cancer staging on both sides of the tumor-stroma interface. These interactions provide a pivotal paracrine signaling to induce malignant phenotype transition, the epithelial-mesenchymal transition (EMT). We explored how the direct contact between platelets-fibrin bundles primes metastasis using platelet-rich plasma (PRP) as a source of growth factors and mimics the provisional fibrin matrix between actively growing breast cancer cells and the tumor stroma. We have demonstrated PRP functions, modulating cell proliferation that is tumor-subtype and cancer cell-type-specific. Epithelial and stromal primary cells were prepared from breast cancer biopsies from 21 women with different cancer subtypes. Cells supplemented with PRP were immunoblotted with anti-phospho and total Src-Tyr-416, FAK-Try-925, E-cadherin, N-cadherin, TGF-β, Smad2, and Snail monoclonal antibodies. Breast tumor cells from luminal B and HER2 subtypes showed the most malignant profiles and the expression of thrombin and other classes of proteases at levels that were detectable through FRET peptide libraries. The angiogenesis process was investigated in the interface obtained between platelet-fibrin-breast tumor cells co-cultured with HUVEC cells. Luminal B and HER2 cells showed robust endothelial cell capillary-like tubes ex vivo. The studied interface contributes to the attachment of endothelial cells, provides a source of growth factors, and is a solid substrate. Thus, replacement of FBS supplementation with PRP supplementation represents an efficient and simple approach for mimicking the real multifactorial tumor microenvironment.

  11. Silencing of tumor suppressor genes RASSF1A, SLIT2, and WIF1 by promoter hypermethylation in hereditary breast cancer.

    Science.gov (United States)

    Alvarez, Carolina; Tapia, Teresa; Cornejo, Valeria; Fernandez, Wanda; Muñoz, Alex; Camus, Mauricio; Alvarez, Manuel; Devoto, Luigi; Carvallo, Pilar

    2013-06-01

    Promoter hypermethylation is gaining strength as one of the main mechanisms through which tumor suppressor genes are silenced during tumor progression. Three tumor suppressor genes are frequently found methylated in their promoter, in concordance with absence of expression, RASSF1A, SLIT2, and WIF1. In addition, a previous array-CGH analysis from our group showed that these genes are found in deleted genomic regions observed in hereditary breast cancer tumors. In the present work we analyzed the methylation status of these three tumor suppressor gene promoters in 47 hereditary breast cancer tumors. Promoter methylation status analysis of hereditary breast tumors revealed high methylation frequencies for the three genes (67% RASSF1A, 80% SLIT2, and 72% WIF1). Additionally, the presence of methylated PCR products was associated with absence of protein expression for the three genes and statistically significant for RASSF1A and WIF1. Interestingly, methylation of all the three genes was found in 4 out of 6 grade I invasive ductal carcinoma tumors. Association between RASSF1A methylation and DCIS tumors was found. These results suggest that silencing of these tumor suppressor genes is an early event in hereditary breast cancer, and could be a marker for pre-malignant phenotypes. Copyright © 2012 Wiley Periodicals, Inc.

  12. ABL kinases promote breast cancer osteolytic metastasis by modulating tumor-bone interactions through TAZ and STAT5 signaling.

    Science.gov (United States)

    Wang, Jun; Rouse, Clay; Jasper, Jeff S; Pendergast, Ann Marie

    2016-02-02

    Bone metastases occur in up to 70% of advanced breast cancer. For most patients with breast cancer, bone metastases are predominantly osteolytic. Interactions between tumor cells and stromal cells in the bone microenvironment drive osteolytic bone metastasis, a process that requires the activation of osteoclasts, cells that break down bone. We report that ABL kinases promoted metastasis of breast cancer cells to bone by regulating the crosstalk between tumor cells and the bone microenvironment. ABL kinases protected tumor cells from apoptosis induced by TRAIL (TNF-related apoptosis-inducing ligand), activated the transcription factor STAT5, and promoted osteolysis through the STAT5-dependent expression of genes encoding the osteoclast-activating factors interleukin-6 (IL-6) and matrix metalloproteinase 1 (MMP1). Furthermore, in breast cancer cells, ABL kinases increased the abundance of the Hippo pathway mediator TAZ and the expression of TAZ-dependent target genes that promote bone metastasis. Knockdown of ABL kinases or treatment with ABL-specific allosteric inhibitor impaired osteolytic metastasis of breast cancer cells in mice. These findings revealed a role for ABL kinases in regulating tumor-bone interactions and provide a rationale for using ABL-specific inhibitors to limit breast cancer metastasis to bone. Copyright © 2016, American Association for the Advancement of Science.

  13. Breast Cancer

    Science.gov (United States)

    Breast cancer affects one in eight women during their lives. No one knows why some women get breast cancer, but there are many risk factors. Risks that ... who have family members with breast or ovarian cancer may wish to be tested for the genes. ...

  14. [Breast cancer surgery].

    Science.gov (United States)

    Vlastos, Georges; Berclaz, Gilles; Langer, Igor; Pittet-Cuenod, Brigitte; Delaloye, Jean-François

    2007-10-24

    Breast conserving surgery followed by radiation therapy is the treatment of choice for early breast cancer. For patients who choice or need a mastectomy, breast reconstruction provides an acceptable alternative. Breast cancer surgery has been evolving through minimally invasive approaches. Sentinel node biopsy has already remplaced axillary lymph node dissection in the evaluation of the axilla. Local ablation of the tumor may be a valuable alternative to surgery in the future.

  15. An integrated genomic approach identifies persistent tumor suppressive effects of transforming growth factor-β in human breast cancer.

    Science.gov (United States)

    Sato, Misako; Kadota, Mitsutaka; Tang, Binwu; Yang, Howard H; Yang, Yu-an; Shan, Mengge; Weng, Jia; Welsh, Michael A; Flanders, Kathleen C; Nagano, Yoshiko; Michalowski, Aleksandra M; Clifford, Robert J; Lee, Maxwell P; Wakefield, Lalage M

    2014-06-02

    Transforming growth factor-βs (TGF-βs) play a dual role in breast cancer, with context-dependent tumor-suppressive or pro-oncogenic effects. TGF-β antagonists are showing promise in early-phase clinical oncology trials to neutralize the pro-oncogenic effects. However, there is currently no way to determine whether the tumor-suppressive effects of TGF-β are still active in human breast tumors at the time of surgery and treatment, a situation that could lead to adverse therapeutic responses. Using a breast cancer progression model that exemplifies the dual role of TGF-β, promoter-wide chromatin immunoprecipitation and transcriptomic approaches were applied to identify a core set of TGF-β-regulated genes that specifically reflect only the tumor-suppressor arm of the pathway. The clinical significance of this signature and the underlying biology were investigated using bioinformatic analyses in clinical breast cancer datasets, and knockdown validation approaches in tumor xenografts. TGF-β-driven tumor suppression was highly dependent on Smad3, and Smad3 target genes that were specifically enriched for involvement in tumor suppression were identified. Patterns of Smad3 binding reflected the preexisting active chromatin landscape, and target genes were frequently regulated in opposite directions in vitro and in vivo, highlighting the strong contextuality of TGF-β action. An in vivo-weighted TGF-β/Smad3 tumor-suppressor signature was associated with good outcome in estrogen receptor-positive breast cancer cohorts. TGF-β/Smad3 effects on cell proliferation, differentiation and ephrin signaling contributed to the observed tumor suppression. Tumor-suppressive effects of TGF-β persist in some breast cancer patients at the time of surgery and affect clinical outcome. Carefully tailored in vitro/in vivo genomic approaches can identify such patients for exclusion from treatment with TGF-β antagonists.

  16. Circulating tumoral cells lack circadian-rhythm in hospitalized metastasic breast cancer patients.

    Science.gov (United States)

    García-Sáenz, José Angel; Martín, Miguel; Maestro, Marisa; Vidaurreta, Marta; Veganzones, Silvia; Villalobos, Laura; Rodríguez-Lajusticia, Laura; Rafael, Sara; Sanz-Casla, María Teresa; Casado, Antonio; Sastre, Javier; Arroyo, Manuel; Díaz-Rubio, Eduardo

    2006-11-01

    The relationship between breast cancer and circadian rhythm variation has been extensively studied. Increased breast tumorigenesis has been reported in melatonin-suppressed experimental models and in observational studies. Circulating Tumor Cells (CTC) circadian- rhythm may optimize the timing of therapies. This is a prospective experimental study to ascertain the day-time and night-time CTC levels in hospitalized metastasic breast cancer (MBC) patients. CTC are isolated and enumerated from a 08:00 AM and 08:00 PM blood collections. 23 MBC and 23 healthy volunteers entered the study. 69 samples were collected (23 samples at 08:00 AM and 23 samples at 08:00 PM from MBC; 23 samples from healthy volunteers). Results from two patients were rejected due to sample processing errors. No CTC were isolated from healthy-volunteers. No-differences between daytime and night-time CTC were observed. Therefore, we could not ascertain CTC circadian-rhythm in hospitalized metastasic breast cancer patients.

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

    Science.gov (United States)

    Khatami, Fatemeh; Aghayan, Hamid Reza; Sanaei, Maryam; Heshmat, Ramin; Tavangar, Seyed Mohammad; Larijani, Bagher

    2017-03-01

    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.

  18. 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.

  19. Blockade of Fas signaling in breast cancer cells suppresses tumor growth and metastasis via disruption of Fas signaling-initiated cancer-related inflammation.

    Science.gov (United States)

    Liu, Qiuyan; Tan, Qinchun; Zheng, Yuanyuan; Chen, Kun; Qian, Cheng; Li, Nan; Wang, Qingqing; Cao, Xuetao

    2014-04-18

    Mechanisms for cancer-related inflammation remain to be fully elucidated. Non-apoptotic functions of Fas signaling have been proposed to play an important role in promoting tumor progression. It has yet to be determined if targeting Fas signaling can control tumor progression through suppression of cancer-related inflammation. In the current study we found that breast cancer cells with constitutive Fas expression were resistant to apoptosis induction by agonistic anti-Fas antibody (Jo2) ligation or Fas ligand cross-linking. Higher expression of Fas in human breast cancer tissue has been significantly correlated with poorer prognosis in breast cancer patients. To determine whether blockade of Fas signaling in breast cancer could suppress tumor progression, we prepared an orthotopic xenograft mouse model with mammary cancer cells 4T1 and found that blockade of Fas signaling in 4T1 cancer cells markedly reduced tumor growth, inhibited tumor metastasis in vivo, and prolonged survival of tumor-bearing mice. Mechanistically, blockade of Fas signaling in cancer cells significantly decreased systemic or local recruitment of myeloid derived suppressor cells (MDSCs) in vivo. Furthermore, blockade of Fas signaling markedly reduced IL-6, prostaglandin E2 production from breast cancer cells by impairing p-p38, and activity of the NFκB pathway. In addition, administration of a COX-2 inhibitor and anti-IL-6 antibody significantly reduced MDSC accumulation in vivo. Therefore, blockade of Fas signaling can suppress breast cancer progression by inhibiting proinflammatory cytokine production and MDSC accumulation, indicating that Fas signaling-initiated cancer-related inflammation in breast cancer cells may be a potential target for treatment of breast cancer.

  20. Citral reduces breast tumor growth by inhibiting the cancer stem cell marker ALDH1A3.

    Science.gov (United States)

    Thomas, Margaret Lois; de Antueno, Roberto; Coyle, Krysta Mila; Sultan, Mohammad; Cruickshank, Brianne Marie; Giacomantonio, Michael Anthony; Giacomantonio, Carman Anthony; Duncan, Roy; Marcato, Paola

    2016-11-01

    Breast cancer stem cells (CSCs) can be identified by increased Aldefluor fluorescence caused by increased expression of aldehyde dehydrogenase 1A3 (ALDH1A3), as well as ALDH1A1 and ALDH2. In addition to being a CSC marker, ALDH1A3 regulates gene expression via retinoic acid (RA) signaling and plays a key role in the progression and chemotherapy resistance of cancer. Therefore, ALDH1A3 represents a druggable anti-cancer target of interest. Since to date, there are no characterized ALDH1A3 isoform inhibitors, drugs that were previously described as inhibiting the activity of other ALDH isoforms were tested for anti-ALDH1A3 activity. Twelve drugs (3-hydroxy-dl-kynurenine, benomyl, citral, chloral hydrate, cyanamide, daidzin, DEAB, disulfiram, gossypol, kynurenic acid, molinate, and pargyline) were compared for their efficacy in inducing apoptosis and reducing ALDH1A3, ALDH1A1 and ALDH2-associated Aldefluor fluorescence in breast cancer cells. Citral was identified as the best inhibitor of ALDH1A3, reducing the Aldefluor fluorescence in breast cancer cell lines and in a patient-derived tumor xenograft. Nanoparticle encapsulated citral specifically reduced the enhanced tumor growth of MDA-MB-231 cells overexpressing ALDH1A3. To determine the potential mechanisms of citral-mediated tumor growth inhibition, we performed cell proliferation, clonogenic, and gene expression assays. Citral reduced ALDH1A3-mediated colony formation and expression of ALDH1A3-inducible genes. In conclusion, citral is an effective ALDH1A3 inhibitor and is able to block ALDH1A3-mediated breast tumor growth, potentially via blocking its colony forming and gene expression regulation activity. The promise of ALDH1A3 inhibitors as adjuvant therapies for patients with tumors that have a large population of high-ALDH1A3 CSCs is discussed. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2013-01-15

    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

  2. Short sleep duration as a contributor to racial disparities in breast cancer tumor grade

    Directory of Open Access Journals (Sweden)

    Kevin Allan

    2017-07-01

    Full Text Available Although African Americans (AAs are less likely to get breast cancer than European Americans (EAs, they get more aggressive forms. We previously showed that short sleep is associated with higher tumor grade. It is well documented that AAs get less sleep, on average, than EAs. We studied the contribution of short sleep to racial disparities in breast cancer aggressiveness among 809 invasive breast cancer patients who responded to a survey on their lifestyle. Multivariable regressions and mediation analyses were performed to assess the effect of sleep duration on the association of race with tumor grade. AAs reported shorter average sleep (mean [standard deviation] 6.57 [1.47] h than EAs (mean [standard deviation] 7.11 [1.16] h; P<0.0001 and were almost twice as likely to report less than 6 h of sleep per night (48.0% vs. 25.3%, P<0.0001. AA patients were more likely to have high-grade tumors (52.6% vs. 28.7% in EAs, P=0.0002. In multivariate analysis, race was associated with tumor grade (P<0.0001. On adjustment for sleep duration, the effect of race was reduced by 7.1%, but remained statistically significant (P=0.0006. However, the Sobel test did not indicate statistical significance (z=1.69, P=0.091. In other models accounting for these and additional confounders, we found similar results. Because of the conservative nature of the mediation analysis and smaller sample size, replication of our results in larger studies with more AA patients is warranted.

  3. Amine-modified hyaluronic acid-functionalized porous silicon nanoparticles for targeting breast cancer tumors

    Science.gov (United States)

    Almeida, Patrick V.; Shahbazi, Mohammad-Ali; Mäkilä, Ermei; Kaasalainen, Martti; Salonen, Jarno; Hirvonen, Jouni; Santos, Hélder A.

    2014-08-01

    Active targeting of nanoparticles to receptor-overexpressing cancer cells has great potential for enhancing the cellular uptake of nanoparticles and for reducing fast clearance of the nanoparticles from the body. Herein, we present a preparation method of a porous silicon (PSi)-based nanodelivery system for breast cancer targeting, by covalently conjugating a synthesized amide-modified hyaluronic acid (HA+) derived polymer on the surface of undecylenic acid-modified thermally hydrocarbonized PSi (UnTHCPSi) nanoparticles. The resulting UnTHCPSi-HA+ nanoparticles showed relatively small size, reduced polydispersibility, high biocompatibility, improved colloidal and human plasma stability, as well as enhanced cellular interactions and internalization. Moreover, we demonstrated that the enhanced cellular association of UnTHCPSi-HA+ relies on the capability of the conjugated HA+ to bind and consequently target CD44 receptors expressed on the surface of breast cancer cells, thus making the HA+-functionalized UnTHCPSi nanoparticles a suitable and promising nanoplatform for the targeting of CD44-overexpressing breast tumors and for drug delivery.Active targeting of nanoparticles to receptor-overexpressing cancer cells has great potential for enhancing the cellular uptake of nanoparticles and for reducing fast clearance of the nanoparticles from the body. Herein, we present a preparation method of a porous silicon (PSi)-based nanodelivery system for breast cancer targeting, by covalently conjugating a synthesized amide-modified hyaluronic acid (HA+) derived polymer on the surface of undecylenic acid-modified thermally hydrocarbonized PSi (UnTHCPSi) nanoparticles. The resulting UnTHCPSi-HA+ nanoparticles showed relatively small size, reduced polydispersibility, high biocompatibility, improved colloidal and human plasma stability, as well as enhanced cellular interactions and internalization. Moreover, we demonstrated that the enhanced cellular association of Un

  4. Inflammatory breast cancer: an overview

    NARCIS (Netherlands)

    Uden, D.J. van; Laarhoven, H.W.M. van; Westenberg, A.H.; Wilt, J.H. de; Blanken-Peeters, C.F.

    2015-01-01

    Inflammatory breast cancer (IBC) is the most aggressive entity of breast cancer. Management involves coordination of multidisciplinary management and usually includes neoadjuvant chemotherapy, ablative surgery if a tumor-free resection margin is expected and locoregional radiotherapy. This

  5. Spontaneous formation of tumorigenic hybrids between breast cancer and multipotent stromal cells is a source of tumor heterogeneity.

    Science.gov (United States)

    Rappa, Germana; Mercapide, Javier; Lorico, Aurelio

    2012-06-01

    Breast cancer progression involves cancer cell heterogeneity, with generation of invasive/metastatic breast cancer cells within populations of nonmetastatic cells of the primary tumor. Sequential genetic mutations, epithelial-to-mesenchymal transition, interaction with local stroma, and formation of hybrids between cancer cells and normal bone marrow-derived cells have been advocated as tumor progression mechanisms. We report herein the spontaneous in vitro formation of heterotypic hybrids between human bone marrow-derived multipotent stromal cells (MSCs) and two different breast carcinoma cell lines, MDA-MB-231 (MDA) and MA11. Hybrids showed predominantly mesenchymal morphological characteristics, mixed gene expression profiles, and increased DNA ploidy. Both MA11 and MDA hybrids were tumorigenic in immunodeficient mice, and some MDA hybrids had an increased metastatic capacity. Both in culture and as xenografts, hybrids underwent DNA ploidy reduction and morphological reversal to breast carcinoma-like morphological characteristics, while maintaining a mixed breast cancer-mesenchymal expression profile. Analysis of coding single-nucleotide polymorphisms by RNA sequencing revealed genetic contributions from both parental partners to hybrid tumors and metastasis. Because MSCs migrate and localize to breast carcinoma, our findings indicate that formation of MSC-breast cancer cell hybrids is a potential mechanism of the generation of invasive/metastatic breast cancer cells. Our findings reconcile the fusion theory of cancer progression with the common observation that breast cancer metastases are generally aneuploid, but not tetraploid, and are histopathologically similar to the primary neoplasm. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  6. Clotrimazole disrupts glycolysis in human breast cancer without affecting non-tumoral tissues.

    Science.gov (United States)

    Coelho, Raquel Guimarães; Calaça, Isadora de Castro; Celestrini, Deborah de Moura; Correia, Ana Helena; Costa, Mauricio Augusto Silva Magalhães; Sola-Penna, Mauro

    2011-08-01

    Human breast cancer tissues, as well as normal tissues from the same patients, were treated with clotrimazole (CTZ) and have their capacities for glucose consumption and lactate production evaluated. This treatment strongly decreased the lactate production rate by tumor tissues (85% inhibition) without affecting the other measurements made, i.e. lactate production by control tissues or glucose consumption by both, control and tumor tissues. This result directly correlates with the inhibition promoted by CTZ on the activity of the major regulatory glycolytic enzyme 6-phosphofructo-1-kinase (PFK) that was observed in tumor tissues (84% inhibition) but not in control tissues. Fractionation of the tissues revealed that this inhibition does not occur in the soluble fraction of the enzyme, but is exclusive of a particulate fraction. It has been previously shown that the particulate fraction of PFK activity in tumors is associated to actin filaments (f-actin). Thus, we investigated whether CTZ would affect the association between PFK and f-actin and we found that the drug directly induces the dissociation of the two proteins in the same extent that it inhibits lactate production, total PFK activity and the particulate PFK activity. We concluded that CTZ disrupts glycolysis on human breast tumor tissues, inhibiting PFK activity by dissociating the enzyme from f-actin. Copyright © 2011 Elsevier Inc. All rights reserved.

  7. 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 subt...... of the United Kingdom. CONCLUSION: These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up....

  8. 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

    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...... counts were significantly associated with poor disease-specific survival (p=0.004). Combining low/low versus high/high tertiles of Chalkley counts and PAI-1 showed actuarial 10-year survival rates of 82% versus 52% (p=0.004). High N-stage (p....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...

  9. 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.

  10. The prognostic value of tumor budding in invasive breast cancer.

    Science.gov (United States)

    Liang, Fenli; Cao, Wei; Wang, Yili; Li, Linrui; Zhang, Guanjun; Wang, Zhuo

    2013-05-01

    We investigated the prognostic value of tumor budding in 160 cases of operable invasive ductal carcinoma, not otherwise specified (IDC-NOS). The number of buds was counted in H&E slides with a maximal invasive margin in a 0.950mm(2) field of vision (200×). According to a cut-off score selected by ROC analysis, the cohort was dichotomized into a low (0-7 budding foci, 107 cases, 66.9%) and a high-grade budding group (8 or more budding foci, 53 cases, 33.1%). The inter-observer test showed a good reproducibility with 0.717 as the К value. High-grade budding was significantly associated with the presence of lymphovascular invasion (LVI) (P=0.001), larger tumor size (P=0.014), and worse clinical outcome (Pbudded cells at the margin displayed epithelial mesenchymal transition (EMT)-like molecular phenotype and decreased proliferative activity. Survival analyses revealed that tumor budding (HR 4.275, Ptumor size (HR 2.468, P=0.002), node status (HR 2.362, Ptumor budding is a reproducible, significant, and independent histopathological prognostic factor in IDC-NOS. Copyright © 2013 Elsevier GmbH. All rights reserved.

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

    Science.gov (United States)

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

    2016-12-01

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

  12. Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy

    OpenAIRE

    Chinnaiyan, Arul M; Prasad, Uttara; Shankar, Sunita; Hamstra, Daniel A.; Shanaiah, Murthy; Chenevert, Thomas L.; Ross, Brian D.; Rehemtulla, Alnawaz

    2000-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent endogenous activator of the cell death pathway and functions by activating the cell surface death receptors 4 and 5 (DR4 and DR5). TRAIL is nontoxic in vivo and preferentially kills neoplastically transformed cells over normal cells by an undefined mechanism. Radiotherapy is a common treatment for breast cancer as well as many other cancers. Here we demonstrate that ionizing radiation can sensitize breast carcinoma ce...

  13. BDNF is associated with SFRP1 expression in luminal and basal-like breast cancer cell lines and primary breast cancer tissues: a novel role in tumor suppression?

    Directory of Open Access Journals (Sweden)

    Laura Huth

    Full Text Available Secreted frizzled related protein 1 (SFRP1 functions as an important inhibitor of the Wnt pathway and is a known tumor suppressor gene, which is epigenetically silenced in a variety of tumors e.g. in breast cancer. However, it is still unclear how SFRP1 exactly affects the Wnt pathway. Our aim was to decipher SFRP1 involvement in biochemical signaling in dependency of different breast cancer subtypes and to identify novel SFRP1-regulated genes. We generated SFRP1 over-expressing in vitro breast cancer models, reflecting the two major subtypes by using basal-like BT20 and luminal-like HER2-positive SKBR3 cells. DNA microarray expression profiling of these models revealed that SFRP1 expression potentially modulates Bone morphogenetic protein- and Smoothened signaling (p<0.01, in addition to the known impact on Wnt signaling. Importantly, further statistical analysis revealed that in dependency of the cancer subtype model SFRP1 may affect the canonical and non-canonical Wnt pathway (p<0.01, respectively. While SFRP1 re-expression generally mediated distinct patterns of transcriptionally induced or repressed genes in BT20 and SKBR3 cells, brain derived neurotrophic factor (BDNF was identified as a SFRP1 induced gene in both cell lines. Although BDNF has been postulated as a putative oncogene, the co-regulation with SFRP1 indicates a potential suppressive function in breast cancer. Indeed, a positive correlation between SFRP1 and BDNF protein expression could be shown (p<0.001 in primary breast cancer samples. Moreover, TCGA dataset based analysis clearly underscores that BDNF mRNA is down-regulated in primary breast cancer samples predicting a poor prognosis of these patients. In line, we functionally provide evidence that stable BDNF re-expression in basal-like BT20 breast cancer cells blocks tumor cell proliferation. Hence, our results suggest that BDNF might rather mediate suppressive than promoting function in human breast cancer whose mode of

  14. Legubicin a Tumor-activated Prodrug for Breast Cancer Therapy

    Science.gov (United States)

    2008-04-01

    reagent. Rabbit anti-legu- main antisera was prepared by immunization with purified human legumain produced in Escherichia coli (8). This antisera...0 5 0 1 0 0 S a li n e D o x L e g - 3 T im e ( D a y s ) Pe rc en t S ur vi va l Figure 4. Efficacy of LEG-3 in 4T1 murine...were purchased from The Scripps Research Institute Rodent Breeding Facility. Tumor induction was performed by s.c. injection of 5 × 105 4T1 cells in

  15. The complex evaluation of tumor oxygen state and vasculature during preoperative chemotherapy in patients with breast cancer

    Science.gov (United States)

    Pavlov, M. V.; Subochev, P. V.; Kalganova, T. I.; Golubyatnikov, G. Yu.; Plekhanov, V. I.; Ilyinskaya, O. E.; Orlova, A. G.; Shakhova, N. M.; Maslennikova, A. V.

    2017-02-01

    Effective breast cancer treatment requires the assessment of metabolic changes of tumor tissue during chemo- and hormonotherapy for prediction tumor response. Evaluation of the dynamics of tumor oxygen state (by diffuse optical spectroscopy imaging) and tumor vasculature (by ultrasound investigation in power Doppler mode) was performed before treatment beginning and before the second cycle of chemotherapy in 16 patients who received preoperative chemotherapy. Changes of these indicators were compared then with tumor pathologic response. Breast tumors demonstrated different dynamics of tumor oxygenation depending on the changes of tumor tissue. The increase of the tumor oxygenation after the first cycle of chemotherapy was observed in five of six patients with grade 4 and 5 of pathologic tumor response. Decrease of the oxygenation level was revealed in one patient with the 4th degree of tumor response. Variable changes of the oxygenation level were mentioned in the patients with moderate (the 3d degree) tumor response. Tumor oxygenation decreased or was unchanged in case of 1 or 2 degree of tumor response in five of six cases. The study of the tumor blood vessels didn't reveal any correlation between vasculature changes and tumor response under the performed treatment. The trend of tumor oxygenation in early time after treatment beginning might be a predictive criterion of tumor sensitivity to chemotherapy.

  16. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters.

    Science.gov (United States)

    Cheung, Kevin J; Padmanaban, Veena; Silvestri, Vanesa; Schipper, Koen; Cohen, Joshua D; Fairchild, Amanda N; Gorin, Michael A; Verdone, James E; Pienta, Kenneth J; Bader, Joel S; Ewald, Andrew J

    2016-02-16

    Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases. We directly observed multicolored tumor cell clusters across major stages of metastasis, including collective invasion, local dissemination, intravascular emboli, circulating tumor cell clusters, and micrometastases. Experimentally aggregating tumor cells into clusters induced a >15-fold increase in colony formation ex vivo and a >100-fold increase in metastasis formation in vivo. Intriguingly, locally disseminated clusters, circulating tumor cell clusters, and lung micrometastases frequently expressed the epithelial cytoskeletal protein, keratin 14 (K14). RNA-seq analysis revealed that K14(+) cells were enriched for desmosome and hemidesmosome adhesion complex genes, and were depleted for MHC class II genes. Depletion of K14 expression abrogated distant metastases and disrupted expression of multiple metastasis effectors, including Tenascin C (Tnc), Jagged1 (Jag1), and Epiregulin (Ereg). Taken together, our findings reveal K14 as a key regulator of metastasis and establish the concept that K14(+) epithelial tumor cell clusters disseminate collectively to colonize distant organs.

  17. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters

    Science.gov (United States)

    Cheung, Kevin J.; Padmanaban, Veena; Silvestri, Vanesa; Schipper, Koen; Cohen, Joshua D.; Fairchild, Amanda N.; Gorin, Michael A.; Verdone, James E.; Pienta, Kenneth J.; Bader, Joel S.; Ewald, Andrew J.

    2016-01-01

    Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases. We directly observed multicolored tumor cell clusters across major stages of metastasis, including collective invasion, local dissemination, intravascular emboli, circulating tumor cell clusters, and micrometastases. Experimentally aggregating tumor cells into clusters induced a >15-fold increase in colony formation ex vivo and a >100-fold increase in metastasis formation in vivo. Intriguingly, locally disseminated clusters, circulating tumor cell clusters, and lung micrometastases frequently expressed the epithelial cytoskeletal protein, keratin 14 (K14). RNA-seq analysis revealed that K14+ cells were enriched for desmosome and hemidesmosome adhesion complex genes, and were depleted for MHC class II genes. Depletion of K14 expression abrogated distant metastases and disrupted expression of multiple metastasis effectors, including Tenascin C (Tnc), Jagged1 (Jag1), and Epiregulin (Ereg). Taken together, our findings reveal K14 as a key regulator of metastasis and establish the concept that K14+ epithelial tumor cell clusters disseminate collectively to colonize distant organs. PMID:26831077

  18. Bioenergy and Breast Cancer: A Report on Tumor Growth and Metastasis

    Directory of Open Access Journals (Sweden)

    Alice Running

    2016-01-01

    Full Text Available As many as 80% of the 296,000 women and 2,240 men diagnosed with breast cancer in the United States will seek out complementary and alternative medicine (CAM treatments. One such therapy is Healing Touch (HT, recognized by the National Center for Complementary and Integrative Health (NCCIH as a treatment modality. Using a multiple experimental groups design, fifty-six six- to eight-week-old Balb/c mice were injected with 4T1 breast cancer tumor cells and randomly divided into intervention and positive control groups. Five days after tumor cell injection, mice in the intervention groups received HT either daily or every other day for 10 minutes by one HT practitioner. At 15 days after tumor cell injection, tumor size was measured, and metastasis was evaluated by a medical pathologist after necropsy. Tumor size did not differ significantly among the groups (F(3,52=0.75, p value = 0.53. The presence of metastasis did not differ across groups (chi-square(3 = 3.902, p=0.272 or when compared within an organ (liver: chi-square(3 = 2.507, p=0.474; lungs: chi-square(3 = 3.804, p=0.283; spleen: chi-square(3 = 0.595, p=0.898. However, these results did indicate a moderate, though insignificant, positive impact of HT and highlight the need for continued research into dose, length of treatment, and measurable outcomes (tumor size, metastasis to provide evidence to suggest application for nursing care.

  19. Targeting Autophagy in the Tumor Stroma to Eradicate Breast Cancer

    Science.gov (United States)

    2013-09-01

    Streptomycin (MMF media) PBS + 0.5% Bovine Serum Albumin (FACS Buffer I) PBS + 5% Calf Serum (FACS Buffer II) 50 mg/ml gentamicin Collagenase (Sigma...f). The details of our standard procedures are as follows: Protocol 1: Primary mammary fibroblast isolation Reagents: DMEM + 10% Calf Serum ...Jayanta   Protocol 2: Isolation of cancer-associated fibroblasts. Reagents: DMEM + 10% Calf Serum (NOT heat inactivated) + 1% Penicillin

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

    Science.gov (United States)

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

    2011-09-29

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

  1. Hormonal Receptor, Human Epidermal Growth Factor and Its Association with Breast Cancer Tumor Characteristics in Albania.

    Science.gov (United States)

    Pajenga, Edlira; Rexha, Tefta; Çeliku, Silva; Ugrinska, Ana; Bejtja, Gazmend

    2016-09-01

    This retrospective study was designed to analyze expression patterns of estrogen receptor (ER), progesterone receptor (PR) and HER2/neu in Albanian patients with breast carcinoma to identify their relationships with tumor size, histological grade (HG), lymph node metastasis and relapse. Patients with either biopsy or metastatic relapse were identified. Demographics, tumor characteristics, ER, PR, and HER2/neu status were retrospectively obtained from the medical records of patients treated with breast cancer during 2006-2011. Hormonal receptors and HER2/neu were assessed by immunohistochemistry. Association of ER, PR and HER2/neu with clinicopathological and molecular characteristics were studied using Fisher's test. P value ≤0.05 was considered significant. There were 110 patients included in the study. Mean patient age was 51.08±10.75 years. The overall immunoexpression of ER, PR and HER2/neu were found positive in 76 (69%), 73 (67%), and 16 (41%) patients, respectively. ER- was associated with higher histological grade (24% vs. 9.2%) and PR+ with tumor size (T2, 78.3 vs. 64.3) (p=0.02 and 0.05, respectively). ER and PR expression were significantly decreased in HER2/neu positive cases while HER2/neu levels correlated with tumor size (p=0.03) and nodal metastasis (p=0.03). No association was detected between ER, PR, HER2/neu and relapse. A combination of ER, PR and HER2/neu and prognostic factors could be of clinical value by defining subgroups in Albanian breast cancer patients that might benefit from more aggressive treatment.

  2. Clinical implications of chemotherapy-induced tumor gene expression in human breast cancers.

    Science.gov (United States)

    Tan, Sing-Huang; Lee, Soo-Chin

    2010-03-01

    There has been much interest in generating gene signatures to predict treatment response in breast cancer. There are at least 15 published studies that describe baseline tumor gene signatures predicting chemotherapy sensitivity. As an extension of these baseline studies, there have been at least 8 published studies evaluating chemotherapy-induced tumor genomic changes over time in human breast cancers. Studies on chemotherapy-induced gene expression changes were reviewed in detail. Drug-induced biological changes within the tumor shed light on mechanisms of drug resistance and provided valuable insights regarding genes and pathways that were regulated by different drugs, including therapeutic targets that could be exploited to overcome resistance. One study also suggested post-chemotherapy gene signatures to be more predictive of response and survival than the unchallenged baseline signatures. Studies on chemotherapy-induced changes, although informative, are logistically demanding to execute, often with significant attrition of collected samples resulting in small datasets. They are further limited by heterogeneity of study population, chemotherapy regimens used, timing of the post-therapy sample and definition of response endpoint, making cross-comparisons of studies and data interpretation difficult. Future studies should address these limitations, and should involve larger sample sets and prospective studies for validation.

  3. Minimal elastographic modeling of breast cancer for model based tumor detection in a digital image elasto tomography (DIET) system

    Science.gov (United States)

    Lotz, Thomas F.; Muller, Natalie; Hann, Christopher E.; Chase, J. Geoffrey

    2011-03-01

    Digital Image Elasto Tomography (DIET) is a non-invasive breast cancer screening technology that images the surface motion of a breast under harmonic mechanical actuation. A new approach capturing the dynamics and characteristics of tumor behavior is presented. A simple mechanical model of the breast is used to identify a transfer function relating the input harmonic actuation to the output surface displacements using imaging data of a silicone phantom. Areas of higher stiffness cause significant changes of damping and resonant frequencies as seen in the resulting Bode plots. A case study on a healthy and tumor silicone breast phantom shows the potential for this model-based method to clearly distinguish cancerous and healthy tissue as well as correctly predicting the tumor position.

  4. Transcription factor c-Myb inhibits breast cancer lung metastasis by suppression of tumor cell seeding.

    Science.gov (United States)

    Knopfová, L; Biglieri, E; Volodko, N; Masařík, M; Hermanová, M; Glaus Garzón, J F; Dúcka, M; Kučírková, T; Souček, K; Šmarda, J; Beneš, P; Borsig, L

    2017-10-30

    Metastasis accounts for most of cancer-related deaths. Paracrine signaling between tumor cells and the stroma induces changes in the tumor microenvironment required for metastasis. Transcription factor c-Myb was associated with breast cancer (BC) progression but its role in metastasis remains unclear. Here we show that increased c-Myb expression in BC cells inhibits spontaneous lung metastasis through impaired tumor cell extravasation. On contrary, BC cells with increased lung metastatic capacity exhibited low c-Myb levels. We identified a specific inflammatory signature, including Ccl2 chemokine, that was expressed in lung metastatic cells but was suppressed in tumor cells with higher c-Myb levels. Tumor cell-derived Ccl2 expression facilitated lung metastasis and rescued trans-endothelial migration of c-Myb overexpressing cells. Clinical data show that the identified inflammatory signature, together with a MYB expression, predicts lung metastasis relapse in BC patients. These results demonstrate that the c-Myb-regulated transcriptional program in BCs results in a blunted inflammatory response and consequently suppresses lung metastasis.Oncogene advance online publication, 30 October 2017; doi:10.1038/onc.2017.392.

  5. Evaluate Risk/Benefit of Nab Paclitaxel in Combination With Gemcitabine and Carboplatin Compared to Gemcitabine and Carboplatin in Triple Negative Metastatic Breast Cancer (or Metastatic Triple Negative Breast Cancer)

    Science.gov (United States)

    2017-06-05

    Breast Tumor; Breast Cancer; Cancer of the Breast; Estrogen Receptor- Negative Breast Cancer; HER2- Negative Breast Cancer; Progesterone Receptor- Negative Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer; Triple-negative Breast Cancer; Triple-negative Metastatic Breast Cancer; Metastatic Breast Cancer

  6. Tumor phenotype and breast density in distinct categories of interval cancer: results of population-based mammography screening in Spain

    Science.gov (United States)

    2014-01-01

    Introduction Interval cancers are tumors arising after a negative screening episode and before the next screening invitation. They can be classified into true interval cancers, false-negatives, minimal-sign cancers, and occult tumors based on mammographic findings in screening and diagnostic mammograms. This study aimed to describe tumor-related characteristics and the association of breast density and tumor phenotype within four interval cancer categories. Methods We included 2,245 invasive tumors (1,297 screening-detected and 948 interval cancers) diagnosed from 2000 to 2009 among 645,764 women aged 45 to 69 who underwent biennial screening in Spain. Interval cancers were classified by a semi-informed retrospective review into true interval cancers (n = 455), false-negatives (n = 224), minimal-sign (n = 166), and occult tumors (n = 103). Breast density was evaluated using Boyd’s scale and was conflated into: 75%. Tumor-related information was obtained from cancer registries and clinical records. Tumor phenotype was defined as follows: luminal A: ER+/HER2- or PR+/HER2-; luminal B: ER+/HER2+ or PR+/HER2+; HER2: ER-/PR-/HER2+; triple-negative: ER-/PR-/HER2-. The association of tumor phenotype and breast density was assessed using a multinomial logistic regression model. Adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. All statistical tests were two-sided. Results Forty-eight percent of interval cancers were true interval cancers and 23.6% false-negatives. True interval cancers were associated with HER2 and triple-negative phenotypes (OR = 1.91 (95% CI:1.22-2.96), OR = 2.07 (95% CI:1.42-3.01), respectively) and extremely dense breasts (>75%) (OR = 1.67 (95% CI:1.08-2.56)). However, among true interval cancers a higher proportion of triple-negative tumors was observed in predominantly fatty breasts (breasts (28.7%, 21.4%, 11.3% and 14.3%, respectively; screening-detected cancers, extreme breast density

  7. A molecular 'signature' of primary breast cancer cultures; patterns resembling tumor tissue

    Directory of Open Access Journals (Sweden)

    Meng Zhenhang

    2004-07-01

    Full Text Available Abstract Background To identify the spectrum of malignant attributes maintained outside the host environment, we have compared global gene expression in primary breast tumors and matched short-term epithelial cultures. Results In contrast to immortal cell lines, a characteristic 'limited proliferation' phenotype was observed, which included over expressed genes associated with the TGFβ signal transduction pathway, such as SPARC, LOXL1, RUNX1, and DAPK1. Underlying this profile was the conspicuous absence of hTERT expression and telomerase activity, a significant increase in TβRII, its cognate ligand, and the CDK inhibitor, p21CIP1/WAF1. Concurrently, tumor tissue and primary cultures displayed low transcript levels of proliferation-related genes, such as, TOP2A, ANKT, RAD51, UBE2C, CENPA, RRM2, and PLK. Conclusions Our data demonstrate that commonly used immortal cell lines do not reflect some aspects of tumor biology as closely as primary tumor cell cultures. The gene expression profile of malignant tissue, which is uniquely retained by cells cultured on solid substrates, could facilitate the development and testing of novel molecular targets for breast cancer.

  8. Malignant phyllodes breast tumor

    OpenAIRE

    Lisa R. Shah-Patel, MD

    2017-01-01

    Malignant phyllodes tumor is a rare tumor of the breast occurring in females usually between the ages of 35 and 55 years. It is often difficult to distinguish benign from malignant phyllodes tumors from other benign entities such as fibroadenomas. This case presentation demonstrates a woman with malignant phyllodes tumor treated with mastectomy with abdominal skin flap reconstruction.

  9. Malignant phyllodes breast tumor

    Directory of Open Access Journals (Sweden)

    Lisa R. Shah-Patel, MD

    2017-12-01

    Full Text Available Malignant phyllodes tumor is a rare tumor of the breast occurring in females usually between the ages of 35 and 55 years. It is often difficult to distinguish benign from malignant phyllodes tumors from other benign entities such as fibroadenomas. This case presentation demonstrates a woman with malignant phyllodes tumor treated with mastectomy with abdominal skin flap reconstruction.

  10. Detection of circulating tumor cell-specific markers in breast cancer patients using the quantitative RT-PCR assay.

    Science.gov (United States)

    Wang, Hye-Young; Ahn, Sungwoo; Kim, Sunghyun; Park, Sunyoung; Jung, Dongju; Park, Sangjung; Han, Hyunju; Sohn, JooHyuk; Kim, SeungIl; Lee, Hyeyoung

    2015-10-01

    Breast cancer is a highly prevalent disease among women worldwide. While the expression of certain proteins within breast cancer tumors is used to determine the prognosis and select therapies, additional markers need to be identified. Circulating tumor cells (CTCs) are constituent cells that have detached from a primary tumor to circulate in the bloodstream. CTCs are considered the main source of breast cancer metastases; therefore, detection of CTCs could be a promising diagnostic method for metastatic breast cancer. In this study, the CircleGen CTC RT-qDx assay was used to analyze the mRNA expression levels of six CTC-specific markers including EpCAM, CK19, HER2, Ki67, hTERT, and vimentin with a total of 692 peripheral whole blood samples from 221 breast cancer patients and 376 healthy individuals. This assay showed high specificity with multiple markers; none of the healthy controls were detected positive, whereas 21.7 and 14 % of breast cancer patients were positive for EpCAM and CK19, respectively. Of the 221 breast cancer patients, 84 (38 %), 46 (20.8 %), 83 (37.6 %), and 39 (17.6 %) were positively for HER2, Ki67, hTERT, and vimentin mRNA, respectively. Of the 84 patients who were HER2 positive, nine (4 %) were also positive for EpCAM, CK19, Ki67, hTERT, and vimentin. Of the 139 breast cancer patients who were HER2 negative, 65 (29.1 %) were negative for EpCAM, CK19, Ki67, hTERT, and vimentin. Furthermore, the EpCAM-positive population decreased from 21.5 to 8.3 % after completion of anti-tumor treatment (TP4). Similarly, the CK19, HER2, hTERT, and vimentin positives also decreased from 13.9 to 9.5 %, from 37.7 to 21.4 %, from 37.2 to 33.3 %, and from 17.5 to 14.3 %, respectively, after completion of anti-tumor treatment. In contrast, the Ki67 positives increased from 20.6 to 41.7 % after completion of anti-tumor treatment. mRNA overexpression of six CTC-specific markers was detected by the CircleGen CTC RT-qDx assay with high specificity, and the obtained m

  11. Breast cancer

    Science.gov (United States)

    ... help you not feel alone. Outlook (Prognosis) New, improved treatments are helping people with breast cancer live ... carcinoma in situ Patient Instructions Breast radiation - discharge Chemotherapy - what to ask your doctor Lymphedema - self-care ...

  12. Prognostic Significance of Progesterone Receptor–Positive Tumor Cells Within Immunohistochemically Defined Luminal A Breast Cancer

    Science.gov (United States)

    Prat, Aleix; Cheang, Maggie Chon U.; Martín, Miguel; Parker, Joel S.; Carrasco, Eva; Caballero, Rosalía; Tyldesley, Scott; Gelmon, Karen; Bernard, Philip S.; Nielsen, Torsten O.; Perou, Charles M.

    2013-01-01

    Purpose Current immunohistochemical (IHC)-based definitions of luminal A and B breast cancers are imperfect when compared with multigene expression-based assays. In this study, we sought to improve the IHC subtyping by examining the pathologic and gene expression characteristics of genomically defined luminal A and B subtypes. Patients and Methods Gene expression and pathologic features were collected from primary tumors across five independent cohorts: British Columbia Cancer Agency (BCCA) tamoxifen-treated only, Grupo Español de Investigación en Cáncer de Mama 9906 trial, BCCA no systemic treatment cohort, PAM50 microarray training data set, and a combined publicly available microarray data set. Optimal cutoffs of percentage of progesterone receptor (PR) –positive tumor cells to predict survival were derived and independently tested. Multivariable Cox models were used to test the prognostic significance. Results Clinicopathologic comparisons among luminal A and B subtypes consistently identified higher rates of PR positivity, human epidermal growth factor receptor 2 (HER2) negativity, and histologic grade 1 in luminal A tumors. Quantitative PR gene and protein expression were also found to be significantly higher in luminal A tumors. An empiric cutoff of more than 20% of PR-positive tumor cells was statistically chosen and proved significant for predicting survival differences within IHC-defined luminal A tumors independently of endocrine therapy administration. Finally, no additional prognostic value within hormonal receptor (HR) –positive/HER2-negative disease was observed with the use of the IHC4 score when intrinsic IHC-based subtypes were used that included the more than 20% PR-positive tumor cells and vice versa. Conclusion Semiquantitative IHC expression of PR adds prognostic value within the current IHC-based luminal A definition by improving the identification of good outcome breast cancers. The new proposed IHC-based definition of luminal A

  13. Breast Cancer Prevention

    Science.gov (United States)

    ... of Breast & Gynecologic Cancers Breast Cancer Screening Research Breast Cancer Prevention (PDQ®)–Patient Version What is prevention? Go ... from starting. Risk-reducing surgery . General Information About Breast Cancer Key Points Breast cancer is a disease in ...

  14. Second Primary Tumors associated with Breast Cancer: Kuwait Cancer Control Center Experience.

    Science.gov (United States)

    Fayaz, Salah; Demian, Gerges Attia; Eissa, Heba El-Sayed; Abuzalouf, Sadeq

    2017-09-01

    To review the clinico-epidemiologic characteristics of patients who presented with two or more primary cancers, one of which was breast cancer (BC) and to develop a follow-up program for the high risk patients. Patients who were diagnosed with BC and one or more non breast cancer (NBC) were retrospectively reviewed. Medical files were retrieved and epidemiological as well as clinical data were analyzed. Sixty-two patients were retrieved. BC was the first primary in 26 patients while it was the second in 36 patients. Two were males and 60 were females. The median age was 48 years and the median follow-up was 11.5 years. The median interval between the 1st and 2nd primary was 6 years. The most commonly associated NBCs were colon and thyroid cancers, each accounts for 24% of cases followed by endometrial cancer, 18%; Hodgkin's disease, 6.5%; renal and ovarian neoplasm and NHL, 5% each. Others included prostate, lung, cervical and gastric cancers, soft tissue sarcoma and osteosarcoma. Thyroid cancer was more common as first cancer while endometrial cancer was more as second cancer. All patients who developed BC following Hodgkin's disease had received chest irradiation. Seven patients developed 3rd primary (4 lung cancers, 2 NHL, and 1 AML). Patients who were diagnosed with BC should be screened for colon and endometrial cancer. Similarly, patients received chest irradiation at young age, and those diagnosed with thyroid or colon cancer should be screened for BC. Protocol of surveillance needs to be defined. Genetic counseling should be offered to individuals who have experienced multiple primary cancers particularly those with family history and young age of onset.

  15. Serum IGF-1, IGFBP-3 levels and circulating tumor cells (CTCs) in early breast cancer patients.

    Science.gov (United States)

    Papadakis, Georgios Z; Mavroudis, Dimitrios; Georgoulias, Vasilios; Souglakos, John; Alegakis, Athanasios K; Samonis, George; Bagci, Ulas; Makrigiannakis, Antonis; Zoras, Odysseas

    2017-04-01

    Insulin-like growth factor (IGF)-axis is involved in human oncogenesis and metastasis development for various solid tumors including breast cancer. Aim of this study was to assess the association between IGF-1, IGF-binding protein-3 (IGFBP-3) serum levels and the presence of circulating tumor cells (CTCs) in the peripheral blood of women diagnosed with early breast cancer (EBC), before and after adjuvant chemotherapy. 171 patients with early-stage breast adenocarcinomas were retrospectively evaluated. Immunoradiometric (IRMA) assays were employed for the in-vitro determination of IGF-1 and IGFBP-3 serum levels in blood samples collected after surgical treatment and before initiation of adjuvant chemotherapy. CTCs' presence was assessed through detection of cytokeratin-19 (CK-19) mRNA transcripts using quantitative real time reverse transcription polymerase chain reaction (RT-PCR). IGF-1, IGFBP-3 serum levels were correlated with CTCs' presence before and after adjuvant chemotherapy as well as with tumor characteristics including tumor size, axillary lymph node status, oestrogen (ER)/progestorene (PR) and human epidermural growth factor receptor 2 (HER2) receptor status. Log-rank test was applied to investigate possible association between IGF-1, IGFBP-3 serum levels and disease-free interval (DFI) and overall survival (OS). Before initiation of adjuvant therapy IGF-1, IGFBP-3 serum levels were moderately associated (Spearman's rho=0.361, p<0.001) with each other, while presenting significant differences across age groups (all p values<0.05). IGF-1 serum levels did not correlate with the presence of CTCs before initiation (p=0.558) or after completion (p=0.474) of adjuvant chemotherapy. Similarly, IGFBP-3 serum levels did not show significant association with detectable CTCs either before (p=0.487) or after (p=0.134) completion of adjuvant chemotherapy. There was no statistically significant association between the clinical outcome of patients in terms of DFI, OS

  16. Concordance of Hypermethylated DNA and the Tumor Markers CA 15-3, CEA, and TPA in Serum during Monitoring of Patients with Advanced Breast Cancer

    DEFF Research Database (Denmark)

    Kristiansen, Søren; Jørgensen, Lars Mønster; Høgh Hansen, Morten

    2015-01-01

    The serological protein tumor markers CA 15-3, CEA, and TPA are frequently used to monitor tumor burden among metastatic breast cancer patients. Breast cancer is associated with global DNA hypomethylation and hypermethylation of some promoter regions. No monitoring study has yet investigated the ...

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    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...

  18. Elevated tumor LDLR expression accelerates LDL cholesterol-mediated breast cancer growth in mouse models of hyperlipidemia.

    Science.gov (United States)

    Gallagher, E J; Zelenko, Z; Neel, B A; Antoniou, I M; Rajan, L; Kase, N; LeRoith, D

    2017-11-16

    Obesity is associated with an increase in cancer-specific mortality in women with breast cancer. Elevated cholesterol, particularly low-density lipoprotein cholesterol (LDL-C), is frequently seen in obese women. Here, we aimed to determine the importance of elevated circulating LDL, and LDL receptor (LDLR) expression in tumor cells, on the growth of breast cancer using mouse models of hyperlipidemia. We describe two novel immunodeficient mouse models of hyperlipidemia (Rag1-/-/LDLR-/- and Rag1-/-/ApoE (apolipoprotein E)-/- mice) in addition to established immunocompetent LDLR-/- and ApoE-/- mice. The mice were used to study the effects of elevated LDL-C in human triple-negative (MDA-MB-231) and mouse Her2/Neu-overexpressing (MCNeuA) breast cancers. Tumors derived from MCNeuA and MDA-MB-231 cells had high LDLR expression and formed larger tumors in mice with high circulating LDL-C concentrations than in mice with lower LDL-C. Silencing the LDLR in the tumor cells led to decreased growth of Her2/Neu-overexpressing tumors in LDLR-/- and ApoE-/- mice, with increased Caspase 3 cleavage. Additionally, in vitro, silencing the LDLR led to decreased cell survival in serum-starved conditions, associated with Caspase 3 cleavage. Examining publically available human data sets, we found that high LDLR expression in human breast cancers was associated with decreased recurrence-free survival, particularly in patients treated with systemic therapies. Overall, our results highlight the importance of the LDLR in the growth of triple-negative and HER2-overexpressing breast cancers in the setting of elevated circulating LDL-C, which may be important contributing factors to the increased recurrence and mortality in obese women with breast cancer.

  19. Differential peripheral blood gene expression profile based on Her2 expression on primary tumors of breast cancer patients.

    Directory of Open Access Journals (Sweden)

    Oana Tudoran

    Full Text Available Breast cancer prognosis and treatment is highly dependent on the molecular features of the primary tumors. These tumors release specific molecules into the environment that trigger characteristic responses into the circulatory cells. In this study we investigated the expression pattern of 84 genes known to be involved in breast cancer signaling in the peripheral blood of breast cancer patients with ER-, PR- primary tumors. The patients were grouped according to Her2 expression on the primary tumors in Her2+ and Her2- cohorts. Transcriptional analysis revealed 15 genes to be differentially expressed between the two groups highlighting that Her2 signaling in primary tumors could be associated with specific blood gene expression. We found CCNA1 to be up-regulated, while ERBB2, RASSF1, CDH1, MKI67, GATA3, GLI1, SFN, PTGS2, JUN, NOTCH1, CTNNB1, KRT8, SRC, and HIC1 genes were down-regulated in the blood of triple negative breast cancer patients compared to Her2+ cohort. IPA network analysis predicts that the identified genes are interconnected and regulate each other. These genes code for cell cycle regulators, cell adhesion molecules, transcription factors or signal transducers that modulate immune signaling, several genes being also associated with cancer progression and treatment response. These results indicate an altered immune signaling in the peripheral blood of triple negative breast cancer patients. The involvement of the immune system is necessary in favorable treatment response, therefore these results could explain the low response rates observed for triple negative breast cancer patients.

  20. The role of TGFBI in mesothelioma and breast cancer: association with tumor suppression

    Directory of Open Access Journals (Sweden)

    Li Bingyan

    2012-06-01

    Full Text Available Abstract Background Transforming growth factor β induced (TGFBI product, an extracellular matrix (ECM protein, has been implicated as a putative tumor suppressor in recent studies. Our previous findings revealed that expression of TGFBI gene is down-regulated in a variety of cancer cell lines and clinical tissue samples. In this study, ectopic expression of TGFBI was used to ascertain its role as a tumor suppressor and to determine the underlying mechanism of mesothelioma and breast cancer. Methods Cells were stably transfected with pRc/CMV2-TGFBI and pRc/CMV2-empty vector with Lipofectamine Plus. Ectopic expression of TGFBI was quantified by using quantitative PCR and Western-blotting. Characterization of cell viability was assessed using growth curve, clonogenic survival and soft agar growth. The potential of tumor formation was evaluated by an in vivo mouse model. Cell cycle was analyzed via flow cytometry. Expressions of p21, p53, p16 and p14 were examined using Western-blotting. Senescent cells were sorted by using a Senescence β-Galactosidase Staining Kit. Telomerase activity was measured using quantitative telomerase detection kit. Results In this study, an ectopic expression of TGFBI in two types of cancer cell lines, a mesothelioma cell line NCI-H28 and a breast cancer cell line MDA-MB-231 was found to have reduced the cellular growth, plating efficiency, and anchorage-independent growth. The tumorigenicity of these cancer cell lines as determined by subcutaneous inoculation in nude mice was similarly suppressed by TGFBI expression. Likewise, TGFBI expression reduced the proportion of S-phase while increased the proportion of G1 phase in these cells. The redistribution of cell cycle phase after re-expression of TGFBI was correspondent with transiently elevated expression of p21 and p53. The activities of senescence-associated β-galactosidase and telomerase were enhanced in TGFBI-transfected cells. Conclusion Collectively, these

  1. Oxalate induces breast cancer.

    Science.gov (United States)

    Castellaro, Andrés M; Tonda, Alfredo; Cejas, Hugo H; Ferreyra, Héctor; Caputto, Beatriz L; Pucci, Oscar A; Gil, German A

    2015-10-22

    Microcalcifications can be the early and only presenting sign of breast cancer. One shared characteristic of breast cancer is the appearance of mammographic mammary microcalcifications that can routinely be used to detect breast cancer in its initial stages, which is of key importance due to the possibility that early detection allows the application of more conservative therapies for a better patient outcome. The mechanism by which mammary microcalcifications are formed is still largely unknown but breast cancers presenting microcalcifications are more often associated with a poorer prognosis. We combined Capillary Electrochromatography, histology, and gene expression (qRT-PCR) to analyze patient-matched normal breast tissue vs. breast tumor. Potential carcinogenicity of oxalate was tested by its inoculation into mice. All data were subjected to statistical analysis. To study the biological significance of oxalates within the breast tumor microenvironment, we measured oxalate concentration in both human breast tumor tissues and adjoining non-pathological breast tissues. We found that all tested breast tumor tissues contain a higher concentration of oxalates than their counterpart non-pathological breast tissue. Moreover, it was established that oxalate induces proliferation of breast cells and stimulates the expression of a pro-tumorigenic gene c-fos. Furthermore, oxalate generates highly malignant and undifferentiated tumors when it was injected into the mammary fatpad in female mice, but not when injected into their back, indicating that oxalate does not induce cancer formation in all types of tissues. Moreover, neither human kidney-epithelial cells nor mouse fibroblast cells proliferate when are treated with oxalate. We found that the chronic exposure of breast epithelial cells to oxalate promotes the transformation of breast cells from normal to tumor cells, inducing the expression of a proto-oncogen as c-fos and proliferation in breast cancer cells

  2. Tumor expression of Nectin-4 as a prognostic marker in breast cancer

    Directory of Open Access Journals (Sweden)

    Hisham Al-Torky

    2015-12-01

    Full Text Available Background: Identification of new molecular tumor associated biomarkers is the most important current challenge in cancer research. Nectin-4 is one of the Nectin glycoproteins, which are cell adhesion molecules have been involved in tumor biology. Objectives: The objective was to evaluate Nectin-4 expression by immunohistochemistry (IHC as a prognostic tumor marker in breast cancer (BC. Patients and Methods: This study was carried out on 100 female patients with BC. Their ages ranged between 29 and 67 years, with a mean of 41.3 years. Fifty other age-matched patients, subjected to reduction mammoplasty, served as controls. Data collected prospectively included patient demographics and tumor characteristics, including histopathological type and grade, IHC for Nectin-4 expression, estrogen receptors (ER, progesterone receptors (PR, and human epidermal growth factor receptor 2 (HER2-Neu. Patients were regularly followed-up for 2 years, recording loco-regional recurrence, distant metastasis, and mortality. Results: Nectin-4 expression by IHC was detected in 62% of BC patients, but in none of the tumor-free controls (P = 0.0001. Nectin-4 expression showed a statistically significant positive correlation with higher tumor grade (P = 0.003 and axillary lymph node involvement (P = 0.0001, but not with increasing tumor size (P = 0.273. It had a significant inverse correlation with ER and PR, and a significant positive correlation with HER2-Neu (P = 0.0001. Furthermore, there was a significant correlation between Nectin-4 expression and the development of distant metastases (P = 0.014, local recurrence (P = 0.046, and mortality (P = 0.049. Conclusions: Nectin-4 is a highly recommended biomarker for predicting progression and prognosis of BC. [Arch Clin Exp Surg 2015; 4(4.000: 178-184

  3. A defined chromosome 6q fragment (at D6S310) harbors a putative tumor suppressor gene for breast cancer.

    Science.gov (United States)

    Theile, M; Seitz, S; Arnold, W; Jandrig, B; Frege, R; Schlag, P M; Haensch, W; Guski, H; Winzer, K J; Barrett, J C; Scherneck, S

    1996-08-15

    Recent evidence obtained by cytogenetic and molecular studies indicates that in breast cancer chromosome 6q is often affected by genetic changes suggesting the existence of putative tumor suppressor genes (TSGs). However the function of gene(s) on this chromosome in breast cancer suppression is not understood. To substantiate further the presence of breast cancer related TSGs at 6q and to define their location, we first performed microcell-mediated transfer of chromosome 6 to CAL51 breast cancer cells for studying possible suppression of malignant phenotype and secondly, we analysed DNAs from 46 primary breast cancers for loss of constitutive heterozygosity (LOH) using 24 poly-morphic microsatellite markers. The chromosome transfer resulted in loss of tumorigenicity and reversion of other neoplastic properties of the microcell hybrids. Polymorphism analysis of single hybrids revealed that they harbored only a small donor chromosome fragment defined by the marker D6S310 (6q23.3-q25) and flanked by D6S292 and D6S311. The LOH data suggest that four tumor suppressor gene loci mapped to the central and distal portion of 6q may be independently deleted in breast cancer. One of these regions corresponds to the region identified by chromosome transfer.

  4. NOTCH2 in breast cancer: association of SNP rs11249433 with gene expression in ER-positive breast tumors without TP53 mutations

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    Ambs Stefan

    2010-05-01

    Full Text Available Abstract Background A recent genome-wide association study (GWAS has identified a single nucleotide polymorphism (SNP rs11249433 in the 1p11.2 region as a novel genetic risk factor for breast cancer, and this association was stronger in patients with estrogen receptor (ER+ versus ER- cancer. Results We found association between SNP rs11249433 and expression of the NOTCH2 gene located in the 1p11.2 region. Examined in 180 breast tumors, the expression of NOTCH2 was found to be lowest in tumors with TP53 mutations and highest in TP53 wild-type/ER+ tumors (p = 0.0059. In the latter group, the NOTCH2 expression was particularly increased in carriers of the risk genotypes (AG/GG of rs11249433 when compared to the non-risk AA genotype (p = 0.0062. Similar association between NOTCH2 expression and rs11249433 was observed in 60 samples of purified monocytes from healthy controls (p = 0.015, but not in total blood samples from 302 breast cancer patients and 76 normal breast tissue samples. We also identified the first possible dominant-negative form of NOTCH2, a truncated version of NOTCH2 consisting of only the extracellular domain. Conclusion This is the first study to show that the expression of NOTCH2 differs in subgroups of breast tumors and by genotypes of the breast cancer-associated SNP rs11249433. The NOTCH pathway has key functions in stem cell differentiation of ER+ luminal cells in the breast. Therefore, increased expression of NOTCH2 in carriers of rs11249433 may promote development of ER+ luminal tumors. Further studies are needed to investigate possible mechanisms of regulation of NOTCH2 expression by rs11249433 and the role of NOTCH2 splicing forms in breast cancer development.

  5. Tiling array-CGH for the assessment of genomic similarities among synchronous unilateral and bilateral invasive breast cancer tumor pairs

    Directory of Open Access Journals (Sweden)

    Ringnér Markus

    2008-07-01

    Full Text Available Abstract Background Today, no objective criteria exist to differentiate between individual primary tumors and intra- or intermammary dissemination respectively, in patients diagnosed with two or more synchronous breast cancers. To elucidate whether these tumors most likely arise through clonal expansion, or whether they represent individual primary tumors is of tumor biological interest and may have clinical implications. In this respect, high resolution genomic profiling may provide a more reliable approach than conventional histopathological and tumor biological factors. Methods 32 K tiling microarray-based comparative genomic hybridization (aCGH was used to explore the genomic similarities among synchronous unilateral and bilateral invasive breast cancer tumor pairs, and was compared with histopathological and tumor biological parameters. Results Based on global copy number profiles and unsupervised hierarchical clustering, five of ten (p = 1.9 × 10-5 unilateral tumor pairs displayed similar genomic profiles within the pair, while only one of eight bilateral tumor pairs (p = 0.29 displayed pair-wise genomic similarities. DNA index, histological type and presence of vessel invasion correlated with the genomic analyses. Conclusion Synchronous unilateral tumor pairs are often genomically similar, while synchronous bilateral tumors most often represent individual primary tumors. However, two independent unilateral primary tumors can develop synchronously and contralateral tumor spread can occur. The presence of an intraductal component is not informative when establishing the independence of two tumors, while vessel invasion, the presence of which was found in clustering tumor pairs but not in tumor pairs that did not cluster together, supports the clustering outcome. Our data suggest that genomically similar unilateral tumor pairs may represent a more aggressive disease that requires the addition of more severe treatment modalities, and

  6. Gallotannin imposes S phase arrest in breast cancer cells and suppresses the growth of triple-negative tumors in vivo.

    Directory of Open Access Journals (Sweden)

    Tiejun Zhao

    Full Text Available Triple-negative breast cancers are associated with poor clinical outcomes and new therapeutic strategies are clearly needed. Gallotannin (Gltn has been previously demonstrated to have potent anti-tumor properties against cholangiocarcinoma in mice, but little is known regarding its capacity to suppress tumor outgrowth in breast cancer models. We tested Gltn for potential growth inhibitory properties against a variety of breast cancer cell lines in vitro. In particular, triple-negative breast cancer cells display higher levels of sensitivity to Gltn. The loss of proliferative capacity in Gltn exposed cells is associated with slowed cell cycle progression and S phase arrest, dependent on Chk2 phosphorylation and further characterized by changes to proliferation related genes, such as cyclin D1 (CcnD1 as determined by Nanostring technology. Importantly, Gltn administered orally or via intraperitoneal (IP injections greatly reduced tumor outgrowth of triple-negative breast cells from mammary fat pads without signs of toxicity. In conclusion, these data strongly suggest that Gltn represents a novel approach to treat triple-negative breast carcinomas.

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

    Science.gov (United States)

    2014-01-01

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

  8. Rapid tumor necrosis and massive hemorrhage induced by bevacizumab and paclitaxel combination therapy in a case of advanced breast cancer

    Directory of Open Access Journals (Sweden)

    Ono M

    2013-10-01

    Full Text Available Mayu Ono, Tokiko Ito, Toshiharu Kanai, Koichi Murayama, Hiroshi Koyama, Kazuma Maeno, Yasuhiro Mochizuki, Asumi Iesato, Toru Hanamura, Toshihiro Okada, Takayuki Watanabe, Ken-ichi ItoDivision of Breast and Endocrine Surgery, Department of Surgery (II, Shinshu University School of Medicine, Matsumoto, JapanAbstract: Bevacizumab when combined with chemotherapy exerts significant activity against many solid tumors through tumor angiogenesis inhibition; however, it can induce severe side effects. We report the rare case of a 27-year-old premenopausal woman with locally advanced breast cancer that was marked by rapid tumor necrosis followed by massive hemorrhage shortly after bevacizumab and paclitaxel administration. On the basis of histopathological examination of a biopsy specimen and computed tomography findings, she was diagnosed with stage IV estrogen and progesterone receptor-negative and human epidermal growth factor receptor type 2-positive breast cancer with multiple organ metastases when she had entered gestational week 24. Cyclophosphamide, Adriamycin®, fluorouracil therapy was initiated, but multiple liver metastases continued to progress. A healthy fetus was delivered by induced delivery and trastuzumab-based treatment was initiated. Although the multiple liver metastases were controlled successfully by trastuzumab combined with paclitaxel, the primary tumor continued to expand even after subsequent administration of three other treatment regimens including anti-human epidermal growth factor receptor type 2 agents and cytotoxic drugs. To inhibit primary tumor growth, a combination therapy with paclitaxel and bevacizumab was subsequently initiated. Following therapy initiation, however, the large tumor occupying the patient's entire left breast became necrotic and ulcerated rapidly. Furthermore, massive hemorrhage from the tumor occurred 5 weeks after bevacizumab-based therapy initiation. Although hemostasis was achieved by manual

  9. Reduction of tumor angiogenesis induced by desmopressin in a breast cancer model.

    Science.gov (United States)

    Ripoll, Giselle V; Garona, Juan; Pifano, Marina; Farina, Hernan G; Gomez, Daniel E; Alonso, Daniel F

    2013-11-01

    Desmopressin (DDAVP), a synthetic peptide analog of vasopressin, is a safe antidiuretic and hemostatic compound that acts as a selective agonist for the vasopressin V2 membrane receptor. It is known that DDAVP can inhibit progression of residual metastatic cells and also improves chemotherapy effects in preclinical breast cancer models. Here, we explored the effects of DDAVP on tumor angiogenesis using the aggressive F3II mammary carcinoma in syngeneic Balb/c mice. Intravenous administration of the compound (2 μg/kg) markedly decreased vascularization of growing subcutaneous tumors, as well as inhibited the early angiogenic response around intradermal inoculation sites. In vitro studies confirmed the presence of vasopressin V2 receptors on F3II cells and a modest antiproliferative activity of DDAVP. Interestingly, conditioned media from F3II monolayers exposed to low doses of DDAVP (100 nM) significantly increased angiostatin formation in the presence of purified plasminogen. Such increase was associated with an enhancement of tumor-secreted urokinase-type plasminogen activator, suggesting the proteolytic conversion of plasminogen to angiostatin in vitro. Similar results were observed with the MCF-7 human breast carcinoma, a cell line known to express the vasopressin V2 receptor. No direct effects of DDAVP (100 nM–1 μM) were found on capillary-like tube formation by human microvascular cells HMVEC. Our studies showed that DDAVP induces anti-angiogenic effects that may be associated with the generation of angiostatin by tumor cells. Further preclinical studies with DDAVP and other vasopressin analogs are warranted to determine their potential in cancer management.

  10. Obesity and overfeeding affecting both tumor and systemic metabolism activates the progesterone receptor to contribute to postmenopausal breast cancer

    Science.gov (United States)

    Giles, Erin D.; Wellberg, Elizabeth A.; Astling, David P.; Anderson, Steven M.; Thor, Ann D.; Jindal, Sonali; Tan, Aik-Choon; Schedin, Pepper S.; MacLean, Paul S.

    2014-01-01

    Obese postmenopausal women have increased risk of breast cancers with poorer clinical outcomes than their lean counterparts. However, the mechanisms underlying these associations are poorly understood. Rodent model studies have recently identified a period of vulnerability for mammary cancer promotion, which emerges during weight gain after the loss of ovarian function (surgical ovariectomy; OVX). Thus, a period of transient weight-gain may provide a lifecycle-specific opportunity to prevent or treat postmenopausal breast cancer. We hypothesized that a combination of impaired metabolic regulation in obese animals prior to OVX plus an OVX-induced positive energy imbalance might cooperate to drive tumor growth and progression. To determine if lean and obese rodents differ in their metabolic response to OVX-induced weight gain, and whether this difference affects later mammary tumor metabolism, we performed a nutrient tracer study during the menopausal window of vulnerability. Lean animals preferentially deposited excess nutrients to mammary and peripheral tissues rather than to the adjacent tumors. Conversely, obese animals deposited excess nutrients into the tumors themselves. Notably, tumors from obese animals also displayed increased expression of the progesterone receptor (PR). Elevated PR expression positively correlated with tumor expression of glycolytic and lipogenic enzymes, glucose uptake and proliferation markers. Treatment with the anti-diabetic drug metformin during ovariectomy-induced weight gain caused tumor regression and downregulation of PR expression in tumors. Clinically, expression array analysis of breast tumors from postmenopausal women revealed that PR expression correlated with a similar pattern of metabolic upregulation, supporting the notion that PR+ tumors have enhanced metabolic capacity after menopause. Our findings have potential explanative power in understanding why obese, postmenopausal women display an increased risk of breast

  11. Obesity and overfeeding affecting both tumor and systemic metabolism activates the progesterone receptor to contribute to postmenopausal breast cancer.

    Science.gov (United States)

    Giles, Erin D; Wellberg, Elizabeth A; Astling, David P; Anderson, Steven M; Thor, Ann D; Jindal, Sonali; Tan, Aik-Choon; Schedin, Pepper S; Maclean, Paul S

    2012-12-15

    Obese postmenopausal women have increased risk of breast cancers with poorer clinical outcomes than their lean counterparts. However, the mechanisms underlying these associations are poorly understood. Rodent model studies have recently identified a period of vulnerability for mammary cancer promotion, which emerges during weight gain after the loss of ovarian function (surgical ovariectomy; OVX). Thus, a period of transient weight gain may provide a life cycle-specific opportunity to prevent or treat postmenopausal breast cancer. We hypothesized that a combination of impaired metabolic regulation in obese animals prior to OVX plus an OVX-induced positive energy imbalance might cooperate to drive tumor growth and progression. To determine if lean and obese rodents differ in their metabolic response to OVX-induced weight gain, and whether this difference affects later mammary tumor metabolism, we performed a nutrient tracer study during the menopausal window of vulnerability. Lean animals preferentially deposited excess nutrients to mammary and peripheral tissues rather than to the adjacent tumors. Conversely, obese animals deposited excess nutrients into the tumors themselves. Notably, tumors from obese animals also displayed increased expression of the progesterone receptor (PR). Elevated PR expression positively correlated with tumor expression of glycolytic and lipogenic enzymes, glucose uptake, and proliferation markers. Treatment with the antidiabetic drug metformin during ovariectomy-induced weight gain caused tumor regression and downregulation of PR expression in tumors. Clinically, expression array analysis of breast tumors from postmenopausal women revealed that PR expression correlated with a similar pattern of metabolic upregulation, supporting the notion that PR+ tumors have enhanced metabolic capacity after menopause. Our findings have potential explanative power in understanding why obese, postmenopausal women display an increased risk of breast

  12. Star-PAP, a poly(A) polymerase, functions as a tumor suppressor in an orthotopic human breast cancer model.

    Science.gov (United States)

    Yu, C; Gong, Y; Zhou, H; Wang, M; Kong, L; Liu, J; An, T; Zhu, H; Li, Y

    2017-02-02

    Star-PAP is a noncanonical poly(A) polymerase and required for the expression of a select set of mRNAs. However, the pathological role of Star-PAP in cancer largely remains unknown. In this study, we observed decreased expression of Star-PAP in breast cancer cell lines and tissues. Ectopic Star-PAP expression inhibited proliferation as well as colony-forming ability of breast cancer cells. In breast cancer patients, high levels of Star-PAP correlated with an improved prognosis. Moreover, by regulating the expression of BIK (BCL2-interacting killer), Star-PAP induced apoptosis of breast cancer cells through the mitochondrial pathway. The growth of breast cancer xenografts in NOD/SCID mice was also inhibited by the doxycycline-induced Star-PAP overexpression. Furthermore, Star-PAP sensitized breast cancer cells to chemotherapy drugs both in vitro and in vivo. In mammary epithelial cells, Star-PAP knockdown partially transformed these cells and induced them to undergo epithelial-mesenchymal transition (EMT). These findings suggested that Star-PAP possesses tumor-suppressing activity and can be a valuable target for developing new cancer therapeutic strategies.

  13. Breast Cancer: Treatment Options

    Science.gov (United States)

    ... Breast Cancer > Breast Cancer: Treatment Options Request Permissions Breast Cancer: Treatment Options Approved by the Cancer.Net Editorial ... as possible. Learn more about palliative care . Recurrent breast cancer If the cancer does return after treatment for ...

  14. Compartment-specific activation of PPARγ governs breast cancer tumor growth, via metabolic reprogramming and symbiosis.

    Science.gov (United States)

    Avena, Paola; Anselmo, Wanda; Whitaker-Menezes, Diana; Wang, Chenguang; Pestell, Richard G; Lamb, Rebecca S; Hulit, James; Casaburi, Ivan; Andò, Sebastiano; Martinez-Outschoorn, Ubaldo E; Lisanti, Michael P; Sotgia, Federica

    2013-05-01

    The role of PPARγ in cancer therapy is controversial, with studies showing either pro-tumorigenic or antineoplastic effects. This debate is very clinically relevant, because PPARγ agonists are used as antidiabetic drugs. Here, we evaluated if the effects of PPARγ on tumorigenesis are determined by the cell type in which PPARγ is activated. Second, we examined if the metabolic changes induced by PPARγ, such as glycolysis and autophagy, play any role in the tumorigenic process. To this end, PPARγ was overexpressed in breast cancer cells or in stromal cells. PPARγ-overexpressing cells were examined with respect to (1) their tumorigenic potential, using xenograft models, and (2) regarding their metabolic features. In xenograft models, we show that when PPARγ is activated in cancer cells, tumor growth is inhibited by 40%. However, when PPARγ is activated in stromal cells, the growth of co-injected breast cancer cells is enhanced by 60%. Thus, the effect(s) of PPARγ on tumorigenesis are dependent on the cell compartment in which PPARγ is activated. Mechanistically, stromal cells with activated PPARγ display metabolic features of cancer-associated fibroblasts, with increased autophagy, glycolysis and senescence. Indeed, fibroblasts overexpressing PPARγ show increased expression of autophagic markers, increased numbers of acidic autophagic vacuoles, increased production of L-lactate, cell hypertrophy and mitochondrial dysfunction. In addition, PPARγ fibroblasts show increased expression of CDKs (p16/p21) and β-galactosidase, which are markers of cell cycle arrest and senescence. Finally, PPARγ induces the activation of the two major transcription factors that promote autophagy and glycolysis, i.e., HIF-1α and NFκB, in stromal cells. Thus, PPARγ activation in stromal cells results in the formation of a catabolic pro-inflammatory microenvironment that metabolically supports cancer growth. Interestingly, the tumor inhibition observed when PPARγ is

  15. Antitumor activity of zoledronic acid in primary breast cancer cells determined by the ATP tumor chemosensitivity assay

    Directory of Open Access Journals (Sweden)

    Fehm Tanja

    2012-07-01

    Full Text Available Abstract Background The NeoAzure study has demonstrated that the use of the bisphosphonate zoledronic acid (Zol in the neoadjuvant setting increases the rate of complete response in primary breast cancer and therefore indicates direct antitumor activity. The purpose of this study was to compare the antitumor effect of Zol with standard chemotherapy in primary breast cancer cells using ATP-tumor chemosensitivity assay (ATP-TCA. Methods Breast cancer specimens were obtained from patients with breast cancer who underwent primary breast cancer surgery at the Department of Obstetrics and Gynecology, Tübingen, Germany, between 2006 through 2009. Antitumor effects of Zol, TAC (Docetaxel, Adriamycin, Cyclophosphamide and FEC (5-Fluorouracil, Epirubicin, Cyclophosphamide were tested in 116 fresh human primary breast cancer specimens using ATP-TCA. ATP-TCA results were analyzed with different cut-off levels for the half maximal inhibitory concentration (IC50, for IC90 and for the sensitivity index (IndexSUM. Each single agent or combination was tested at six doubling dilutions from 6.25, 12.5, 25, 50, 100, and 200% of test drug concentrations (TDC derived from the plasma peak concentrations determined by pharmacokinetic data. The assay was carried out in duplicate wells with positive and negative controls. Results The median IndexSUM value was lower for Zol than for the combined regimen FEC (36.8% and TAC (12.9%, respectively, indicating increased antitumor activity of Zol in primary breast cancer cells. The difference regarding Zol and FEC was significant (p  Conclusion Zoledronic acid has a strong antitumor effect on primary breast cancer cells in vitro which is equal or superior to commonly used chemotherapeutic regimens for treating breast cancer.

  16. Expression of ARs in triple negative breast cancer tumors: a potential prognostic factor?

    Directory of Open Access Journals (Sweden)

    Giannos A

    2015-07-01

    Full Text Available Aris Giannos,1 Martin Filipits,2 Flora Zagouri,2,3 Anita Brandstetter,2 Alexandra Tsigginou,1 Maria Sotiropoulou,4 Irene Papaspyrou,4 Theodoros N Sergentanis,5 Theodora Psaltopoulou,5 Alexandros Rodolakis,1 Aris Antsaklis,1 Meletios-Athanasios Dimopoulos,2 Constantine Dimitrakakis1 1Department of Obstetrics and Gynaecology, Alexandra General Hospital, Medical School, University of Athens, Athens, Greece; 2Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; 3Department of Clinical Therapeutics, Alexandra General Hospital, Medical School, University of Athens, Athens, Greece; 4Department of Pathology, Alexandra General Hospital, Athens, Greece; 5Department of Hygiene, Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece Background/aim: In light of the controversial published literature, this study aims to examine the potential prognostic role of AR immunohistochemical expression in triple negative breast cancer (TNBC.Patients and methods: Ninety patients with TNBC were included in this study; the associations between AR expression (Allred score, clinicopathological variables (stage, grade, histological subtype, tumor size, nodal status, age at diagnosis, Ki67 expression, and p53 expression, and overall survival were evaluated.Results: AR expression was not associated with stage, grade, histological subtype, tumor size, nodal status, age at diagnosis, Ki67 expression, and p53 expression. AR immunopositivity was not associated with overall survival either at the univariate or at the multivariate Cox regression analysis (multivariate hazard ratio =0.66, 95% confidence interval: 0.26–1.70, P=0.393.Conclusion: AR expression does not seem to play a prognostic role in TNBC. Keywords: biomarkers, prognosis, AR, triple negative breast cancer

  17. Prognostic value of hematogenous dissemination and biological profile of the tumor in early breast cancer patients: A prospective observational study

    OpenAIRE

    Gubern Josep M; Mariscal Antonio; Rull Miquel; Julian Juan F; Castellá Eva; Margelí Mireia; Solá Montserrat; Barnadas Agustí; Fraile Manuel

    2011-01-01

    Abstract Background The aim of this study was to investigate the incidence and prognostic value of disseminated tumor cells in bone marrow of breast carcinoma patients with early disease, and to analyze this finding in relation to lymph node involvement, determined by sentinel lymph node (SLN) biopsy analysis, and to prognostic factors of interest. Methods 104 patients with operable (T < 3 cm) breast cancer and clinically- and sonographically-negative axillary lymph nodes were scheduled for S...

  18. Circulating Tumor Cells in Metastatic Breast Cancer: A Prognostic and Predictive Marker

    Directory of Open Access Journals (Sweden)

    Sayyed Farshid Moussavi-Harami

    2014-05-01

    Full Text Available The role of circulating tumor cells (CTCs as a marker for disease progression in metastatic cancer is controversial. The current review will serve to summarize the evidence on CTCs as a marker of disease progression in patients with metastatic breast cancer. The immunohistochemistry (IHC-based CellSearch® is the only FDA-approved isolation technique for quantifying CTCs in patients with metastatic breast cancer. We searched PubMed and Web of Knowledge for clinical studies that assessed the prognostic and predictive value of CTCs using IHC-based isolation. The patient outcomes reported include median and Cox-proportional hazard ratios for overall survival (OS and progression-free survival (PFS. All studies reported shorter OS for CTC-positive patients versus CTC-negative. A subset of the selected trials reported significant lower median PFS for CTC-positive patients. The reported trials support the utility of CTC enumeration for patient prognosis. But further studies are required to determine the utility of CTC enumeration for guiding patient therapy. There are three clinical trials ongoing to test this hypothesis. These studies, and others, will further establish the role of CTCs in clinical practice.

  19. Breast Cancer Treatment

    Science.gov (United States)

    ... of Breast & Gynecologic Cancers Breast Cancer Screening Research Breast Cancer Treatment (PDQ®)–Patient Version General Information About Breast Cancer Go to Health Professional Version Key Points Breast ...

  20. Stages of Breast Cancer

    Science.gov (United States)

    ... of Breast & Gynecologic Cancers Breast Cancer Screening Research Breast Cancer Treatment (PDQ®)–Patient Version General Information About Breast Cancer Go to Health Professional Version Key Points Breast ...

  1. Breast cancer screening

    Science.gov (United States)

    Mammogram - breast cancer screening; Breast exam - breast cancer screening; MRI - breast cancer screening ... is performed to screen women to detect early breast cancer when it is more likely to be cured. ...

  2. Signaling Components of the Anti-Tumor Hormone Somatostatin in Breast Cancer Cells

    National Research Council Canada - National Science Library

    Tentler, John

    1999-01-01

    .... Experimentally and clinically, somatostatin can inhibit breast cancer cell growth, possibly by inhibiting the secretion of growth factors, or by acting directly on the cells themselves to induce...

  3. Signaling Components of the Anti-Tumor Hormone Somatostatin in Breast Cancer Cells

    National Research Council Canada - National Science Library

    Tentler, John

    2000-01-01

    .... Experimentally and clinically, somatostatin can inhibit breast cancer cell growth, possibly by inhibiting the secretion of growth factors, or by acting directly on the cells themselves to induce...

  4. Impact of Marital Status on Tumor Stage at Diagnosis and on Survival in Male Breast Cancer.

    Science.gov (United States)

    Adekolujo, Orimisan Samuel; Tadisina, Shourya; Koduru, Ujwala; Gernand, Jill; Smith, Susan Jane; Kakarala, Radhika Ramani

    2017-07-01

    The effect of marital status (MS) on survival varies according to cancer type and gender. There has been no report on the impact of MS on survival in male breast cancer (MBC). This study aims to determine the influence of MS on tumor stage at diagnosis and survival in MBC. Men with MBC ≥18 years of age in the SEER database from 1990 to 2011 were included in the study. MS was classified as married and unmarried (including single, divorced, separated, widowed). Kaplan-Meier method was used to estimate the 5-year cancer-specific survival. Multivariate regression analyses were done to determine the effect of MS on presence of Stage IV disease at diagnosis and on cancer-specific mortality. The study included 3,761 men; 2,647 (70.4%) were married. Unmarried men were more often diagnosed with Stage IV MBC compared with married (10.7% vs. 5.5%, p < .001). Unmarried men (compared with married) were significantly less likely to undergo surgery (92.4% vs. 96.7%, p < .001). Overall unmarried males with Stages II, III, and IV MBC have significantly worse 5-year cancer-specific survival compared with married. On multivariate analysis, being unmarried was associated with increased hazard of death (HR = 1.43, p < .001) and increased likelihood of Stage IV disease at diagnosis ( OR = 1.96, p < .001). Unmarried males with breast cancer are at greater risk for Stage IV disease at diagnosis and poorer outcomes compared with married males.

  5. Molecular detection of peripheral blood breast cancer mRNA transcripts as a surrogate biomarker for circulating tumor cells.

    Directory of Open Access Journals (Sweden)

    Adriana Lasa

    Full Text Available Circulating tumor cells (CTCs are becoming a scientifically recognized indicator of primary tumors and/or metastasis. These cells can now be accurately detected and characterized as the result of technological advances. We analyzed the presence of CTCs in the peripheral blood of patients with metastatic breast cancer by real-time reverse-transcription PCR (RT-qPCR using a panel of selected genes. The analysis of a single marker, without an EpCAM based enrichment approach, allowed the positive identification of 35% of the metastatic breast cancer patients. The analysis of five genes (SCGB2, TFF1, TFF3, Muc1, KRT20 performed in all the samples increased the detection to 61%. We describe a sensitive, reproducible and easy to implement approach to characterize CTC in patients with metastasic breast cancer.

  6. Molecular detection of peripheral blood breast cancer mRNA transcripts as a surrogate biomarker for circulating tumor cells.

    Science.gov (United States)

    Lasa, Adriana; Garcia, Arnal; Alonso, Carmen; Millet, Pilar; Cornet, Mónica; Ramón y Cajal, Teresa; Baiget, Montserrat; Barnadas, Agusti

    2013-01-01

    Circulating tumor cells (CTCs) are becoming a scientifically recognized indicator of primary tumors and/or metastasis. These cells can now be accurately detected and characterized as the result of technological advances. We analyzed the presence of CTCs in the peripheral blood of patients with metastatic breast cancer by real-time reverse-transcription PCR (RT-qPCR) using a panel of selected genes. The analysis of a single marker, without an EpCAM based enrichment approach, allowed the positive identification of 35% of the metastatic breast cancer patients. The analysis of five genes (SCGB2, TFF1, TFF3, Muc1, KRT20) performed in all the samples increased the detection to 61%. We describe a sensitive, reproducible and easy to implement approach to characterize CTC in patients with metastasic breast cancer.

  7. Diffusion-weighted imaging in assessing pathological response of tumor in breast cancer subtype to neoadjuvant chemotherapy.

    Science.gov (United States)

    Liu, Shangang; Ren, Ruimei; Chen, Zhaoqiu; Wang, Yongsheng; Fan, Tingyong; Li, Chengli; Zhang, Pinliang

    2015-09-01

    To investigate the efficacy of diffusion-weighted imaging (DWI) for reflecting and predicting pathological tumor response in breast cancer subtype to neoadjuvant chemotherapy (NAC). The retrospective study included 176 patients with breast cancer who underwent magnetic resonance imaging (MRI) examinations before and after NAC prior to surgery. The pre- and post-NAC apparent diffusion coefficient (ADC) values of tumor were measured respectively on DWI. The pathological response was classified into either a complete response (pCR) or as a noncomplete response (pNCR) to NAC with the Miller & Payne system. The relationship between the ADC value and the pathological response was assessed according to intrinsic subtypes (Luminal A, Luminal B, HER2-enriched, and triple negative) defined by immunohistochemical features. Multiple comparisons respectively showed that pre-NAC and post-NAC ADC were significantly different among four subtypes (P breast cancer subtypes. © 2015 Wiley Periodicals, Inc.

  8. Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility.

    Science.gov (United States)

    Yu, Min; Bardia, Aditya; Aceto, Nicola; Bersani, Francesca; Madden, Marissa W; Donaldson, Maria C; Desai, Rushil; Zhu, Huili; Comaills, Valentine; Zheng, Zongli; Wittner, Ben S; Stojanov, Petar; Brachtel, Elena; Sgroi, Dennis; Kapur, Ravi; Shioda, Toshihiro; Ting, David T; Ramaswamy, Sridhar; Getz, Gad; Iafrate, A John; Benes, Cyril; Toner, Mehmet; Maheswaran, Shyamala; Haber, Daniel A

    2014-07-11

    Circulating tumor cells (CTCs) are present at low concentrations in the peripheral blood of patients with solid tumors. It has been proposed that the isolation, ex vivo culture, and characterization of CTCs may provide an opportunity to noninvasively monitor the changing patterns of drug susceptibility in individual patients as their tumors acquire new mutations. In a proof-of-concept study, we established CTC cultures from six patients with estrogen receptor-positive breast cancer. Three of five CTC lines tested were tumorigenic in mice. Genome sequencing of the CTC lines revealed preexisting mutations in the PIK3CA gene and newly acquired mutations in the estrogen receptor gene (ESR1), PIK3CA gene, and fibroblast growth factor receptor gene (FGFR2), among others. Drug sensitivity testing of CTC lines with multiple mutations revealed potential new therapeutic targets. With optimization of CTC culture conditions, this strategy may help identify the best therapies for individual cancer patients over the course of their disease. Copyright © 2014, American Association for the Advancement of Science.

  9. MDA-7/IL-24 functions as a tumor suppressor gene in vivo in transgenic mouse models of breast cancer.

    Science.gov (United States)

    Menezes, Mitchell E; Shen, Xue-Ning; Das, Swadesh K; Emdad, Luni; Guo, Chunqing; Yuan, Fang; Li, You-Jun; Archer, Michael C; Zacksenhaus, Eldad; Windle, Jolene J; Subler, Mark A; Ben-David, Yaacov; Sarkar, Devanand; Wang, Xiang-Yang; Fisher, Paul B

    2015-11-10

    Melanoma differentiation associated gene-7/Interleukin-24 (MDA-7/IL-24) is a novel member of the IL-10 gene family that selectively induces apoptosis and toxic autophagy in a broad spectrum of human cancers, including breast cancer, without harming normal cells or tissues. The ability to investigate the critical events underlying cancer initiation and progression, as well as the capacity to test the efficacy of novel therapeutics, has been significantly advanced by the development of genetically engineered mice (GEMs) that accurately recapitulate specific human cancers. We utilized three transgenic mouse models to better comprehend the in vivo role of MDA-7/IL-24 in breast cancer. Using the MMTV-PyMT spontaneous mammary tumor model, we confirmed that exogenously introducing MDA-7/IL-24 using a Cancer Terminator Virus caused a reduction in tumor burden and also produced an antitumor "bystander" effect. Next we performed xenograft studies in a newly created MMTV-MDA-7 transgenic model that over-expresses MDA-7/IL-24 in the mammary glands during pregnancy and lactation, and found that MDA-7/IL-24 overexpression delayed tumor growth following orthotopic injection of a murine PDX tumor cell line (mPDX) derived from a tumor formed in an MMTV-PyMT mouse. We also crossed the MMTV-MDA-7 line to MMTV-Erbb2 transgenic mice and found that MDA-7/IL-24 overexpression delayed the onset of mammary tumor development in this model of spontaneous mammary tumorigenesis as well. Finally, we assessed the role of MDA-7/IL-24 in immune regulation, which can potentially contribute to tumor suppression in vivo. Our findings provide further direct in vivo evidence for the role of MDA-7/IL-24 in tumor suppression in breast cancer in immune-competent transgenic mice.

  10. Macroscopic stiffness of breast tumors predicts metastasis.

    Science.gov (United States)

    Fenner, Joseph; Stacer, Amanda C; Winterroth, Frank; Johnson, Timothy D; Luker, Kathryn E; Luker, Gary D

    2014-07-01

    Mechanical properties of tumors differ substantially from normal cells and tissues. Changes in stiffness or elasticity regulate pro-metastatic behaviors of cancer cells, but effects have been documented predominantly in isolated cells or in vitro cell culture systems. To directly link relative stiffness of tumors to cancer progression, we combined a mouse model of metastatic breast cancer with ex vivo measurements of bulk moduli of freshly excised, intact tumors. We found a high, inverse correlation between bulk modulus of resected tumors and subsequent local recurrence and metastasis. More compliant tumors were associated with more frequent, larger local recurrences and more extensive metastases than mice with relatively stiff tumors. We found that collagen content of resected tumors correlated with bulk modulus values. These data establish that relative differences in tumor stiffness correspond with tumor progression and metastasis, supporting further testing and development of tumor compliance as a prognostic biomarker in breast cancer.

  11. Metastases of transverse colon cancer to bilateral ovaries (Krukenberg tumor) and the left breast: A case report.

    Science.gov (United States)

    Luo, Xin-Yu; Wang, Jue; Zhao, Jia; Chen, Rui; Zha, Xiao-Ming

    2017-07-01

    Breast cancer has the highest rate of incidence among all types of cancer in women. Only ~0.43% of breast malignancies occur as a result of metastatic lesions from extramammary tumors. The present study reports an extremely rare case of transverse colon cancer metastasizing to the bilateral ovaries and the left breast. The patient was a 47-year old female, who had a lump in the left breast without axillary lymphadenopathy. Specimens obtained by core needle biopsy were submitted for hematoxylin and eosin examination, and results revealed that the lump was a poorly differentiated adenocarcinoma. Since the patient had elevated levels of the carcinoembryonic antigen and a medical history of a Krukenberg tumor metastasized from colon cancer, immunohistochemical examinations were applied. Results identified that caudal-related homeobox protein 2 and cytokeratin 20 were positively stained, whilst cytokeratin 7 was negatively stained. Therefore, this patient was diagnosed as having colon cancer that had metastasized to the bilateral ovaries and the left breast. As the life expectancy of patients with cancer is increasing, types of metastases that used to be seen as rare are increasingly becoming more common. For clinicians, diagnosis should be cautious, and differential diagnosis should always be kept in mind.

  12. Profiling of microRNAs in tumor interstitial fluid of breast tumors - a novel resource to identify biomarkers for prognostic classification and detection of cancer.

    Science.gov (United States)

    Halvorsen, Ann Rita; Helland, Åslaug; Gromov, Pavel; Wielenga, Vera Timmermans; Talman, Maj-Lis Møller; Brunner, Nils; Sandhu, Vandana; Børresen-Dale, Anne-Lise; Gromova, Irina; Haakensen, Vilde D

    2017-02-01

    It has been hypothesized based on accumulated data that a class of small noncoding RNAs, termed microRNAs, are key factors in intercellular communication. Here, microRNAs present in interstitial breast tumor fluids have been analyzed to identify relevant markers for a diagnosis of breast cancer and to elucidate the cross-talk that exists among cells in a tumor microenvironment. Matched tumor interstitial fluid samples (TIF, n = 60), normal interstitial fluid samples (NIF, n = 51), corresponding tumor tissue specimens (n = 54), and serum samples (n = 27) were collected from patients with breast cancer, and detectable microRNAs were analyzed and compared. In addition, serum data from 32 patients with breast cancer and 22 healthy controls were obtained for a validation study. To identify potential serum biomarkers of breast cancer, first the microRNA profiles of TIF and NIF samples were compared. A total of 266 microRNAs were present at higher level in the TIF samples as compared to normal counterparts. Sixty-one of these microRNAs were present in > 75% of the serum samples and were subsequently tested in a validation set. Seven of the 61 microRNAs were associated with poor survival, while 23 were associated with the presence of immune cells and adipocytes. To our knowledge, these data demonstrate for the first time that profiling of microRNAs in TIF can identify novel biomarkers for the prognostic classification and detection of breast cancer. In addition, the present findings demonstrate that microRNAs may represent the cross-talk that occurs between tumor cells and their surrounding stroma. © 2016 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

  13. Study into the displacement of tumor localization needle during navigated breast cancer surgery

    Science.gov (United States)

    Yan, Christina; Ungi, Tamas; Gauvin, Gabrielle; Jabs, Doris; Lasso, Andras; Engel, Jay; Rudan, John; Fichtinger, Gabor

    2017-03-01

    PURPOSE: Early stage breast cancer is typically treated with lumpectomy. During lumpectomy, electromagnetic tracking can be used to monitor tumor position using a localization needle with an electromagnetic sensor fixed on the needle shaft. This needle is stabilized in the tumor with tissue locking wire hooks, which are deployed once the needle is inserted. The localization needle may displace from its initial position of insertion due to mechanical forces, providing false spatial information about the tumor position and increasing the probability of an incomplete resection. This study investigates whether gravitational and mechanical forces affected the magnitude of needle displacement. METHODS: Ten ultrasound scans were evaluated to measure needle displacement in vivo. Needle position was approximated by the distance between the needle tip and the tumor boundary on a 2D ultrasound image, and needle displacement was defined by the change in position. The angle between the localization needle and the coronal plane was computed in an open-source platform. RESULTS: A significant relationship (p = 0.04) was found between the needle to coronal plane angle and increased needle displacement. Needles inserted vertically, pointing towards the operating room ceiling, tended to exhibit greater needle displacement. Average needle displacement was 1.7 +/-1.2 mm. CONCLUSION: Angle between the needle and the horizontal plane has been shown to affect needle displacement, and should be taken into consideration when inserting the localization needle. Future works can be directed towards improving the clinical workflow and mechanical design of the localization needle to reduce slippage during surgery.

  14. Raloxifene reduces triple-negative breast cancer tumor growth and decreases EGFR expression.

    Science.gov (United States)

    Taurin, Sebastien; Allen, Kirstie M; Scandlyn, Marissa J; Rosengren, Rhonda J

    2013-09-01

    The poor prognosis of patients with triple-negative breast cancer (TNBC) and the lack of targeted treatments have raised the need for alternative therapies. Previous studies have suggested an effect of raloxifene, a selective estrogen receptor modulator that is independent of the estrogen receptor (ER). Therefore, we assessed the therapeutic value of raloxifene in TNBC mouse models. Mice received a daily oral treatment with different doses of raloxifene. Tumor progression was monitored weekly; in addition microvessel density, proliferation, migration and invasion, apoptosis and tumorigenicity were analyzed. This study demonstrates that raloxifene (0.85 mg/kg) prevents TNBC tumor growth and induces tumor regression. The treated tumors showed a 54% decreased microvascular density and proliferation and a 7-fold increase in apoptosis. The underlying therapeutic mechanism of raloxifene was associated with a 27-fold decrease in the expression of the epidermal growth factor receptor (EGFR). Moreover, raloxifene promoted the translocation of EGFR into endosomes associated with decreased cell migration, cell invasion and tumorigenicity in vitro. Together, these data showed that raloxifene acts independently of the ER and may be relevant for the treatment as well as control the progression of TNBC.

  15. Tumor characteristics and family history in relation to mammographic density and breast cancer: The French E3N cohort.

    Science.gov (United States)

    Maskarinec, Gertraud; Dartois, Laureen; Delaloge, Suzette; Hopper, John; Clavel-Chapelon, Françoise; Baglietto, Laura

    2017-08-01

    Mammographic density is a known heritable risk factor for breast cancer, but reports how tumor characteristics and family history may modify this association are inconsistent. Dense and total breast areas were assessed using Cumulus™ from pre-diagnostic mammograms for 820 invasive breast cancer cases and 820 matched controls nested within the French E3N cohort study. To allow comparisons across models, percent mammographic density (PMD) was standardized to the distribution of the controls. Odds ratios (OR) and 95% confidence intervals (CI) of breast cancer risk for mammographic density were estimated by conditional logistic regression while adjusting for age and body mass index. Heterogeneity according to tumor characteristic and family history was assessed using stratified analyses. Overall, the OR per 1 SD for PMD was 1.50 (95% CI, 1.33-1.69). No evidence for significant heterogeneity by tumor size, lymph node status, grade, and hormone receptor status (estrogen, progesterone, and HER2) was detected. However, the association of PMD was stronger for women reporting a family history of breast cancer (OR 1SD =2.25; 95% CI, 1.67-3.04) than in women reporting none (OR 1SD =1.41; 95% CI, 1.24-1.60; p heterogeneity =0.002). Similarly, effect modification by FHBC was observed using categories of PMD (p heterogeneity =0.02) with respective ORs of 15.16 (95% CI, 4.23-54.28) vs. 3.14 (95% CI, 1.89-5.22) for ≥50% vs. breast cancer risk with a family history supports the hypothesis of shared genetic factors responsible for familial aggregation of breast cancer and the heritable component of mammographic density. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Immunotherapeutic Approach to Breast Cancer: The Anti-Tumor Effect of Anti-IL-6 Monoclonal Antibodies in Malignant Mammary Tumor Implanted-Mice.

    Science.gov (United States)

    Abou-Shousha, Seham A; Abdel-Mawla, Ashour Abdel-Mawla A S; Hassan, Safia M

    2016-01-01

    It has been established that suppression of apoptosis during carcinogenesis is the main cause of development and progression of breast cancer. Breast cancer patients have higher circulating levels of IL-6 protecting cancer cells from apoptosis and positively correlated with poor prognosis of the disease. The current work is carried out to fulfill one of our in vivo preclinical studies' for approaching a novel breast cancer immunotherapy through induction of tumor cell apoptosis. The study aims at investigating the potential of anti-IL-6 monoclonal antibodies (mAbs) to suppress IL-6 anti-apoptotic activities in tumor microenvironment of malignant mammary tumor implanted-mice. To achieve this goal, 4 groups of mice were used, group I: served as control, group II: mice implanted with Ehrlich ascites carcinoma cell lines (EAC), through intramuscular injection till tumor inoculation, group III: injected intratumorally with10 µl saline for 3 successive days, and group IV: mice were injected intratumorally one day after tumor inoculation with a dose of 1.5 mg / kg of recombinent anti-IL-6 monoclonal antibodies in10 µl saline for 3 successive days. Apoptosis was evaluated in tumor samples from anti-IL-6 treated tumor implanted mice and compared with controls. Levels of apoptosis in tumor tissue samples of tumor implanted mice treated with anti-IL-6 were significantly (P=0.009) higher than untreated ones. In conclusion, anti-IL-6 monoclonal antibodies have the potential to suppress the anti-apoptotic effect of interleukin-6 (IL-6) within the tumor microenvironment of tumor implanted in mice. Copyright© by the Egyptian Association of Immunologists.

  17. Performance analysis of a dedicated breast MR-HIFU system for tumor ablation in breast cancer patients

    NARCIS (Netherlands)

    Deckers, R.; Merckel, L. G.; de Senneville, B. Denis; Schubert, G.; Koehler, M.; Knuttel, F.M.; Mali, W.P.Th.M.; Moonen, C. T. W.; van den Bosch, Maurice; Bartels, L. W.

    2015-01-01

    MR-guided HIFU ablation is a promising technique for the non-invasive treatment of breast cancer. A phase I study was performed to assess the safety and treatment accuracy and precision of MR-HIFU ablation in breast cancer patients (n = 10) using a newly developed MR-HIFU platform dedicated to

  18. The Role of Tumor Metastases Suppressor Gene, Drg-1, in Breast Cancer

    Science.gov (United States)

    2008-03-01

    catenin. Nuclear staining beta-catenin 36 72 Breast Carcinoma Phyllodes tumor 73 74 75 Reduced...AD_________________ Award Number: W81XWH-05-1-0309 TITLE: The Role of Tumor Metastases Suppressor...TYPE Annual 3. DATES COVERED (From - To) 1 MAR 2007 - 29 FEB 2008 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER The Role of Tumor Metastases

  19. Comprehensive prognostic analysis in breast cancer integrating clinical, tumoral, micro-environmental and immunohistochemical criteria.

    Science.gov (United States)

    de Mascarel, Isabelle; Debled, Marc; Brouste, Véronique; Mauriac, Louis; Sierankowski, Ghislaine; Velasco, Valérie; Croce, Sabrina; Chibon, Frédéric; Boudeau, Jêrome; Debant, Anne; MacGrogan, Gaëtan

    2015-01-01

    Significant morphological, clinical and biological prognostic factors vary according to molecular subtypes of breast tumors, yet comprehensive analysis of such factors linked to survival in each group is lacking. Clinicopathological and micro-environmental criteria, estrogen (ER), progesterone (PR) receptors, HER2, Ki67, basal markers, CD24, CD44, ALDH1, BCL2, E-Cadherin and Trio were assessed in 1070 primary operable breast cancers from a single center according to five main molecular subtypes and associations with distant metastasis-free survival (DMFS) were examined. There were 682 (64 %) luminal A (LA), 166 (16 %) Luminal B HER2 negative (LBH-), 47 (4 %) Luminal B HER2 positive (LBH+), 108 (10 %) triple negative (TN) and 67 (6 %) HER2-enriched tumors (H2+). Median follow-up was 13.7 years. At 5 years, DMFS in LA (90 %) was better than in LBH- (80.9 %), hazard ratio (HR) = 2.22 [1.44-3.43] P < 0.001; LBH+ (74.5 %), HR = 3.14 [1.69-5.84] P < 0.001, TN (71.5 %) HR = 3.63 [2.34-5.63], P < 0.001; and H2+ (65.2 %), HR = 4.69 [2.90-7.59], P < 0.001. In multivariable analysis, factors associated with shorter DMFS varied according to molecular subtype, with tumor size being associated with shorter DMFS in the LBH-, LBH+ and TN groups and the Rho GEF Trio and BCL2 phenotypes in TN tumors only. These findings help to define new clinicophenotypic models and to identify new therapeutic strategies in the specific molecular subgroups.

  20. HER2 is not a cancer subtype but rather a pan-cancer event and is highly enriched in AR-driven breast tumors.

    Science.gov (United States)

    Daemen, Anneleen; Manning, Gerard

    2018-01-30

    Approximately one in five breast cancers are driven by amplification and overexpression of the human epidermal growth factor receptor 2 (HER2) receptor kinase, and HER2-enriched (HER2E) is one of four major transcriptional subtypes of breast cancer. We set out to understand the genomics of HER2 amplification independent of subtype, and the underlying drivers and biology of HER2E tumors. We investigated published genomic data from 3155 breast tumors and 5391 non-breast tumors. HER2 amplification is a distinct driver event seen in all breast cancer subtypes, rather than a subtype marker, with major characteristics restricted to amplification and overexpression of HER2 and neighboring genes. The HER2E subtype has a distinctive transcriptional landscape independent of HER2A that reflects androgen receptor signaling as replacement for estrogen receptor (ER)-driven tumorigenesis. HER2 amplification is also an event in 1.8% of non-breast tumors. These discoveries reveal therapeutic opportunities for combining anti-HER2 therapy with anti-androgen agents in breast cancer, and highlight the potential for broader therapeutic use of HER2 inhibitors.

  1. Tumor slice culture system to assess drug response of primary breast cancer

    NARCIS (Netherlands)

    A.T. Naipal (Kishan); N.S. Verkaik (Nicole); S.H. Sanchez (Humberto); C.H.M. van Deurzen (Carolien); M.A. den Bakker (Michael); J.H.J. Hoeijmakers (Jan); R. Kanaar (Roland); M.P. Vreeswijk (Maaike); A. Jager (Agnes); D.C. van Gent (Dik)

    2016-01-01

    textabstractBackground The high incidence of breast cancer has sparked the development of novel targeted and personalized therapies. Personalization of cancer treatment requires reliable prediction of chemotherapy responses in individual patients. Effective selection can prevent unnecessary

  2. Aberrant expression of novel and previously described cell membrane markers in human breast cancer cell lines and tumors.

    Science.gov (United States)

    Huang, Huayi; Groth, Jeff; Sossey-Alaoui, Khalid; Hawthorn, Lesleyann; Beall, Stephanie; Geradts, Joseph

    2005-06-15

    In a previous gene expression array study, we identified some 300 genes that were differentially expressed in human epidermal growth factor receptor tyrosine kinase 2 (HER2)-positive versus HER2-negative breast cancer cells. We have now done validation experiments on a group of three cell membrane components that had previously not been implicated in breast cancer. We also studied the expression of three other cell membrane proteins known to play a role in mammary neoplasia. By immunohistochemistry, we examined up to 130 archival breast carcinomas for Celsr2, E-cadherin, Kai1, and CD9 expression. The expression levels of NET-6 and TROP-2 were determined by quantitative reverse transcription-PCR in a subset of frozen tumors. We also studied fresh pellets and paraffin-embedded cell buttons of nine human breast cell lines. The relationship between the expression of all six membrane proteins and a variety of pathologic and biological variables, including estrogen receptor, HER2, and epidermal growth factor receptor status, was also examined. The NET-6 gene was transfected into a low-expressing cell line, and the effect on cellular morphology, growth, and invasion in vitro was recorded. Celsr2 was down-regulated in one cell line and in 7% of breast cancers. E-cadherin, Kai1, and CD9 were down-regulated in 35%, 76%, and 79% of tumors, respectively, confirming the important role of these markers in human mammary neoplasia. In breast cancer cell lines and tissues, TROP-2 was generally expressed at low levels, although a few specimens showed relative overexpression. NET-6 levels were lower in HER2-negative breast carcinoma cells. In addition, NET-6 was markedly down-regulated in estrogen receptor-negative breast cancers, and expression was lowest in "basal-like" tumors. Ectopic expression of NET-6 in low-expressing MDA-MB-231 cells altered cellular morphology, inhibited growth in vitro, and decreased invasion in a Boyden chamber assay. We have confirmed the expression of

  3. Improvement of protein immobilization for the elaboration of tumor-associated antigen microarrays: application to the sensitive and specific detection of tumor markers from breast cancer sera.

    Science.gov (United States)

    Yang, Zhugen; Chevolot, Yann; Géhin, Thomas; Solassol, Jérôme; Mange, Alain; Souteyrand, Eliane; Laurenceau, Emmanuelle

    2013-02-15

    There is an urgent need to identify relevant tumor markers showing high sensitivity and specificity for early diagnosis and prognosis of breast cancer. Protein microarrays have demonstrated to be cost-effective, high through-put and powerful tools for screening and identifying tumor markers with only minute samples. Autoantibodies directed against tumor-associated antigens (TAAs) were shown to be relevant tumor markers. However, due to the variability of immune response from one individual to another and depending on the type of cancer, detection of only one type of anti-TAA autoantibody is not sufficient to give a reliable and precise diagnosis. It is necessary to use a set of several TAAs for determining specific autoimmune profiles. Therefore, combining various TAAs on different surfaces could improve sensitivity and specificity for anti-TAA autoantibody detection. Herein a panel of 10 proteins, including well-known tumor-associated antigens (TAAs) and potential new biomarkers of breast cancer, were immobilized onto microstructured microarray under optimized conditions (spotting pH buffer, surface chemistry, blocking procedure), in order to determine an autoimmune signature of breast cancer. Sera from 29 breast cancer patients and 28 healthy donors were screened in sandwich immunoassays on the miniaturized system to detect the eventual presence of anti-TAAs autoantibodies. Results indicated that the detection level of each anti-TAA autoantibody in a given serum sample was strongly dependant on the surface chemistry. Combining five TAAs (p53, Hsp60, Hsp70, Her2-Fc, NY-ESO-1) on two different surface chemistries (NHS and APDMES) allowed the significant detection of more than 82% breast cancer sera. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Molecular Detection of Peripheral Blood Breast Cancer mRNA Transcripts as a Surrogate Biomarker for Circulating Tumor Cells

    OpenAIRE

    Adriana Lasa; Arnal Garcia; Carmen Alonso; Pilar Millet; Mónica Cornet; Cajal, Teresa Ramón y; Montserrat Baiget; Agusti Barnadas

    2013-01-01

    Circulating tumor cells (CTCs) are becoming a scientifically recognized indicator of primary tumors and/or metastasis. These cells can now be accurately detected and characterized as the result of technological advances. We analyzed the presence of CTCs in the peripheral blood of patients with metastatic breast cancer by real-time reverse-transcription PCR (RT-qPCR) using a panel of selected genes. The analysis of a single marker, without an EpCAM based enrichment approach, allowed the positi...

  5. Palbociclib in Combination With Tamoxifen as First Line Therapy for Metastatic Hormone Receptor Positive Breast Cancer

    Science.gov (United States)

    2017-08-23

    Hormone Receptor Positive Malignant Neoplasm of Breast; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; Estrogen Receptor Positive Breast Cancer; Progesterone Receptor Positive Tumor; Metastatic Breast Cancer

  6. Genetic Analysis in Blood and Tumor Samples From Patients With Advanced or Metastatic Estrogen Receptor Positive and HER2 Negative Breast Cancer Receiving Palbociclib and Endocrine Therapy

    Science.gov (United States)

    2017-11-16

    Estrogen Receptor Positive; HER2/Neu Negative; Recurrent Breast Carcinoma; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

  7. DC-SCRIPT is a novel regulator of the tumor suppressor gene CDKN2B and induces cell cycle arrest in ERα-positive breast cancer cells.

    Science.gov (United States)

    Ansems, Marleen; Søndergaard, Jonas Nørskov; Sieuwerts, Anieta M; Looman, Maaike W G; Smid, Marcel; de Graaf, Annemarie M A; de Weerd, Vanja; Zuidscherwoude, Malou; Foekens, John A; Martens, John W M; Adema, Gosse J

    2015-02-01

    Breast cancer is one of the most common causes of cancer-related deaths in women. The estrogen receptor (ERα) is well known for having growth promoting effects in breast cancer. Recently, we have identified DC-SCRIPT (ZNF366) as a co-suppressor of ERα and as a strong and independent prognostic marker in ESR1 (ERα gene)-positive breast cancer patients. In this study, we further investigated the molecular mechanism on how DC-SCRIPT inhibits breast cancer cell growth. DC-SCRIPT mRNA levels from 190 primary ESR1-positive breast tumors were related to global gene expression, followed by gene ontology and pathway analysis. The effect of DC-SCRIPT on breast cancer cell growth and cell cycle arrest was investigated using novel DC-SCRIPT-inducible MCF7 breast cancer cell lines. Genome-wide expression profiling of DC-SCRIPT-expressing MCF7 cells was performed to investigate the effect of DC-SCRIPT on cell cycle-related gene expression. Findings were validated by real-time PCR in a cohort of 1,132 ESR1-positive breast cancer patients. In the primary ESR1-positive breast tumors, DC-SCRIPT expression negatively correlated with several cell cycle gene ontologies and pathways. DC-SCRIPT expression strongly reduced breast cancer cell growth in vitro, breast tumor growth in vivo, and induced cell cycle arrest. In addition, in the presence of DC-SCRIPT, multiple cell cycles related genes were differentially expressed including the tumor suppressor gene CDKN2B. Moreover, in 1,132 primary ESR1-positive breast tumors, DC-SCRIPT expression also correlated with CDKN2B expression. Collectively, these data show that DC-SCRIPT acts as a novel regulator of CDKN2B and induces cell cycle arrest in ESR1-positive breast cancer cells.

  8. Neutralization of TNFα in tumor with a novel nanobody potentiates paclitaxel-therapy and inhibits metastasis in breast cancer.

    Science.gov (United States)

    Ji, Xuemei; Peng, Zhengxin; Li, Xiaorui; Yan, Zhonghui; Yang, Yue; Qiao, Zheng; Liu, Yu

    2017-02-01

    Metastatic disease is the major cause of death from cancer, and immunotherapy and chemotherapy have had limited success in reversing its progression. Researchers have suggested that inflammatory factors in the tumor environment can promote cancer invasion and metastasis, stimulating cancer progression. Thus, novel strategies that target cytokines and modulate the tumor microenvironment may emerge as important approaches for treating metastatic breast cancer. Specific neutralization of pathogenic TNF signaling using a TNFα antibody has gained increasing attention. Considering this, a selective human TNFα neutralized antibody was generated based on nanobody technology. A TNFα-specific nanobody was produced in Pichia pastoris with a molecular mass of 15 kDa and affinity constant of 2.05 nM. In the proliferation experiment, the TNFα nanobody could inhibit the proliferation of the breast cancer cell line MCF-7 induced by hTNFα in a dose-dependent manner. In the microinvasion model, the TNFα nanobody could inhibit the migration of the breast cancer cell lines MCF-7, MDA-MB-231 and the invasiveness of MDA-MB-231 induced by hTNFα in a dose-dependent manner. Drug administration of the combination of paclitaxel with the TNFα nanobody in vivo significantly enhanced the efficacy against 4T-1 breast tumor proliferation and lung metastasis; meanwhile, E-cadherin tumor epithelial marker expression was upregulated, supporting the anti-tumor therapeutic relevance of paclitaxel and the TNFα nanobody on EMT. This study highlights the importance of neutralizing low TNFα levels in the tumor microenvironment to sensitize the chemotherapeutic response, which has attractive potential for clinical applications. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Dietary targeting of tumor suppressors and oncogenes for breast cancer prevention

    Science.gov (United States)

    Breast cancer is a complex disease that arises from genetic and epigenetic changes in molecules that are critical for growth control, DNA repair, apoptosis, and differentiation. The incidence of breast cancer varies worldwide, implicating diet and lifestyle disparities among the general population a...

  10. Beyond breast and ovarian cancers: PARP inhibitors for BRCA mutation-associated and BRCA-like solid tumors

    Directory of Open Access Journals (Sweden)

    Ciara C. O'Sullivan

    2014-02-01

    Full Text Available Poly(ADP-ribose polymerase inhibitors (PARPi have shown clinical activity in patients with germline BRCA1/2 mutation (gBRCAm-associated breast and ovarian cancers. Accumulating evidence suggests that PARPi may have a wider application in the treatment of cancers defective in DNA damage repair pathways, such as prostate, lung, endometrial, and pancreatic cancers. Several PARPi are currently in phase I/II clinical investigation, as single agents and/or in combination therapy in these solid tumors. Understanding more about the molecular abnormalities involved in BRCA-like phenotype in solid tumors beyond breast and ovarian cancers, exploring novel therapeutic trial strategies and drug combinations, and defining potential predictive biomarkers, are critical to expanding the field of PARPi therapy. This will improve clinical outcome in advanced solid tumors. Here we briefly review the preclinical data and clinical development of PARPi, and discuss its future of development in solid tumors beyond gBRCAm associated breast and ovarian cancers.

  11. Caffeine mediates sustained inactivation of breast cancer-associated myofibroblasts via up-regulation of tumor suppressor genes.

    Science.gov (United States)

    Al-Ansari, Mysoon M; Aboussekhra, Abdelilah

    2014-01-01

    Active cancer-associated fibroblasts (CAFs) or myofibroblasts play important roles not only in the development and progression of breast carcinomas, but also in their prognosis and treatment. Therefore, targeting these cells through suppressing their supportive procarcinogenic paracrine effects is mandatory for improving the current therapies that are mainly targeting tumor cells. To this end, we investigated the effect of the natural and pharmacologically safe molecule, caffeine, on CAF cells and their various procarcinogenic effects. We have shown here that caffeine up-regulates the tumor suppressor proteins p16, p21, p53 and Cav-1, and reduces the expression/secretion of various cytokines (IL-6, TGF-β, SDF-1 and MMP-2), and down-regulates α-SMA. Furthermore, caffeine suppressed the migratory/invasiveness abilities of CAF cells through PTEN-dependent Akt/Erk1/2 inactivation. Moreover, caffeine reduced the paracrine pro-invasion/-migration effects of CAF cells on breast cancer cells. These results indicate that caffeine can inactivate breast stromal myofibroblasts. This has been confirmed by showing that caffeine also suppresses the paracrine pro-angiogenic effect of CAF cells through down-regulating HIF-1αand its downstream effector VEGF-A. Interestingly, these effects were sustained in absence of caffeine. The present findings provide a proof of principle that breast cancer myofibroblasts can be inactivated, and thereby caffeine may provide a safe and effective prevention against breast tumor growth/recurrence through inhibition of the procarcinogenic effects of active stromal fibroblasts.

  12. Evidence for a Role of Tumor-Derived Laminin-511 in the Metastatic Progression of Breast Cancer

    Science.gov (United States)

    Chia, Jenny; Kusuma, Nicole; Anderson, Robin; Parker, Belinda; Bidwell, Bradley; Zamurs, Laura; Nice, Edouard; Pouliot, Normand

    2007-01-01

    Most studies investigating laminins (LMs) in breast cancer have focused on LM-111 or LM-332. Little is known, however, about the expression and function of α5 chain-containing LM-511/521 during metastatic progression. Expression of LM-511/521 subunits was examined in genetically related breast tumor lines and corresponding primary tumors and metastases in a syngeneic mouse model using real-time quantitative polymerase chain reaction, in situ hybridization, and immunohistochemistry. The results from our investigation indicate that LM-511 rather than LM-111, -332, or -521 correlates with metastatic potential in mouse mammary tumors. LM-511 was a potent adhesive substrate for both murine and human breast carcinoma cells and promoted strong haptotactic responses in metastatic lines. Haptotaxis was mediated by α3 integrin in both MCF-7 and MDA-MB-231 cells and was strongly inhibited by blocking antibodies against this integrin subunit. However, whereas nonmetastatic MCF-7 cells migrated toward LM-511 primarily via α3β1 integrin, results from antibody perturbation experiments and flow cytometry analysis suggest that this response is mediated by an as yet unidentified α3β integrin heterodimer (other than α3β1) in MDA-MB-231 cells. These results are consistent with earlier reports implicating α3 integrins in breast cancer progression and support the role of LM-511 as a functional substrate regulating breast cancer metastasis. PMID:17525279

  13. Breast cancer diagnosis and mortality by tumor stage and migration background in a nationwide cohort study in Sweden.

    Science.gov (United States)

    Abdoli, Gholamreza; Bottai, Matteo; Sandelin, Kerstin; Moradi, Tahereh

    2017-02-01

    Survival in breast cancer patients has steadily increased over the years, but with considerable disparities between individuals with different migration background and social position. We explored differences in diagnosis and all-cause mortality in breast cancer patients by stage of disease at the time of diagnosis and by country of birth, while considering the effect of comorbidity, regional and socio-demographic factors. We used Swedish national registers to follow a cohort of 35,268 patients (4232 foreign-born) with breast cancer between 2004 and 2009 in Sweden. We estimated relative risk ratio (RRR) for diagnosis, hazard ratio (HR) for all-cause mortality and relative excess rate (RER) for breast cancer mortality using multinomial logistic regression models, multivariable Cox proportional hazard, and Poisson regression, respectively. We observed 4178 deaths due to any causes. Among them 418 women were born abroad. Foreign-born patients were on average 3 years younger at the time of breast cancer diagnosis and had higher risk of stage II tumors compared with Sweden-born women (RRR = 1.09, 95% CI 1.00-1.19). Risk of dying was 20% higher in foreign-born compared with Sweden-born breast cancer patients, if the tumor was diagnosed at stages III-IV after adjustment for age at diagnosis, education, county of residence and Charlson's comorbidity index (HR = 1.20, 95% CI 0.95-1.51 and RER = 1.21, 95% CI 0.95-1.55). The worse prognosis in foreign-born patients with advanced tumors compared with Sweden-born patients is not explained by educational level or comorbidity. The reasons behind the observed disparities should be further studied. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Distinction between isolated tumor cells and micrometastases in breast cancer: is it reliable and useful?

    Science.gov (United States)

    de Mascarel, Isabelle; MacGrogan, Gaetan; Debled, Marc; Brouste, Veronique; Mauriac, Louis

    2008-04-15

    In routine practice, the distinction between isolated tumor cells (ITC) and micrometastases (MIC) in patients with breast cancer is sometimes difficult to discern. The authors assessed differences in classifying patients according to the American Joint Commission on Cancer (AJCC) and the International Union Against Cancer (UICC) definitions and method of sizing. We assessed the characteristics of metastatic deposits in only 1 involved lymph node in 337 patients with operable breast cancer (median follow-up, 15.3 years). When sizing multiple clusters, either the diameter of the area with close clusters (Method 1) or the size of the largest cluster (Method 2) was taken into account. Patients were classified and their survival was assessed according to the 2 sizing methods and the criteria used for definitions (size in AJCC; size and topography in UICC). With the AJCC definitions, 32 patients would be differently classified according to the method of sizing. With the UICC definitions, some patients with parenchymal ITC would be classified as pN1mi, 38 by Method 1 and 53 by Method 2. Some pathologists would classify the 66 patients who had isolated capsular vascular invasion as pN0. Classification was uncertain in 136 (40%) to 151 (45 %) patients. Survival was not significantly different between pN0(i+) and pN1(mi) patients. The distinction between ITC and MIC was often difficult and without any prognostic significance. Precise guidelines are more useful for staging than for therapy. Thus, complete axillary dissection is usually performed in pN0(i+) and pN1(mi) patients, whereas chemotherapy is not indicated or debatable when MIC is the only 1 pejorative criterion.

  15. Overexpression of L1 cell adhesion molecule correlates with aggressive tumor progression of patients with breast cancer and promotes motility of breast cancer cells.

    Science.gov (United States)

    Zhang, Jian; Yang, Fei; Ding, Yong; Zhen, Linlin; Han, Xuedong; Jiao, Feng; Tang, Jinhai

    2015-01-01

    L1 cell adhesion molecule (L1CAM) has been observed to be aberrantly expressed and implicated in progression of several types of human cancers. However, its roles in breast cancer have not been fully elucidated. In this study, we aimed to investigate the clinical significance of L1CAM in human breast cancer and to validate whether it participates in cancer cell migration and invasion. Immunohistochemical analysis of 100 breast cancer and matched non-cancerous breast tissues was performed to detect the expression and sub-cellular localization of L1CAM protein. Its associations with clinicopathological characteristics of breast cancer patients were statistically analyzed and its phenotypic effects were also evaluated in vitro. Of the 100 breast cancer patients, 89 (89.0%) were positive for L1CAM immunostaining localized in the membrane of cancer cells. The immunoreactive scores of L1CAM protein in breast cancer tissues were significantly higher than those in matched non-cancerous breast tissues (Pbreast cancer patients. Moreover, we found that RNA interference-mediated knockdown of L1CAM could inhibit the migration and invasion abilities of breast cancer cells in vitro. Our results suggest that the overexpression of L1CAM may be related to several established markers of poor prognosis in breast cancer patients. L1CAM might be a potential therapeutic target against metastatic breast cancer.

  16. Breast cancer statistics, 2013.

    Science.gov (United States)

    DeSantis, Carol; Ma, Jiemin; Bryan, Leah; Jemal, Ahmedin

    2014-01-01

    In this article, the American Cancer Society provides an overview of female breast cancer statistics in the United States, including data on incidence, mortality, survival, and screening. Approximately 232,340 new cases of invasive breast cancer and 39,620 breast cancer deaths are expected to occur among US women in 2013. One in 8 women in the United States will develop breast cancer in her lifetime. Breast cancer incidence rates increased slightly among African American women; decreased among Hispanic women; and were stable among whites, Asian Americans/Pacific Islanders, and American Indians/Alaska Natives from 2006 to 2010. Historically, white women have had the highest breast cancer incidence rates among women aged 40 years and older; however, incidence rates are converging among white and African American women, particularly among women aged 50 years to 59 years. Incidence rates increased for estrogen receptor-positive breast cancers in the youngest white women, Hispanic women aged 60 years to 69 years, and all but the oldest African American women. In contrast, estrogen receptor-negative breast cancers declined among most age and racial/ethnic groups. These divergent trends may reflect etiologic heterogeneity and the differing effects of some factors, such as obesity and parity, on risk by tumor subtype. Since 1990, breast cancer death rates have dropped by 34% and this decrease was evident in all racial/ethnic groups except American Indians/Alaska Natives. Nevertheless, survival disparities persist by race/ethnicity, with African American women having the poorest breast cancer survival of any racial/ethnic group. Continued progress in the control of breast cancer will require sustained and increased efforts to provide high-quality screening, diagnosis, and treatment to all segments of the population. © 2013 American Cancer Society, Inc.

  17. 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.

  18. Iron imaging reveals tumor and metastasis macrophage hemosiderin deposits in breast cancer.

    Science.gov (United States)

    Leftin, Avigdor; Ben-Chetrit, Nir; Klemm, Florian; Joyce, Johanna A; Koutcher, Jason A

    2017-01-01

    Iron-deposition is a metabolic biomarker of macrophages in both normal and pathological situations, but the presence of iron in tumor and metastasis-associated macrophages is not known. Here we mapped and quantified hemosiderin-laden macrophage (HLM) deposits in murine models of metastatic breast cancer using iron and macrophage histology, and in vivo MRI. Iron MRI detected high-iron pixel clusters in mammary tumors, lung metastasis, and brain metastasis as well as liver and spleen tissue known to contain the HLMs. Iron histology showed these regions to contain clustered macrophages identified by their common iron status and tissue-intrinsic association with other phenotypic macrophage markers. The in vivo MRI and ex vivo histological images were further processed to determine the frequencies and sizes of the iron deposits, and measure the number of HLMs in each deposit to estimate the in vivo MRI sensitivity for these cells. Hemosiderin accumulation is a macrophage biomarker and intrinsic contrast source for cellular MRI associated with the innate function of macrophages in iron metabolism systemically, and in metastatic cancer.

  19. Overexpression of L1 cell adhesion molecule correlates with aggressive tumor progression of patients with breast cancer and promotes motility of breast cancer cells

    OpenAIRE

    Zhang, Jian; Yang, Fei; Ding, Yong; Zhen, Linlin; Han, Xuedong; Jiao, Feng; Tang, Jinhai

    2015-01-01

    Background and purpose: L1 cell adhesion molecule (L1CAM) has been observed to be aberrantly expressed and implicated in progression of several types of human cancers. However, its roles in breast cancer have not been fully elucidated. In this study, we aimed to investigate the clinical significance of L1CAM in human breast cancer and to validate whether it participates in cancer cell migration and invasion. Methods: Immunohistochemical analysis of 100 breast cancer and matched non-cancerous ...

  20. CDKN1C/p57kip2 is a candidate tumor suppressor gene in human breast cancer

    Directory of Open Access Journals (Sweden)

    Pistey Robert

    2008-03-01

    Full Text Available Abstract Background CDKN1C (also known as p57KIP2 is a cyclin-dependent kinase inhibitor previously implicated in several types of human cancer. Its family members (CDKN1A/p21CIP1 and B/p27KIP1 have been implicated in breast cancer, but information about CDKN1C's role is limited. We hypothesized that decreased CDKN1C may be involved in human breast carcinogenesis in vivo. Methods We determined rates of allele imbalance or loss of heterozygosity (AI/LOH in CDKN1C, using an intronic polymorphism, and in the surrounding 11p15.5 region in 82 breast cancers. We examined the CDKN1C mRNA level in 10 cancers using quantitative real-time PCR (qPCR, and the CDKN1C protein level in 20 cancers using immunohistochemistry (IHC. All samples were obtained using laser microdissection. Data were analyzed using standard statistical tests. Results AI/LOH at 11p15.5 occurred in 28/73 (38% informative cancers, but CDKN1C itself underwent AI/LOH in only 3/16 (19% cancers (p = ns. In contrast, CDKN1C mRNA levels were reduced in 9/10 (90% cancers (p Conclusion CDKN1C is expressed in normal epithelium of most breast cancer cases, mainly in the myothepithelial layer. This expression decreases, at both the mRNA and protein level, in the large majority of breast cancers, and does not appear to be mediated by AI/LOH at the gene. Thus, CDKN1C may be a breast cancer tumor suppressor.

  1. Clinico-Pathologic Subtypes of Breast Cancer Primary Tumors Are Related to Prognosis after Recurrence

    Science.gov (United States)

    Sánchez, Cesar; Camus, Mauricio; Medina, Lidia; Oddo, David; Artigas, Rocío; Pérez Sepúlveda, Alejandra; Domínguez, Francisco; Razmilic, Dravna; Navarro, María Elena; Galindo, Hector; Acevedo, Francisco

    2016-12-01

    Background: Pathological factors, based mainly on immunohistochemistry (IHC) and histological differentiation, are mostly used to differentiate breast cancer (BC) subtypes. Our present aim was to describe the characteristics and survival of a relapsing BC patient cohort based on clinico-pathologic subtypes determined for the primary tumors. Methods: We used a clinico- pathological definition of BC subtypes based on histological grade (HG), estrogen receptor (ER), progesterone receptor (PgR),and epidermal growth factor receptor type 2 (HER2) expression assessed by IHC. We determined variables associated with loco-regional recurrence (LRR), second primaries (SP), systemic recurrence (SR) and post-recurrence survival (PRS). Results: Out of 1,702 patients, 240 (14%) had an event defined as recurrence. Those with recurrent disease were significantly younger than those without,and were initially diagnosed at more advanced stages, with larger tumors, greater lymph nodal involvement and higher HG. With a median follow up of 61 months (1-250), 4.6% of patients without recurrence and 56.6% of patients with an event defined as recurrence had died. The median PRS for the LRR group was 77 months; 75 months for those who developed a SP and 22 months for patients with an SR (p <0.0001). In SR cases, the median PRS was shorter for ER- tumors than for ER+ tumors (15 vs. 26 months, respectively; p = 0.0019, HR 0.44; CI: 0.25-0.44). Conclusions: Subtype, defined through classic histopathologic parameters determined for primary tumors, was found to eb related to type of recurrence and also to prognosis after relapse. Creative Commons Attribution License

  2. A monoclonal antibody cocktail for detection of micrometastatic tumor cells in the bone marrow of breast cancer patients.

    Science.gov (United States)

    Taha, M; Ordoñez, N G; Kulkarni, S; Owen, M; Ro, J S; Hortobagyi, G; Reading, C L; Dicke, K A; Spitzer, G

    1989-05-01

    We investigated whether monoclonal antibodies (MoAbs) reactive against both acidic and basic cytokeratins alone were sufficient to detect minimal numbers of contaminating epithelial tumor cells in the bone marrow of breast cancer patients. Monoclonal anti-cytokeratin antibodies (AE1 and AE3) were used to stain 14 breast carcinomas by the avidin-biotin-peroxidase technique. Nine tumors (64.3%) showed high reactivity and five (35.7%) showed low or moderate reactivity. Nine MoAbs that proved to be unreactive to light density bone marrow cells by immunoalkaline phosphatase histochemistry were screened for reactivity to breast carcinomas having only low or moderate positivity to cytokeratin antibodies. Three of nine MoAbs showed high percentages of positivity and were selected to supplement the anti-cytokeratin antibodies for immunohistochemical detection of minimal marrow disease in breast cancer patients. A MoAb cocktail was prepared, further tested for reactivity to another five breast carcinomas, and compared with cytokeratin staining alone. The cocktail labeled 100% of carcinoma cells in all the examined specimens. To determine the sensitivity of this panel for detecting minimal numbers of contaminating tumor cells in bone marrow, in vitro mixing experiments were performed. T47D breast carcinoma cells were mixed with bone marrow mononuclear cells at ratios from one tumor cell per 10 bone marrow cells up to one tumor cell per 1 x 10(6) marrow cells, and cytospin preparations were subsequently stained with the MoAb cocktail by the immunoalkaline phosphatase method. Our approach could detect one tumor cell in 1 x 10(5) hematopoietic cells.

  3. Anterior gradient protein 3 is associated with less aggressive tumors and better outcome of breast cancer patients

    Directory of Open Access Journals (Sweden)

    Obacz J

    2015-06-01

    Full Text Available Joanna Obacz,1 Veronika Brychtova,1 Jan Podhorec,1 Pavel Fabian,2 Petr Dobes,1 Borivoj Vojtesek,1 Roman Hrstka1 1Regional Centre for Applied Molecular Oncology (RECAMO, 2Department of Pathology, Masaryk Memorial Cancer Institute, Brno, Czech Republic Abstract: Anterior gradient protein (AGR 3 is a highly related homologue of pro-oncogenic AGR2 and belongs to the family of protein disulfide isomerases. Although AGR3 was found in breast, ovary, prostate, and liver cancer, it remains of yet poorly defined function in tumo-rigenesis. This study aimed to determine AGR3 expression in a cohort of 129 primary breast carcinomas and evaluate the clinical and prognostic significance of AGR3 in these tumors. The immunohistochemical analysis revealed the presence of AGR3 staining to varying degrees in 80% of analyzed specimens. The percentage of AGR3-positive cells significantly correlated with estrogen receptor, progesterone receptor (both P<0.0001 as well as low histological grade (P=0.003, and inversely correlated with the level of Ki-67 expression (P<0.0001. In the whole cohort, AGR3 expression was associated with longer progression-free survival (PFS, whereas AGR3-positive subgroup of low-histological grade tumors showed both significantly longer PFS and overall survival. In conclusion, AGR3 is associated with the level of differentiation, slowly proliferating tumors, and more favorable prognosis of breast cancer patients. Keywords: AGR3, patient survival, protein disulfide isomerase, ER-positive breast cancer, immuno­histochemistry

  4. Thrombospondin promoted anti-tumor of adenovirus-mediated calreticulin in breast cancer: Relationship with anti-CD47.

    Science.gov (United States)

    Chen, Qifeng; Fang, Xiaoming; Jiang, Chaohui; Yao, Ning; Fang, Xudong

    2015-07-01

    Calreticulin (CRT) protein has multifaceted role in carcinogenesis, however its role in breast cancer remains unidentified. In this study, we attempted to evaluate the effect of overexpressed CRT on breast cancer cells viability and proliferation. Levels of mRNA and protein expression for CRT and CD47 in cells were determined by Quantitative RT-PCR analysis and Western blot, respectively. Cells apoptosis was evaluated using Annexin V-FITC assay with flow cytometry. Cell viability was assessed using MTT assay. Cell migration and autophagy were also evaluated. In breast cancer cells of MCF-7 and MDA-MB-231, both CRT and CD47 expression were enhanced, compared with that in normal breast cells of MCF-10A. Overexpression of CRT by MCF-7 and MDA-MB-231 cells transfected with significantly suppressed cell migration, viability as well as promote cell apoptosis while exerted no effected on cell autophagy. Interestingly, combining of thrombospondin (TSP) and overexpression of CRT significantly induced cell autophagy and inhibited tumor growth in MCF-7 cells xenograft. In result of chip assay, we observed that TSP treatment promoted interaction of TSP with CRT and CD47. TSP promoted anti-tumor of adenovirus-mediated CRT via forming complexes with CRT and CD47 in breast cancer. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  5. NEMO, a Transcriptional Target of Estrogen and Progesterone, Is Linked to Tumor Suppressor PML in Breast Cancer.

    Science.gov (United States)

    Elsarraj, Hanan S; Valdez, Kelli E; Hong, Yan; Grimm, Sandra L; Ricci, Lawrence R; Fan, Fang; Tawfik, Ossama; May, Lisa; Cusick, Therese; Inciardi, Marc; Redick, Mark; Gatewood, Jason; Winblad, Onalisa; Hilsenbeck, Susan; Edwards, Dean P; Hagan, Christy R; Godwin, Andrew K; Fabian, Carol; Behbod, Fariba

    2017-07-15

    The beneficial versus detrimental roles of estrogen plus progesterone (E+P) in breast cancer remains controversial. Here we report a beneficial mechanism of E+P treatment in breast cancer cells driven by transcriptional upregulation of the NFκB modulator NEMO, which in turn promotes expression of the tumor suppressor protein promyelocytic leukemia (PML). E+P treatment of patient-derived epithelial cells derived from ductal carcinoma in situ (DCIS) increased secretion of the proinflammatory cytokine IL6. Mechanistic investigations indicated that IL6 upregulation occurred as a result of transcriptional upregulation of NEMO, the gene that harbored estrogen receptor (ER) binding sites within its promoter. Accordingly, E+P treatment of breast cancer cells increased ER binding to the NEMO promoter, thereby increasing NEMO expression, NFκB activation, and IL6 secretion. In two mouse xenograft models of DCIS, we found that RNAi-mediated silencing of NEMO increased tumor invasion and progression. This seemingly paradoxical result was linked to NEMO-mediated regulation of NFκB and IL6 secretion, increased phosphorylation of STAT3 on Ser727, and increased expression of PML, a STAT3 transcriptional target. In identifying NEMO as a pivotal transcriptional target of E+P signaling in breast cancer cells, our work offers a mechanistic explanation for the paradoxical antitumorigenic roles of E+P in breast cancer by showing how it upregulates the tumor suppressor protein PML. Cancer Res; 77(14); 3802-13. ©2017 AACR. ©2017 American Association for Cancer Research.

  6. Breast cancer

    CERN Multimedia

    2002-01-01

    "Cancer specialists will soon be able to compare mammograms with computerized images of breast cancer from across Europe, in a bid to improve diagnosis and treatment....The new project, known as MammoGrid, brings together computer and medical imaging experts, cancer specialists, radiologists and epidemiologists from Bristol, Oxford, Cambridge, France and Italy" (1 page).

  7. Interleukin-19 in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Ying-Yin Chen

    2013-01-01

    Full Text Available Inflammatory cytokines within the tumor microenvironment are linked to progression in breast cancer. Interleukin- (IL- 19, part of the IL-10 family, contributes to a range of diseases and disorders, such as asthma, endotoxic shock, uremia, psoriasis, and rheumatoid arthritis. IL-19 is expressed in several types of tumor cells, especially in squamous cell carcinoma of the skin, tongue, esophagus, and lung and invasive duct carcinoma of the breast. In breast cancer, IL-19 expression is correlated with increased mitotic figures, advanced tumor stage, higher metastasis, and poor survival. The mechanisms of IL-19 in breast cancer have recently been explored both in vitro and in vivo. IL-19 has an autocrine effect in breast cancer cells. It directly promotes proliferation and migration and indirectly provides a microenvironment for tumor progression, which suggests that IL-19 is a prognostic marker in breast cancer and that antagonizing IL-19 may have therapeutic potential.

  8. Activation of the aryl hydrocarbon receptor by TCDD inhibits mammary tumor metastasis in a syngeneic mouse model of breast cancer.

    Science.gov (United States)

    Wang, Tao; Wyrick, Katie L; Meadows, Gary G; Wills, Tamara B; Vorderstrasse, Beth A

    2011-12-01

    Treatment with aryl hydrocarbon receptor (AhR) agonists can slow or reverse the growth of primary mammary tumors in rodents, which has fostered interest in developing selective AhR modulators for treatment of breast cancer. However, the major goal of breast cancer therapy is to inhibit metastasis, the primary cause of mortality in women with this disease. Studies conducted using breast cancer cell lines have demonstrated that AhR agonists suppress proliferation, invasiveness, and colony formation in vitro; however, further exploration using in vivo models of metastasis is warranted. To test the effect of AhR activation on metastasis, 4T1.2 mammary tumor cells were injected into the mammary gland fat pad of syngeneic Balb/c mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Primary tumor growth was monitored for 4 weeks, at which time metastasis was determined. TCDD treatment suppressed metastasis by approximately 50%, as measured both in the lung and in mammary glands at sites distant from the primary tumor. Primary tumor growth was not suppressed by TCDD exposure nor was proliferation of 4T1.2 cells affected by TCDD treatment in vitro. Taken together, these results suggest that the protective effect of AhR activation was selective for the metastatic process and not simply the result of a direct decrease in tumor cell proliferation or survival at the primary site. These observations in immunologically intact animals warrant further investigation into the mechanism of the protective effects of AhR activation and support the promise for use of AhR modulators to treat breast cancer.

  9. Breast cancer-derived transforming growth factor-β and tumor necrosis factor-α compromise interferon-α production by tumor-associated plasmacytoid dendritic cells.

    Science.gov (United States)

    Sisirak, Vanja; Vey, Nelly; Goutagny, Nadège; Renaudineau, Sarah; Malfroy, Marine; Thys, Sandra; Treilleux, Isabelle; Labidi-Galy, Sana Intidhar; Bachelot, Thomas; Dezutter-Dambuyant, Colette; Ménétrier-Caux, Christine; Blay, Jean-Yves; Caux, Christophe; Bendriss-Vermare, Nathalie

    2013-08-01

    We previously reported that plasmacytoid dendritic cells (pDCs) infiltrating breast tumors are impaired for their interferon-α (IFN-α) production, resulting in local regulatory T cells amplification. We designed our study to decipher molecular mechanisms of such functional defect of tumor-associated pDC (TApDC) in breast cancer. We demonstrate that besides IFN-α, the production by Toll-like receptor (TLR)-activated healthy pDC of IFN-β and TNF-α but not IP-10/CXCL10 nor MIP1-α/CCL3 is impaired by the breast tumor environment. Importantly, we identified TGF-β and TNF-α as major soluble factors involved in TApDC functional alteration. Indeed, recombinant TGF-β1 and TNF-α synergistically blocked IFN-α production of TLR-activated pDC, and neutralization of TGF-β and TNF-α in tumor-derived supernatants restored pDCs' IFN-α production. The involvment of tumor-derived TGF-β was further confirmed in situ by the detection of phosphorylated Smad2 in the nuclei of TApDC in breast tumor tissues. Mechanisms of type I IFN inhibition did not involve TLR downregulation but the inhibition of IRF-7 expression and nuclear translocation in pDC after their exposure to tumor-derived supernatants or recombinant TGF-β1 and TNF-α. Our findings indicate that targeting TApDC to restore their IFN-α production might be an achievable strategy to induce antitumor immunity in breast cancer by combining TLR7/9-based immunotherapy with TGF-β and TNF-α antagonists. Copyright © 2013 UICC.

  10. 6 Common Cancers - Breast Cancer

    Science.gov (United States)

    ... Home Current Issue Past Issues 6 Common Cancers - Breast Cancer Past Issues / Spring 2007 Table of Contents For ... slow her down. Photo: AP Photo/Brett Flashnick Breast Cancer Breast cancer is a malignant (cancerous) growth that ...

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

    Directory of Open Access Journals (Sweden)

    Amandine Bemmo

    2010-08-01

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

  12. 5′-AMP-activated Protein Kinase (AMPK) Supports the Growth of Aggressive Experimental Human Breast Cancer Tumors*

    Science.gov (United States)

    Laderoute, Keith R.; Calaoagan, Joy M.; Chao, Wan-ru; Dinh, Dominc; Denko, Nicholas; Duellman, Sarah; Kalra, Jessica; Liu, Xiaohe; Papandreou, Ioanna; Sambucetti, Lidia; Boros, Laszlo G.

    2014-01-01

    Rapid tumor growth can establish metabolically stressed microenvironments that activate 5′-AMP-activated protein kinase (AMPK), a ubiquitous regulator of ATP homeostasis. Previously, we investigated the importance of AMPK for the growth of experimental tumors prepared from HRAS-transformed mouse embryo fibroblasts and for primary brain tumor development in a rat model of neurocarcinogenesis. Here, we used triple-negative human breast cancer cells in which AMPK activity had been knocked down to investigate the contribution of AMPK to experimental tumor growth and core glucose metabolism. We found that AMPK supports the growth of fast-growing orthotopic tumors prepared from MDA-MB-231 and DU4475 breast cancer cells but had no effect on the proliferation or survival of these cells in culture. We used in vitro and in vivo metabolic profiling with [13C]glucose tracers to investigate the contribution of AMPK to core glucose metabolism in MDA-MB-231 cells, which have a Warburg metabolic phenotype; these experiments indicated that AMPK supports tumor glucose metabolism in part through positive regulation of glycolysis and the nonoxidative pentose phosphate cycle. We also found that AMPK activity in the MDA-MB-231 tumors could systemically perturb glucose homeostasis in sensitive normal tissues (liver and pancreas). Overall, our findings suggest that the contribution of AMPK to the growth of aggressive experimental tumors has a critical microenvironmental component that involves specific regulation of core glucose metabolism. PMID:24993821

  13. 5'-AMP-activated protein kinase (AMPK) supports the growth of aggressive experimental human breast cancer tumors.

    Science.gov (United States)

    Laderoute, Keith R; Calaoagan, Joy M; Chao, Wan-ru; Dinh, Dominc; Denko, Nicholas; Duellman, Sarah; Kalra, Jessica; Liu, Xiaohe; Papandreou, Ioanna; Sambucetti, Lidia; Boros, Laszlo G

    2014-08-15

    Rapid tumor growth can establish metabolically stressed microenvironments that activate 5'-AMP-activated protein kinase (AMPK), a ubiquitous regulator of ATP homeostasis. Previously, we investigated the importance of AMPK for the growth of experimental tumors prepared from HRAS-transformed mouse embryo fibroblasts and for primary brain tumor development in a rat model of neurocarcinogenesis. Here, we used triple-negative human breast cancer cells in which AMPK activity had been knocked down to investigate the contribution of AMPK to experimental tumor growth and core glucose metabolism. We found that AMPK supports the growth of fast-growing orthotopic tumors prepared from MDA-MB-231 and DU4475 breast cancer cells but had no effect on the proliferation or survival of these cells in culture. We used in vitro and in vivo metabolic profiling with [(13)C]glucose tracers to investigate the contribution of AMPK to core glucose metabolism in MDA-MB-231 cells, which have a Warburg metabolic phenotype; these experiments indicated that AMPK supports tumor glucose metabolism in part through positive regulation of glycolysis and the nonoxidative pentose phosphate cycle. We also found that AMPK activity in the MDA-MB-231 tumors could systemically perturb glucose homeostasis in sensitive normal tissues (liver and pancreas). Overall, our findings suggest that the contribution of AMPK to the growth of aggressive experimental tumors has a critical microenvironmental component that involves specific regulation of core glucose metabolism. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. 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.

  15. Synergistic anti-tumor activity of Nimotuzumab in combination with Trastuzumab in HER2-positive breast cancer.

    Science.gov (United States)

    Yang, Yun; Guo, Rui; Tian, Xiaoting; Zhang, Ziheng; Zhang, Pengfei; Li, Changzheng; Feng, Zhiwei

    2017-08-05

    Breast cancer is characterized with poor prognosis and high recurrence. HER2 is highly expressed in breast cancer and is a target for cancer therapy and prevention. Here, we investigated the anti-tumor activity of the combination of an HER2 inhibitor, trastuzumab with an EGFR-inhibitor, nimotuzumab in HER2-overexpressing breast cancer. Our data showed that a greater anti-tumor activity from the combination of trastuzumab and nimotuzumab than any alone usage of above antibody both in vitro and in vivo. Based on the combination index value, our data demonstrated that nimotuzumab synergistically enhanced trastuzumab-induced cell growth inhibition. Furthermore, we investigated the possible mechanism of this synergistic efficacy induced by trastuzumab plus nimotuzumab. Data showed that the combination was more potent in reducing the phosphorylation of HER2 and ERK1/2. We also found that the synergistic inhibition was partly attributed to the ROS generation and repression of NRF2 pathway that is known to promote cell growth. These results support the clinical development of this two-drug regimen for the treatment of HER2-amplified breast cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Prognostic significance of axillary dissection in breast cancer patients with micrometastases or isolated tumor cells in sentinel nodes

    DEFF Research Database (Denmark)

    Tvedskov, Tove Filtenborg; Jensen, Maj-Britt; Ejlertsen, Bent

    2015-01-01

    . In this nationwide study, we found a low risk of AR on 1.58 % and we did not find a significantly increased risk of AR if ALND was omitted in patients with micrometastases or ITC in sentinel nodes. Furthermore, no significant difference in overall survival was seen between patients with and without ALND when......We estimated the impact of axillary lymph node dissection (ALND) on the risk of axillary recurrence (AR) and overall survival (OS) in breast cancer patients with micrometastases or isolated tumor cells (ITC) in sentinel nodes. We used the Danish Breast Cancer Cooperative Group (DBCG) database...... to identify patients with micrometastases or ITC in sentinel nodes following surgery for primary breast cancer between 2002 and 2008. A Cox proportional hazard regression model was developed to assess the hazard ratios (HR) for AR and OS between patients with and without ALND. We identified 2074 patients...

  17. Breast Cancer

    Science.gov (United States)

    ... a reduced risk of breast cancer. The Mediterranean diet focuses mostly on plant-based foods, such as fruits and vegetables, whole grains, legumes, and nuts. People who follow the Mediterranean diet choose healthy fats, such as olive oil, over ...

  18. Breast Cancer

    Science.gov (United States)

    ... disease. It’s estimated that about 10% of breast cancer cases are hereditary (run in the family). In many of these cases, you inherited a gene from your parents that has mutated (changed from ...

  19. Changes in keratin expression during metastatic progression of breast cancer: impact on the detection of circulating tumor cells.

    Science.gov (United States)

    Joosse, Simon A; Hannemann, Juliane; Spötter, Julia; Bauche, Andreas; Andreas, Antje; Müller, Volkmar; Pantel, Klaus

    2012-02-15

    Circulating tumor cells (CTC) might function as early markers for breast cancer metastasis or monitoring therapy efficacy. Enrichment and identification of CTCs are based on epithelial markers that might be modulated during epithelial-mesenchymal transition. Little is known about the expression of keratins in CTCs and whether all CTCs can be detected with antibodies directed against a limited panel of keratins. Protein expression of keratin 2, 4-10, 13-16, 18, and 19 were assessed by a cocktail of antibodies (C11, AE1, AE3, and K7) and keratin antibodies C11 and A45-B/B3 alone in 11 breast cancer cell lines and 50 primary breast carcinomas and their lymph node metastases. Furthermore, CTCs were assessed in blood of 70 metastatic breast cancer patients. Claudin-low cell lines did not show expression of normal breast epithelial keratins but were positive for K14 and K16, detected by the cocktail only. Primary breast carcinomas showed changes in keratin expression during metastatic progression to the lymph nodes. In 35 of 70 patients CTCs were identified, of which 83%, 40%, and 57% were identified by the cocktail, C11 and A45-B/B3, respectively. Identification of CTCs by the cocktail was associated with shorter survival (P keratin expression with potential biologic relevance. Individual keratin antibodies recognizing only a limited set of keratins inherit the risk to miss biologically relevant CTCs in cancer patients, and antibody cocktails including these keratins are therefore recommended. ©2012 AACR.

  20. Adaptive enhancement and visualization techniques for 3D THz images of breast cancer tumors

    Science.gov (United States)

    Wu, Yuhao; Bowman, Tyler; Gauch, John; El-Shenawee, Magda

    2016-03-01

    This paper evaluates image enhancement and visualization techniques for pulsed terahertz (THz) images of tissue samples. Specifically, our research objective is to effectively differentiate between heterogeneous regions of breast tissues that contain tumors diagnosed as triple negative infiltrating ductal carcinoma (IDC). Tissue slices and blocks of varying thicknesses were prepared and scanned using our lab's THz pulsed imaging system. One of the challenges we have encountered in visualizing the obtained images and differentiating between healthy and cancerous regions of the tissues is that most THz images have a low level of details and narrow contrast, making it difficult to accurately identify and visualize the margins around the IDC. To overcome this problem, we have applied and evaluated a number of image processing techniques to the scanned 3D THz images. In particular, we employed various spatial filtering and intensity transformation techniques to emphasize the small details in the images and adjust the image contrast. For each of these methods, we investigated how varying filter sizes and parameters affect the amount of enhancement applied to the images. Our experimentation shows that several image processing techniques are effective in producing THz images of breast tissue samples that contain distinguishable details, making further segmentation of the different image regions promising.

  1. Pregnancy stimulates tumor angiogenesis in breast carcinoma.

    Science.gov (United States)

    Genin, Anne-Sophie; Antoine, Martine; Aractingi, Selim; Rouzier, Roman

    2014-01-01

    The mechanisms responsible for the poor prognosis of pregnancy-associated breast cancer (PABC) remain not well-understood. We studied angiogenesis and lymphangiogenesis as they are known prognostic factors in breast cancer. We conducted a case control study of breast cancer comparing women with and without PABC matched for age and histological parameters. Surgical specimen sections were immunostained with anti-CD31 for angiogenesis and anti-D2-40 for lymphangiogenesis, then analyzed using vessel density, ratio of the vascular area and the Chalkley count. Seventeen patients with PABC and 22 controls were included. Angiogenesis was significantly increased in tumor tissues, and tended to be higher in healthy breast tissues from the PABC group compared to controls. In contrast, no difference between the two groups was found concerning lymphangiogenesis both in tumor and healthy breast tissues. Pregnancy enhances angiogenesis in breast cancer. This phenomenon appears to explain the poor prognosis of PABC.

  2. Epidemiology of breast cancer subtypes in two prospective cohort studies of breast cancer survivors

    National Research Council Canada - National Science Library

    Kwan, Marilyn L; Kushi, Lawrence H; Weltzien, Erin; Maring, Benjamin; Kutner, Susan E; Fulton, Regan S; Lee, Marion M; Ambrosone, Christine B; Caan, Bette J

    2009-01-01

    The aim of this study was to describe breast tumor subtypes by common breast cancer risk factors and to determine correlates of subtypes using baseline data from two pooled prospective breast cancer...

  3. Tumor-specific expression of αvβ3 integrin promotes spontaneous metastasis of breast cancer to bone

    Science.gov (United States)

    Sloan, Erica K; Pouliot, Normand; Stanley, Kym L; Chia, Jenny; Moseley, Jane M; Hards, Daphne K; Anderson, Robin L

    2006-01-01

    Introduction Studies in xenograft models and experimental models of metastasis have implicated several β3 integrin-expressing cell populations, including endothelium, platelets and osteoclasts, in breast tumor progression. Since orthotopic human xenograft models of breast cancer are poorly metastatic to bone and experimental models bypass the formation of a primary tumor, however, the precise contribution of tumor-specific αvβ3 to the spontaneous metastasis of breast tumors from the mammary gland to bone remains unclear. Methods We used a syngeneic orthotopic model of spontaneous breast cancer metastasis to test whether exogenous expression of αvβ3 in a mammary carcinoma line (66cl4) that metastasizes to the lung, but not to bone, was sufficient to promote its spontaneous metastasis to bone from the mammary gland. The tumor burden in the spine and the lung following inoculation of αvβ3-expressing 66cl4 (66cl4beta3) tumor cells or control 66cl4pBabe into the mammary gland was analyzed by real-time quantitative PCR. The ability of these cells to grow and form osteolytic lesions in bone was determined by histology and tartrate-resistant acid phosphatase staining of bone sections following intratibial injection of tumor cells. The adhesive, migratory and invasive properties of 66cl4pBabe and 66cl4beta3 cells were evaluated in standard in vitro assays. Results The 66cl4beta3 tumors showed a 20-fold increase in metastatic burden in the spine compared with 66cl4pBabe. A similar trend in lung metastasis was observed. αvβ3 did not increase the proliferation of 66cl4 cells in vitro or in the mammary gland in vivo. Similarly, αvβ3 is not required for the proliferation of 66cl4 cells in bone as both 66cl4pBabe and 66cl4beta3 proliferated to the same extent when injected directly into the tibia. 66cl4beta3 tumor growth in the tibia, however, increased osteoclast recruitment and bone resorption compared with 66cl4 tumors. Moreover, αvβ3 increased 66cl4 tumor cell

  4. Evaluation of tumor extent in breast cancer patients using real-time MR navigated ultrasound: Preliminary study

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Jung Min, E-mail: imchangjm@gmail.com [Department of Radiology, Seoul National University Hospital, 28, Yongon-dong, Chongno-gu, Seoul 110-744 (Korea, Republic of); Han, Wonshik, E-mail: hanw@snu.ac.kr [Department of Surgery, Seoul National University Hospital, 28, Yongon-dong, Chongno-gu, Seoul 110-744 (Korea, Republic of); Moon, Hyeong-Gon, E-mail: moonhgsurgi@gmail.com [Department of Surgery, Seoul National University Hospital, 28, Yongon-dong, Chongno-gu, Seoul 110-744 (Korea, Republic of); Yi, Ann, E-mail: an_nie@naver.com [Department of Radiology, Seoul Metropolitan Government Seoul National University, Boramae Medical Center, 41, Boramae-gil, Dongjak-gu, Seoul 156-707 (Korea, Republic of); Cho, Nariya, E-mail: river7774@gmail.com [Department of Radiology, Seoul National University Hospital, 28, Yongon-dong, Chongno-gu, Seoul 110-744 (Korea, Republic of); Koo, Hye Ryoung, E-mail: huilings@hanmail.net [Department of Radiology, Seoul National University Hospital, 28, Yongon-dong, Chongno-gu, Seoul 110-744 (Korea, Republic of); Park, In Ae, E-mail: iapark@snu.ac.kr [Department of Pathology, Seoul National University Hospital, 28, Yongon-dong, Chongno-gu, Seoul 110-744 (Korea, Republic of); Kim, Seung Ja, E-mail: winnerkim89@gmail.com [Department of Radiology, Seoul Metropolitan Government Seoul National University, Boramae Medical Center, 41, Boramae-gil, Dongjak-gu, Seoul 156-707 (Korea, Republic of); Noh, Dong-Young, E-mail: dynoh@plaza.snu.ac.kr [Department of Surgery, Seoul National University Hospital, 28, Yongon-dong, Chongno-gu, Seoul 110-744 (Korea, Republic of); Moon, Woo Kyung, E-mail: moonwk@snu.ac.kr [Department of Radiology, Seoul National University Hospital, 28, Yongon-dong, Chongno-gu, Seoul 110-744 (Korea, Republic of)

    2012-11-15

    Objectives: To evaluate the accuracy of real-time MR navigated ultrasound (MRnav US) for tumor extent measurements in breast cancer and to investigate variables influencing the accuracy of MRnav US in comparison with US alone. Methods: Fifty-three patients with 60 malignancies underwent preoperative breast MRI and US with or without MRI navigation. Maximum lesion sizes based on MRnav US and US alone were measured, and their relationship with the pathology was analyzed considering the differences in the clinicopathologic variables of the patients. Results: Among 60 breast cancers, mean lesion size at initial breast US without MRI navigation and at MRI-navigated US was 19 mm and 24 mm, respectively, compared with 28 mm on the histopathology. Overall, the tumor size estimated with MRnav US was more strongly correlated with the histologic tumor size than with US alone. Accurate measurements by MRnav US were significantly more frequent in the lesions that were presented as a mass type on MRI. In addition, the accurate measurement of mass extent was improved with MRnav US in patients who had non-mass type lesions on MRI and who had undergone neoadjuvant systemic chemotherapy when compared with US alone. Conclusion: MRnav US was more accurate for tumor extent estimation than US alone, and specific clinicopathologic variables can affect the accuracy of MRnav US.

  5. GPNMB cooperates with neuropilin-1 to promote mammary tumor growth and engages integrin α5β1 for efficient breast cancer metastasis.

    Science.gov (United States)

    Maric, G; Annis, M G; Dong, Z; Rose, A A N; Ng, S; Perkins, D; MacDonald, P A; Ouellet, V; Russo, C; Siegel, P M

    2015-10-01

    Glycoprotein nmb (GPNMB) promotes breast tumor growth and metastasis and its expression in tumor epithelium correlates with poor prognosis in breast cancer patients. Despite its biological and clinical significance, little is known regarding the molecular mechanisms engaged by GPNMB. Herein, we show that GPNMB engages distinct functional domains and mechanisms to promote primary tumor growth and metastasis. We demonstrate that neuropilin-1 (NRP-1) expression is increased in breast cancer cells that overexpress GPNMB. Interestingly, the GPNMB-driven increase in NRP-1 expression potentiated vascular endothelial growth factor signaling in breast cancer cells and was required for the growth, but not metastasis, of these cells in vivo. Interrogation of RNAseq data sets revealed a positive correlation between GPNMB and NRP-1 levels in human breast tumors. Furthermore, we ascribe pro-growth and pro-metastatic functions of GPNMB to its ability to bind α5β1 integrin and increase downstream signaling in breast cancer cells. We show that GPNMB enhances breast cancer cell adhesion to fibronectin, increases α5β1 expression and associates with this receptor through its RGD motif. GPNMB recruitment into integrin complexes activates Src and Fak signaling pathways in an RGD-dependent manner. Importantly, both the RGD motif and cytoplasmic tail of GPNMB are required to promote primary mammary tumor growth; however, only mutation of the RGD motif impaired the formation of lung metastases. Together, these findings identify novel and distinct molecular mediators of GPNMB-induced breast cancer growth and metastasis.

  6. Evaluation of a Hanging-Breast PET System for Primary Tumor Visualization in Patients With Stage I-III Breast Cancer: Comparison With Standard PET/CT.

    Science.gov (United States)

    Teixeira, Suzana C; Rebolleda, José Ferrér; Koolen, Bas B; Wesseling, Jelle; Jurado, Raúl Sánchez; Stokkel, Marcel P M; Del Puig Cózar Santiago, María; van der Noort, Vincent; Rutgers, Emiel J Th; Valdés Olmos, Renato A

    2016-06-01

    The purposes of this study were to evaluate the performance of a mammography with molecular imaging PET (MAMMI-PET) system for breast imaging in the hanging-breast position for the visualization of primary breast cancer lesions and to compare this method with whole-body PET/CT. Between March 2011 and March 2014, a prospective evaluation included women with one or more histologically confirmed primary breast cancer lesions (index lesions). After injection of 180-240 MBq of (18)F-FDG, whole-body PET/CT and MAMMI-PET acquisitions were performed, index lesions were scored 0, 1, or 2 for FDG uptake relative to background. Detection and FDG uptake were compared by breast length, maximal tumor diameter, affected breast quadrants, tumor grade, and histologic and immunologic sub-types. Finally, the two PET modalities were compared for detection of index lesions. For 234 index lesions (diameter, 5-170 mm), the overall sensitivity was 88.9% for MAMMI-PET and 91% for PET/CT (p = 0.61). Twenty-three (9.8%) index lesions located too close to the pectoral muscle were missed with MAMMI-PET, and 20 index lesions were missed with PET/CT. Lesion visibility on MAMMI-PET images was influenced by tumor grade (p = 0.034) but not by cancer subtype (p = 0.65). Although in an overall evaluation MAMMI-PET was not superior to PET/CT, MAMMI-PET does have higher sensitivity for primary breast cancer lesions within the scanning range of the device. Optimization of the positioning device may increase visualization of the most dorsal lesions.

  7. Comparison of immune microenvironments between primary tumors and brain metastases in patients with breast cancer.

    Science.gov (United States)

    Ogiya, Rin; Niikura, Naoki; Kumaki, Nobue; Yasojima, Hiroyuki; Iwasa, Tsutomu; Kanbayashi, Chizuko; Oshitanai, Risa; Tsuneizumi, Michiko; Watanabe, Ken-Ichi; Matsui, Akira; Fujisawa, Tomomi; Saji, Shigehira; Masuda, Norikazu; Tokuda, Yutaka; Iwata, Hiroji

    2017-11-28

    Immune checkpoint inhibitors are reported to be effective in patients with brain metastases. However, detailed characteristics of the brain metastasis immune microenvironment remain unexplored. The median tumor-infiltrating lymphocyte (TIL) category in brain metastases was 5% (1-70%). In 46 pair-matched samples, the percentages of TILs were significantly higher in primary breast tumors than in brain metastases (paired t-test, P L1, PD-L2, and HLA class I was also performed. There are significantly fewer TILs in brain metastases than in primary breast tumors.

  8. Breast Cancer Disparities: A Multicenter Comparison of Tumor Diagnosis, Characteristics, and Surgical Treatment in China and the U.S.

    Science.gov (United States)

    Sivasubramaniam, Priya G; Zhang, Bai-Lin; Zhang, Qian; Smith, Jennifer S; Zhang, Bin; Tang, Zhong-Hua; Chen, Guo-Ji; Xie, Xiao-Ming; Xu, Xiao-Zhou; Yang, Hong-Jian; He, Jian-Jun; Li, Hui; Li, Jia-Yuan; Fan, Jin-Hu; Qiao, You-Lin

    2015-09-01

    Incidence of and mortality rates for breast cancer continue to rise in the People's Republic of China. The purpose of this study was to analyze differences in characteristics of breast malignancies between China and the U.S. Data from 384,262 breast cancer patients registered in the U.S. Surveillance, Epidemiology, and End Results (SEER) program from 2000 to 2010 were compared with 4,211 Chinese breast cancer patients registered in a Chinese database from 1999 to 2008. Outcomes included age, race, histology, tumor and node staging, laterality, surgical treatment method, and reconstruction. The Pearson chi-square and Fisher's exact tests were used to compare rates. Infiltrating ductal carcinoma was the most common type of malignancy in the U.S. and China. The mean number of positive lymph nodes was higher in China (2.59 vs. 1.31, p China (stage IIA vs. I, p China (32.63 vs. 21.57 mm). Mean age at diagnosis was lower in China (48.28 vs. 61.29 years, p China, and 0.02% in China underwent reconstructive surgery. Chinese women were diagnosed at younger ages with higher stage and larger tumors and underwent more aggressive surgical treatment. Prospective trials should be conducted to address screening, surgical, and tumor discrepancies between China and the U.S. Breast cancer patients in China are diagnosed at later stages than those in America, which might contribute to different clinical management and lower 5-year survival rate. This phenomenon suggests that an earlier detection and treatment program should be widely implemented in China. By comparing the characteristics of Chinese and Chinese-American patients, we found significant differences in tumor size, lymph nodes metastasis, and age at diagnosis. These consequences indicated that patients with similar genetic backgrounds may have different prognoses due to the influence of environment and social economic determinates. ©AlphaMed Press.

  9. Relation between primary tumor FDG avidity and site of first distant metastasis in patients with breast cancer.

    Science.gov (United States)

    Lim, Chae Hong; Moon, Seung Hwan; Cho, Young Seok; Im, Young-Hyuck; Choe, Yearn Seong; Kim, Byung-Tae; Lee, Kyung-Han

    2016-08-01

    Identification of tumor imaging features associated with metastatic pattern may allow better understanding of cancer dissemination. Here, we investigated how primary tumor F-fluorodeoxyglucose (FDG) avidity influences the first site of breast cancer metastasis.Subjects were 264 patients with advanced breast cancer who underwent positron emission tomography/computed tomography at diagnosis and had metastasis at presentation (n = 193) or metastatic relapse after surgery (n = 71). Primary tumor FDG avidity (maximum SUV [SUVmax] ≥10.1) was compared with histology and first metastatic sites.The most common site of first metastasis was the bone, occurring in 62.7% of patients with metastasis at presentation and 38.0% of those with metastatic relapse. First metastasis to lung occurred in 30.1% and 35.2%, and to liver in 25.4% and 15.2% of respective groups. In patients with metastasis at presentation, primary tumors were FDG avid in 98/193 cases, and this was associated with more frequent first metastasis to lung (37.8% vs 22.1%; P = 0.018). In patients with metastasis relapse, primary tumors were FDG avid in 31/71 cases, and this was associated with more frequent first metastasis to lung (48.4% vs 25.0%; P = 0.041) and liver (29.0% vs 5.0%; P = 0.008). In patients with metastasis relapse, primary tumors that were FDG avid but hormone receptor negative had more first metastasis to lung (57.9% vs 26.9%; P = 0.016).FDG-avid primary breast tumors have favored first spread to the lung and liver, which suggests that tumor cells with heightened glycolytic activity better colonize these organs.

  10. Shikonin Inhibits the Proliferation of Human Breast Cancer Cells by Reducing Tumor-Derived Exosomes

    Directory of Open Access Journals (Sweden)

    Yao Wei

    2016-06-01

    Full Text Available Shikonin is a naphthoquinone isolated from the traditional Chinese medicine Lithospermum. It has been used in the treatment of various tumors. However, the effects of shikonin on such diseases have not been fully elucidated. In the present study, we detected the exosome release of a breast cancer cell line (MCF-7 with shikonin treatment and found a positive relationship between the level of secreted exosomes and cell proliferation. We next analyzed miRNA profiles in MCF-7 cells and exosomes and found that some miRNAs are specifically sorted and abundant in exosomes. Knockdown of the most abundant miRNAs in exosomes and the MCF-7 proliferation assay showed that miR-128 in exosomes negatively regulates the level of Bax in MCF-7 recipient cells and inhibits cell proliferation. These results show that shikonin inhibits the proliferation of MCF-7 cells through reducing tumor-derived exosomal miR-128. The current study suggests that shikonin suppresses MCF-7 growth by the inhibition of exosome release.

  11. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters

    National Research Council Canada - National Science Library

    Kevin J. Cheung; Veena Padmanaban; Vanesa Silvestri; Koen Schipper; Joshua D. Cohen; Amanda N. Fairchild; Michael A. Gorin; James E. Verdone; Kenneth J. Pienta; Joel S. Bader; Andrew J. Ewald

    2016-01-01

    ...? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases...

  12. Do EBV Encoded Small RNAs Interfere With Tumor Suppressor APC in EBV Associated Breast Cancers

    National Research Council Canada - National Science Library

    Ghosh, Sajal K

    2005-01-01

    ...) nasopharyngeal carcinoma Hodgkin%s disease and lympho proliferative disorders of immuno suppressed patients as well as significant portion of estrogen receptor negative invasive breast cancers and large numbers of rapidly growing...

  13. Molecular characterization of circulating tumor cells from patients with metastatic breast cancer reflects evolutionary changes in gene expression under the pressure of systemic therapy

    Czech Academy of Sciences Publication Activity Database

    Aaltonen, K. E.; Novosadová, Vendula; Bendahl, P.-O.; Graffman, C.; Larsson, A.-M.; Ryden, L.

    2017-01-01

    Roč. 8, č. 28 (2017), s. 45544-45565 ISSN 1949-2553 Keywords : metastatic breast cancer * circulating tumor cells * gene expression Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.168, year: 2016

  14. Homocysteine Is an Oncometabolite in Breast Cancer, Which Promotes Tumor Progression and Metastasis

    Science.gov (United States)

    2017-01-01

    ANGPTL-4 and MMP-9 in breast cancer cell lines. TASK 5: Analyze the influence of homocysteine and ANGPTL-4 on the permeability of lung...of protein lysates for western blotting, and preparation of RNA for qPCR. Lungs were perfused with India ink and Fekete solution to visualize... permeability of lung microvascular endothelial cells. Lung is the one of the primary sites for breast cancer metastasis, and it is believed that the

  15. Cytokines, Neovascularization and Breast Cancer

    Science.gov (United States)

    1996-10-01

    Rationale Angiogenesis is important in the growth and metastases of human breast cancer . We hypothesize that this process is under the control of...staining patern seen in invasive cancer , in situ cancer , and benign breast tissue. Note that staining was graded as the most intensly staining area. The...blocked, tumors do not grow or metastasize . The purpose of this study was to demonstrate that breast cancer cells are capable of participating in this

  16. Distribution of molecular breast cancer subtypes among Algerian women and correlation with clinical and tumor characteristics: a population-based study.

    Science.gov (United States)

    Cherbal, Farid; Gaceb, Hadjer; Mehemmai, Chiraz; Saiah, Insaf; Bakour, Rabah; Rouis, Abdelhalim Ould; Boualga, Kada; Benbrahim, Wassila; Mahfouf, Hassen

    2015-01-01

    Breast cancer is currently the leading cause of cancer morbidity and mortality among Algerian women. Molecular classification of breast cancer is an important factor for prognosis and clinical outcome. There are limited data regarding molecular breast cancer subtypes among Algerian women. The objective of the present study was to analyze the proportion and distribution of molecular subtypes and to determine their associations with some clinical and tumor characteristics: age at diagnosis, menopausal status, histological type and histological grade. The study population included 3014 female breast cancers. We analyzed breast cancers from cancer registries of academic medical oncology service of public hospital of Rouiba, anticancer center of Blida, and anticancer center of Batna. Breast cancers were diagnosed between 2008 and 2013. Molecular subtype classification was done based on immunohistochemical surrogates for ER (Estrogen receptor), PR (Progesterone receptor) and HER2 (human epidermal growth factor receptor-2) status obtained from medical records for 3014 breast cancer patients. Breast cancer subtypes definitions were as follow: Luminal A (ER+ and/or PR+, HER2-), Luminal B (ER+ and/or PR+, HER2+), TNBC (ER-, PR - , HER2-), HER2+ (ER-, PR-, HER2+). Molecular subtypes were correlated with the clinicopathological characteristics of the tumors. The mean age at diagnosis cancer was 48.5 years. Proportions of the luminal A, TNBC, luminal B and HER2+ breast cancer subtypes were 50.59%, 20.80%, 19.67% and 8.92%, respectively. We noted a significant difference in the distribution of age at diagnosis among the four cancer subtypes (P= 0.004). Luminal A, Luminal B, TNBC and HER2+ subtypes were significantly different by premenopausal and postmenopausal status (P= 0.01). Invasive Ductal Carcinoma was the most common histological type in all breast cancer subtypes. Tumors with histological grade 2 and 3 were more common in patients for the four breast cancer subtypes. For

  17. Quantitative ultrasound evaluation of tumor cell death response in locally advanced breast cancer patients receiving chemotherapy.

    Science.gov (United States)

    Sadeghi-Naini, Ali; Papanicolau, Naum; Falou, Omar; Zubovits, Judit; Dent, Rebecca; Verma, Sunil; Trudeau, Maureen; Boileau, Jean Francois; Spayne, Jacqueline; Iradji, Sara; Sofroni, Ervis; Lee, Justin; Lemon-Wong, Sharon; Yaffe, Martin; Kolios, Michael C; Czarnota, Gregory J

    2013-04-15

    Quantitative ultrasound techniques have been recently shown to be capable of detecting cell death through studies conducted on in vitro and in vivo models. This study investigates for the first time the potential of early detection of tumor cell death in response to clinical cancer therapy administration in patients using quantitative ultrasound spectroscopic methods. Patients (n = 24) with locally advanced breast cancer received neoadjuvant chemotherapy treatments. Ultrasound data were collected before treatment onset and at 4 times during treatment (weeks 1, 4, and 8, and preoperatively). Quantitative ultrasound parameters were evaluated for clinically responsive and nonresponding patients. Results indicated that quantitative ultrasound parameters showed significant changes for patients who responded to treatment, and no similar alteration was observed in treatment-refractory patients. Such differences between clinically and pathologically determined responding and nonresponding patients were statistically significant (P < 0.05) after 4 weeks of chemotherapy. Responding patients showed changes in parameters related to cell death with, on average, an increase in mid-band fit and 0-MHz intercept of 9.1 ± 1.2 dBr and 8.9 ± 1.9 dBr, respectively, whereas spectral slope was invariant. Linear discriminant analysis revealed a sensitivity of 100% and a specificity of 83.3% for distinguishing nonresponding patients by the fourth week into a course of chemotherapy lasting several months. This study reports for the first time that quantitative ultrasound spectroscopic methods can be applied clinically to evaluate cancer treatment responses noninvasively. The results form a basis for monitoring chemotherapy effects and facilitating the personalization of cancer treatment.

  18. miR-199a-5p confers tumor-suppressive role in triple-negative breast cancer.

    Science.gov (United States)

    Chen, Jiawei; Shin, Vivian Y; Siu, Man T; Ho, John C W; Cheuk, Isabella; Kwong, Ava

    2016-11-14

    Triple-negative breast cancer (TNBC) remains a poor prognostic factor for breast cancer since no effective targeted therapy is readily available. Our previous studies confirmed miR-199a-5p is a TNBC-specific circulating biomarker, however, its functional roles in breast cancer is largely unknown. Thus, we investigated the functional implication of miR-199a-5p in TNBC and its potential underlying mechanisms. MTT assay was performed to investigate the cell proliferation after transient transfection of miR-199a-5p in MDA-MB-231 cell line, followed by cell cycle analysis. Transwell invasion assay and wound healing assay were used to study the invasion and migration ability respectively. To further investigate the stemness-related characteristics of miR-199a-5p in breast cancer cells, single-cell clonogenic assay and aldehyde dehydrogenase (ALDH) assay were performed. 32 normal and 100 breast cancer patients' plasma were recruited to identify the potential circulating markers by qPCR. Cell proliferation assay revealed significant inhibition after miR-199a-5p ectopic expression (p breast cancer plasma especially in TNBC (p = 0.0248). PIK3CD was identified as a potential downstream target of miR-199a-5p. Taken together, we unraveled, for the first time, the tumor-suppressive role of miR-199a-5p in TNBC, which attributed to EMT and cancer stemness properties, providing a novel therapeutic options towards this aggressive disease.

  19. Risks of Breast Cancer Screening

    Science.gov (United States)

    ... of Breast & Gynecologic Cancers Breast Cancer Screening Research Breast Cancer Screening (PDQ®)–Patient Version What is screening? ... cancer screening: Cancer Screening Overview General Information About Breast Cancer Key Points Breast cancer is a disease ...

  20. Pattern of Tumor Shrinkage during Neoadjuvant Chemotherapy Is Associated with Prognosis in Low-Grade Luminal Early Breast Cancer.

    Science.gov (United States)

    Fukada, Ippei; Araki, Kazuhiro; Kobayashi, Kokoro; Shibayama, Tomoko; Takahashi, Shunji; Gomi, Naoya; Kokubu, Yumi; Oikado, Katsunori; Horii, Rie; Akiyama, Futoshi; Iwase, Takuji; Ohno, Shinji; Hatake, Kiyohiko; Sata, Naohiro; Ito, Yoshinori

    2018-01-01

    Purpose To evaluate the association between tumor shrinkage patterns shown with magnetic resonance (MR) imaging during neoadjuvant chemotherapy (NAC) and prognosis in patients with low-grade luminal breast cancer. Materials and Methods This retrospective study was approved by the institutional review board and informed consent was obtained from all subjects. The low-grade luminal breast cancer was defined as hormone receptor-positive and human epidermal growth factor receptor 2-negative with nuclear grades 1 or 2. The patterns of tumor shrinkage as revealed at MR imaging were categorized into two types: concentric shrinkage (CS) and non-CS. Among 854 patients who had received NAC in a single institution from January 2000 to December 2009, 183 patients with low-grade luminal breast cancer were retrospectively evaluated for the development set. Another data set from 292 patients who had received NAC in the same institution between January 2010 and December 2012 was used for the validation set. Among these 292 patients, 121 patients with low-grade luminal breast cancer were retrospectively evaluated. Results In the development set, the median observation period was 67.9 months. Recurrence was observed in 31 patients, and 16 deaths were related to breast cancer. There were statistically significant differences in both the disease-free survival (DFS) and overall survival (OS) rates between patterns of tumor shrinkage (P breast cancer. DFS rate was significantly longer in patients with the CS pattern (72.8 months; 95% confidence interval [CI]: 69.9, 75.6 months) than in those with the non-CS pattern (56.0 months; 95% CI: 49.1, 62.9 months; P ≤ .001). The CS pattern was associated with an excellent prognosis (median OS, 80.6 months; 95% CI: 79.3, 81.8 months vs 65.0 months; 95% CI: 60.1, 69.8 months; P = .004). Multivariate analysis demonstrated that the CS pattern had the only significant independent association with DFS (P = .007) and OS (P = .037) rates. Conclusion

  1. Transcriptome analysis of basal and luminal tumor-initiating cells in ErbB2-driven breast cancer

    Directory of Open Access Journals (Sweden)

    Nicholas Borcherding

    2015-06-01

    Full Text Available Breast cancer is the leading cause of cancer-related mortality for females worldwide [1]. Improving early screening strategies and understanding the events that lead to tumor initiation have led to demonstrable improvements in clinical outcome. Our previous work revealed a variance in the tumorigenic capacity between different mammary epithelial cell populations in an MMTV-ErbB2 mouse model. In order to greater understand how different mammary epithelial cells influence the tumorigenic capacity in ErbB2-induced breast cancer, we transplanted different cell populations from pre-neoplastic MMTV-ErbB2 female mice into recipient mice for tumorigenic study. We found that different mammary epithelial cells bear different tumorigenic potentials even when induced by the same ErbB2 proto-oncogene. To understand the difference in tumors formed from different epithelial cells, we performed gene expression profiling using these tumors (GSE64487. Several genes were further validated using real-time reverse transcription polymerase chain reaction (RT-PCR. Here we provide further details on the experimental methods and microarray analysis. This data provides a resource to further understanding how different mammary cell populations can initiate ErbB2-driven tumors and the role of these cell populations as putative tumor-initiating cells (TICs.

  2. Quantification of free circulating tumor DNA as a diagnostic marker for breast cancer.

    Science.gov (United States)

    Catarino, Raquel; Ferreira, Maria M; Rodrigues, Helena; Coelho, Ana; Nogal, Ana; Sousa, Abreu; Medeiros, Rui

    2008-08-01

    To determine whether the amounts of circulating DNA could discriminate between breast cancer patients and healthy individuals by using real-time PCR quantification methodology. Our standard protocol for quantification of cell-free plasma DNA involved 175 consecutive patients with breast cancer and 80 healthy controls. We found increased levels of circulating DNA in breast cancer patients compared to control individuals (105.2 vs. 77.06 ng/mL, p < 0.001). We also found statistically significant differences in circulating DNA amounts in patients before and after breast surgery (105.2 vs. 59.0 ng/mL, p = 0.001). Increased plasma cell-free DNA concentration was a strong risk factor for breast cancer, conferring an increased risk for the presence of this disease (OR, 12.32; 95% CI, 2.09-52.28; p < 0.001). Quantification of circulating DNA by real-time PCR may be a good and simple tool for detection of breast cancer with a potential to clinical applicability together with other current methods used for monitoring the disease.

  3. Expression of protein tyrosine phosphatase alpha (RPTPalpha) in human breast cancer correlates with low tumor grade, and inhibits tumor cell growth in vitro and in vivo

    DEFF Research Database (Denmark)

    Ardini, E; Agresti, R; Tagliabue, E

    2000-01-01

    of Src family kinases, and regulation of integrin signaling, cell adhesion, and growth factor responsiveness. To explore its potential contribution to human neoplasia, we surveyed RPTPalpha protein levels in primary human breast cancer. We found RPTPalpha levels to vary widely among tumors, with 29......% of cases manifesting significant overexpression. High RPTPalpha protein levels correlated significantly with low tumor grade and positive estrogen receptor status. Expression of RPTPalpha in breast carcinoma cells led to growth inhibition, associated with increased accumulation in G0 and G1, and delayed...... tumor growth and metastasis. To our knowledge, this is the first example of a study correlating expression level of a specific bona fide PTP with neoplastic disease status in humans....

  4. Elevated nuclear expression of the SMRT corepressor in breast cancer is associated with earlier tumor recurrence.

    Science.gov (United States)

    Smith, Carolyn L; Migliaccio, Ilenia; Chaubal, Vaishali; Wu, Meng-Fen; Pace, Margaret C; Hartmaier, Ryan; Jiang, Shiming; Edwards, Dean P; Gutiérrez, M Carolina; Hilsenbeck, Susan G; Oesterreich, Steffi

    2012-11-01

    Silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), also known as nuclear corepressor 2 (NCOR2) is a transcriptional corepressor for multiple members of the nuclear receptor superfamily of transcription factors, including estrogen receptor-α (ERα). In the classical model of corepressor action, SMRT binds to antiestrogen-bound ERα at target promoters and represses ERα transcriptional activity and gene expression. Herein SMRT mRNA and protein expression was examined in a panel of 30 breast cancer cell lines. Expression of both parameters was found to vary considerably amongst lines and the correlation between protein and mRNA expression was very poor (R (2) = 0.0775). Therefore, SMRT protein levels were examined by immunohistochemical staining of a tissue microarray of 866 patients with stage I-II breast cancer. Nuclear and cytoplasmic SMRT were scored separately according to the Allred score. The majority of tumors (67 %) were negative for cytoplasmic SMRT, which when detected was found at very low levels. In contrast, nuclear SMRT was broadly detected. There was no significant difference in time to recurrence (TTR) according to SMRT expression levels in the ERα-positive tamoxifen-treated patients (P = 0.297) but the difference was significant in the untreated patients (P = 0.01). In multivariate analysis, ERα-positive tamoxifen-untreated patients with high nuclear SMRT expression (SMRT 5-8, i.e., 2nd to 4th quartile) had a shorter TTR (HR = 1.94, 95 % CI, 1.24-3.04; P = 0.004) while there was no association with SMRT expression for ERα-positive tamoxifen-treated patients. There was no association between SMRT expression and overall survival for patients, regardless of whether they received tamoxifen. Thus while SMRT protein expression was not predictive of outcome after antiestrogen therapy, it may have value in predicting tumor recurrence in patients not receiving adjuvant tamoxifen therapy.

  5. Importance of Extracranial Disease Status and Tumor Subtype for Patients Undergoing Radiosurgery for Breast Cancer Brain Metastases

    Energy Technology Data Exchange (ETDEWEB)

    Dyer, Michael A.; Kelly, Paul J. [Department of Radiation Oncology, Dana-Farber/Brigham and Women' s Cancer Center, Boston, MA (United States); Harvard Medical School, Boston, MA (United States); Chen, Yu-Hui [Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA (United States); Pinnell, Nancy E. [Department of Radiation Oncology, Dana-Farber/Brigham and Women' s Cancer Center, Boston, MA (United States); Claus, Elizabeth B. [Harvard Medical School, Boston, MA (United States); Department of Neurosurgery, Brigham and Women' s Hospital, Boston, MA (United States); Yale University School of Medicine, New Haven, CT (United States); Lee, Eudocia Q. [Harvard Medical School, Boston, MA (United States); Center for Neuro-Oncology, Dana-Farber/Brigham and Women' s Center, Boston, MA (United States); Weiss, Stephanie E. [Department of Radiation Oncology, Dana-Farber/Brigham and Women' s Cancer Center, Boston, MA (United States); Harvard Medical School, Boston, MA (United States); Arvold, Nils D. [Harvard Radiation Oncology Program, Boston, MA (United States); Lin, Nancy U. [Harvard Medical School, Boston, MA (United States); Department of Medical Oncology, Dana-Farber/Brigham and Women' s Cancer Center, Boston, MA (United States); Alexander, Brian M., E-mail: bmalexander@lroc.harvard.edu [Department of Radiation Oncology, Dana-Farber/Brigham and Women' s Cancer Center, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)

    2012-07-15

    Purpose: In this retrospective study, we report on outcomes and prognostic factors for patients treated with stereotactic radiosurgery (SRS) for breast cancer brain metastases. Methods and Materials: We identified 132 consecutive patients with breast cancer who were treated with SRS for brain metastases from January 2000 through June 2010. We retrospectively reviewed records of the 51 patients with adequate follow-up data who received SRS as part of the initial management of their brain metastases. Overall survival (OS) and time to central nervous system (CNS) progression from the date of SRS were calculated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model. Results: Triple negative subtype was associated with CNS progression on univariate analysis (hazard ratio [HR] = 5.0, p = 0.008). On multivariate analysis, triple negative subtype (HR = 8.6, p = 0.001), Luminal B subtype (HR = 4.3, p = 0.03), and omission of whole-brain radiation therapy (HR = 3.7, p = 0.02) were associated with CNS progression. With respect to OS, Karnofsky Performance Status (KPS) {<=} 80% (HR = 2.0, p = 0.04) and progressive extracranial disease (HR = 3.1, p = 0.002) were significant on univariate analysis; KPS {<=} 80% (HR = 4.1, p = 0.0004), progressive extracranial disease (HR = 6.4, p < 0.0001), and triple negative subtype (HR = 2.9, p = 0.04) were significant on multivariate analysis. Although median survival times were consistent with those predicted by the breast cancer-specific Graded Prognostic Assessment (Breast-GPA) score, the addition of extracranial disease status further separated patient outcomes. Conclusions: Tumor subtype is associated with risk of CNS progression after SRS for breast cancer brain metastases. In addition to tumor subtype and KPS, which are incorporated into the Breast-GPA, progressive extracranial disease may be an important prognostic factor for OS.

  6. Cancer progression by breast tumors with Pit-1-overexpression is blocked by inhibition of metalloproteinase (MMP)-13.

    Science.gov (United States)

    Sendon-Lago, Juan; Seoane, Samuel; Eiro, Noemi; Bermudez, Maria A; Macia, Manuel; Garcia-Caballero, Tomas; Vizoso, Francisco J; Perez-Fernandez, Roman

    2014-12-20

    The POU class 1 homeobox 1 transcription factor (POU1F1, also known as Pit-1) is expressed in the mammary gland and its overexpression induces profound phenotypic changes in proteins involved in cell proliferation, apoptosis, and invasion. Patients with breast cancer and elevated expression of Pit-1 show a positive correlation with the occurrence of distant metastasis. In this study we evaluate the relationship between Pit-1 and two collagenases: matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-13 (MMP-13), which have been related to metastasis in breast cancer. We began by transfecting the MCF-7 and MDA-MB-231 human breast adenocarcinoma cell lines with the Pit-1 overexpression vector (pRSV-hPit-1). Afterward, the mRNA, protein, and transcriptional regulation of both MMP-1 and MMP-13 were evaluated by real-time PCR, Western blot, chromatin immunoprecipitation (ChIP), and luciferase reporter assays. We also evaluated Pit-1 overexpression with MMP-1 and MMP-13 knockdown in a severe combined immunodeficiency (SCID) mouse tumor xenograft model. Finally, by immunohistochemistry we correlated Pit-1 with MMP-1 and MMP-13 protein expression in 110 human breast tumors samples. Our data show that Pit-1 increases mRNA and protein of both MMP-1 and MMP-13 through direct transcriptional regulation. In SCID mice, knockdown of MMP-13 completely blocked lung metastasis in Pit-1-overexpressing MCF-7 cells injected into the mammary fat pad. In breast cancer patients, expression of Pit-1 was found to be positively correlated with the presence of both MMP-1 and MMP-13. Our data indicates that Pit-1 regulates MMP-1 and MMP-13, and that inhibition of MMP-13 blocked invasiveness to lung in Pit-1-overexpressed breast cancer cells.

  7. Trace elements as tumor biomarkers and prognostic factors in breast cancer: a study through energy dispersive x-ray fluorescence

    Science.gov (United States)

    2012-01-01

    Background The application and better understanding of traditional and new breast tumor biomarkers and prognostic factors are increasing due to the fact that they are able to identify individuals at high risk of breast cancer, who may benefit from preventive interventions. Also, biomarkers can make possible for physicians to design an individualized treatment for each patient. Previous studies showed that trace elements (TEs) determined by X-Ray Fluorescence (XRF) techniques are found in significantly higher concentrations in neoplastic breast tissues (malignant and benign) when compared with normal tissues. The aim of this work was to evaluate the potential of TEs, determined by the use of the Energy Dispersive X-Ray Fluorescence (EDXRF) technique, as biomarkers and prognostic factors in breast cancer. Methods By using EDXRF, we determined Ca, Fe, Cu, and Zn trace elements concentrations in 106 samples of normal and breast cancer tissues. Cut-off values for each TE were determined through Receiver Operating Characteristic (ROC) analysis from the TEs distributions. These values were used to set the positive or negative expression. This expression was subsequently correlated with clinical prognostic factors through Fisher’s exact test and chi-square test. Kaplan Meier survival curves were also evaluated to assess the effect of the expression of TEs in the overall patient survival. Results Concentrations of TEs are higher in neoplastic tissues (malignant and benign) when compared with normal tissues. Results from ROC analysis showed that TEs can be considered a tumor biomarker because, after establishing a cut-off value, it was possible to classify different tissues as normal or neoplastic, as well as different types of cancer. The expression of TEs was found statistically correlated with age and menstrual status. The survival curves estimated by the Kaplan-Meier method showed that patients with positive expression for Cu presented a poor overall survival (p

  8. Epidemiology of Breast Cancer

    OpenAIRE

    南, 優子; ミナミ, ユウコ; MINAMI, Yuko

    2007-01-01

    During recent decades, breast cancer incidence has been increasing in Japan. Epidemiological studies have clarified the trend in breast cancer incidence and identified risk factors for breast cancer. Established risk factors for breast cancer include early age at menarche, late age at first birth, low parity, postmenopausal obesity, family history of breast cancer, and history of benign breast disease. Breast-feeding and physical activity may also be associated with breast cancer risk. Detail...

  9. Granzyme B-based cytolytic fusion protein targeting EpCAM specifically kills triple negative breast cancer cells in vitro and inhibits tumor growth in a subcutaneous mouse tumor model

    NARCIS (Netherlands)

    Amoury, Manal; Kolberg, Katharina; Pham, Anh-Tuan; Hristodorov, Dmitrij; Mladenov, Radoslav; Di Fiore, Stefano; Helfrich, Wijnand; Kiessling, Fabian; Fischer, Rainer; Pardo, Alessa; Thepen, Theophilus; Hussain, Ahmad F.; Nachreiner, Thomas; Barth, Stefan

    2016-01-01

    Triple-negative breast cancer (TNBC) is associated with poor prognosis and high prevalence among young premenopausal women. Unlike in other breast cancer subtypes, no targeted therapy is currently available. Overexpression of epithelial cell adhesion molecule (EpCAM) in 60% of TNBC tumors correlates

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

    DEFF Research Database (Denmark)

    Larsson, L.-I.; Holck, Susanne

    2007-01-01

    that there is a considerable heterogeneity in the cellular distribution of thymosin beta4 in breast cancer. In most tumors examined, cancer cells showed low or intermediate reactivity for thymosin beta4, whereas leukocytes and macrophages showed intense reactivity. In addition, endothelial cells showed variable reactivity...... to thymosin beta4, whereas myofibroblasts were negative. There was no correlation between the intensity of tumor cell staining and histological grade, whereas there was a tendency toward a correlation between endothelial cell staining and grade. These results demonstrate that multiple cell types within......Previous studies have shown that the G-actin sequestering polypeptide thymosin beta4 frequently is overexpressed in cancers and that such overexpression correlates to malignant progression. However, the localization of thymosin beta4 in human cancers has not been determined. We now demonstrate...

  11. Diagnosis of malignant tumors of female breast cancer by transmission optical tomography

    Directory of Open Access Journals (Sweden)

    I. V. Pyanov

    2012-01-01

    Full Text Available A review of the literature on diagnostic systems for the detection of breast cancer by optical tomography was presented. The actuality of the method of transmission of optical tomography and its advantages over existing methods of medical diagnosis of cancer have been substanti- ated. We have analyzed tomographic systems used for the diagnosis of breast cancer. The basic advantages and disadvantages of tomograph- ic systems using various types of radiation have been indicated. The results of review can be used in the development of technique for optical transmission tomography.

  12. Therapeutic Touch Has Significant Effects on Mouse Breast Cancer Metastasis and Immune Responses but Not Primary Tumor Size.

    Science.gov (United States)

    Gronowicz, Gloria; Secor, Eric R; Flynn, John R; Jellison, Evan R; Kuhn, Liisa T

    2015-01-01

    Evidence-based integrative medicine therapies have been introduced to promote wellness and offset side-effects from cancer treatment. Energy medicine is an integrative medicine technique using the human biofield to promote well-being. The biofield therapy chosen for study was Therapeutic Touch (TT). Breast cancer tumors were initiated in mice by injection of metastatic 66cl4 mammary carcinoma cells. The control group received only vehicle. TT or mock treatments were performed twice a week for 10 minutes. Two experienced TT practitioners alternated treatments. At 26 days, metastasis to popliteal lymph nodes was determined by clonogenic assay. Changes in immune function were measured by analysis of serum cytokines and by fluorescent activated cells sorting (FACS) of immune cells from the spleen and lymph nodes. No significant differences were found in body weight gain or tumor size. Metastasis was significantly reduced in the TT-treated mice compared to mock-treated mice. Cancer significantly elevated eleven cytokines. TT significantly reduced IL-1-a, MIG, IL-1b, and MIP-2 to control/vehicle levels. FACS demonstrated that TT significantly reduced specific splenic lymphocyte subsets and macrophages were significantly elevated with cancer. Human biofield therapy had no significant effect on primary tumor but produced significant effects on metastasis and immune responses in a mouse breast cancer model.

  13. Therapeutic Touch Has Significant Effects on Mouse Breast Cancer Metastasis and Immune Responses but Not Primary Tumor Size

    Directory of Open Access Journals (Sweden)

    Gloria Gronowicz

    2015-01-01

    Full Text Available Evidence-based integrative medicine therapies have been introduced to promote wellness and offset side-effects from cancer treatment. Energy medicine is an integrative medicine technique using the human biofield to promote well-being. The biofield therapy chosen for study was Therapeutic Touch (TT. Breast cancer tumors were initiated in mice by injection of metastatic 66cl4 mammary carcinoma cells. The control group received only vehicle. TT or mock treatments were performed twice a week for 10 minutes. Two experienced TT practitioners alternated treatments. At 26 days, metastasis to popliteal lymph nodes was determined by clonogenic assay. Changes in immune function were measured by analysis of serum cytokines and by fluorescent activated cells sorting (FACS of immune cells from the spleen and lymph nodes. No significant differences were found in body weight gain or tumor size. Metastasis was significantly reduced in the TT-treated mice compared to mock-treated mice. Cancer significantly elevated eleven cytokines. TT significantly reduced IL-1-a, MIG, IL-1b, and MIP-2 to control/vehicle levels. FACS demonstrated that TT significantly reduced specific splenic lymphocyte subsets and macrophages were significantly elevated with cancer. Human biofield therapy had no significant effect on primary tumor but produced significant effects on metastasis and immune responses in a mouse breast cancer model.

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

    Science.gov (United States)

    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.

  15. 7-Hydroxystaurosporine and Irinotecan Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors or Triple Negative Breast Cancer (Currently Accruing Only Triple-negative Breast Cancer Patients Since 6/8/2007)

    Science.gov (United States)

    2013-09-27

    Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Estrogen Receptor-negative Breast Cancer; Extensive Stage Small Cell Lung Cancer; Gastrointestinal Stromal Tumor; HER2-negative Breast Cancer; Metastatic Gastrointestinal Carcinoid Tumor; Ovarian Sarcoma; Ovarian Stromal Cancer; Progesterone Receptor-negative Breast Cancer; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adult Primary Liver Cancer; Recurrent Anal Cancer; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Borderline Ovarian Surface Epithelial-stromal Tumor; Recurrent Breast Cancer; Recurrent Cervical Cancer; Recurrent Colon Cancer; Recurrent Endometrial Carcinoma; Recurrent Esophageal Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Recurrent Prostate Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Cell Lung Cancer; Recurrent Small Intestine Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral

  16. Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer.

    Science.gov (United States)

    Osorio, Ana; de la Hoya, Miguel; Rodríguez-López, Raquel; Martínez-Ramírez, Angel; Cazorla, Alicia; Granizo, Juan José; Esteller, Manel; Rivas, Carmen; Caldés, Trinidad; Benítez, Javier

    2002-05-10

    The BRCA1 and BRCA2 genes are responsible for a high proportion of familial breast cancer; germline mutations in these genes confer a lifetime risk of about 70% for developing breast cancer. Most of the described deleterious mutations are small deletions or insertions that originate a truncated protein; however, in many cases, they are amino acid changes whose significance is unknown. In these cases, there are some tests that can analyze the meaning of these variants, but most remain unclassified. The BRCA genes are tumor suppressors and it is believed that complete loss of the wild-type allele is a common mechanism of inactivation in tumors from patients carrying a germline deleterious mutation in these genes; if this is true, loss of heterozygosity (LOH) analysis in the tumor sample could help to distinguish if a rare variant is either a deleterious mutation or a common polymorphism. In the present study, we performed LOH analysis at the BRCA loci in 47 tumors from patients who belonged to high-risk breast cancer families and were carriers of any type of alteration in these genes. Our results suggest that (i) loss of the wild-type allele is the most common mechanism of inactivation in tumors from patients who carry a deleterious mutation in any of the genes, (ii) this loss is not common when we analyze familial tumors not associated with mutations in BRCA and (iii) LOH can be used to clarify variants of unknown significance in the BRCA genes. Copyright 2002 Wiley-Liss, Inc.

  17. To clip or not to clip the breast tumor bed? A retrospective look at the geographic miss index and normal tissue index of 110 patients with breast cancer.

    Science.gov (United States)

    Ebner, Florian; de Gregorio, Nikolaus; Rempen, Andreas; Mohr, Peter; de Gregorio, Amelie; Wöckel, Achim; Janni, Wolfgang; Witucki, Gerlo

    2017-06-01

    Planning of breast radiation for patients with breast conserving surgery often relies on clinical markers such as scars. Lately, surgical clips have been used to identify the tumor location. The purpose of this study was to evaluate the geographic miss index (GMI) and the normal tissue index (NTI) for the electron boost in breast cancer treatment plans with and without surgical clips. A retrospective descriptive study of 110 consecutive post-surgical patients who underwent breast-conserving treatment in early breast cancer, in which the clinical treatment field with the radiologic (clipped) field were compared and GMI/NTI for the electron boost were calculated respectively. The average clinical field was 100 mm (range, 100-120 mm) and the clipped field was 90 mm (range, 80-100 mm). The average GMI was 11.3% (range, 0-44%), and the average NTI was 27.5% (range, 0-54%). The GMI and NTI were reduced through the use of intra-surgically placed clips. The impact of local tumor control on the survival of patients with breast cancer is also influenced by the precision of radiotherapy. Additionally, patients demand an appealing cosmetic result. This makes "clinical" markers such as scars unreliable for radiotherapy planning. A simple way of identifying the tissue at risk is by intra-surgical clipping of the tumor bed. Our results show that the use of surgical clips can reduce the diameter of the radiotherapy field and increase the accuracy of radiotherapy planning. With the placement of surgical clips, more tissue at risk is included in the radiotherapy field. Less normal tissue receives radiotherapy with the use of surgical clips.

  18. Monitoring of tumor growth and metastasis potential in MDA-MB-435s/tk-luc human breast cancer xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Y.-F. [Department of Radiological Sciences, National Yang-Ming University, 155, Sec. 2, Li-Nong Street, Pei-tou 112, Taipei, Taiwan (China); Lin, Y.-Y. [Department of Radiological Sciences, National Yang-Ming University, 155, Sec. 2, Li-Nong Street, Pei-tou 112, Taipei, Taiwan (China); Wang, H.-E. [Department of Radiological Sciences, National Yang-Ming University, 155, Sec. 2, Li-Nong Street, Pei-tou 112, Taipei, Taiwan (China); Liu, R.-S. [Department of Nuclear Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Nuclear Medicine Department, Veterans General Hospital, Taipei, Taiwan (China); Pang Fei [Department of Veterinary Medicine, National Taiwan University, Taipei, Taiwan (China); Hwang, J.-J. [Department of Radiological Sciences, National Yang-Ming University, 155, Sec. 2, Li-Nong Street, Pei-tou 112, Taipei, Taiwan (China)]. E-mail: jjhwang@ym.edu.tw

    2007-02-01

    Molecular imaging of reporter gene expression provides a rapid, sensitive and non-invasive monitoring of tumor behaviors. In this study, we reported the establishment of a novel animal model for longitudinal examination of tumor growth kinetics and metastatic spreading in vivo. The highly metastatic human breast carcinoma MDA-MB-435s cell line was engineered to stably express herpes simplex virus type 1 thymidine kinase (HSV-1-tk) and luciferase (luc). Both {sup 131}I-FIAU and D-luciferin were used as reporter probes. For orthotopic tumor formation, MDA-MB-435s/tk-luc cells were implanted into the first nipple of 6-week-old female NOD/SCID mice. For metastatic study, cells were injected via the lateral tail vein. Mice-bearing MDA-MB-435s/tk-luc tumors were scanned for tumor growth and metastatsis using Xenogen IVIS50 system. Gamma scintigraphy and whole-body autoradiography were also applied to confirm the tumor localization. The results of bioluminescence imaging as well as histopathological finding showed that tumors could be detected in femur, spine, ovary, lungs, kidney, adrenal gland, lymph nodes and muscle at 16 weeks post i.v. injection, and correlated photons could be quantified. This MDA-MB-435s/tk-luc human breast carcinoma-bearing mouse model combined with multimodalities of molecular imaging may facilitate studies on the molecular mechanisms of cancer invasion and metastasis.

  19. Monitoring of tumor growth and metastasis potential in MDA-MB-435s/ tk-luc human breast cancer xenografts

    Science.gov (United States)

    Chang, Ya-Fang; Lin, Yi-Yu; Wang, Hsin-Ell; Liu, Ren-Shen; Pang, Fei; Hwang, Jeng-Jong

    2007-02-01

    Molecular imaging of reporter gene expression provides a rapid, sensitive and non-invasive monitoring of tumor behaviors. In this study, we reported the establishment of a novel animal model for longitudinal examination of tumor growth kinetics and metastatic spreading in vivo. The highly metastatic human breast carcinoma MDA-MB-435s cell line was engineered to stably express herpes simplex virus type 1 thymidine kinase (HSV-1- tk) and luciferase ( luc). Both 131I-FIAU and D-luciferin were used as reporter probes. For orthotopic tumor formation, MDA-MB-435s/ tk-luc cells were implanted into the first nipple of 6-week-old female NOD/SCID mice. For metastatic study, cells were injected via the lateral tail vein. Mice-bearing MDA-MB-435s/ tk-luc tumors were scanned for tumor growth and metastatsis using Xenogen IVIS50 system. Gamma scintigraphy and whole-body autoradiography were also applied to confirm the tumor localization. The results of bioluminescence imaging as well as histopathological finding showed that tumors could be detected in femur, spine, ovary, lungs, kidney, adrenal gland, lymph nodes and muscle at 16 weeks post i.v. injection, and correlated photons could be quantified. This MDA-MB-435s/ tk-luc human breast carcinoma-bearing mouse model combined with multimodalities of molecular imaging may facilitate studies on the molecular mechanisms of cancer invasion and metastasis.

  20. EpCAM-Independent Enrichment of Circulating Tumor Cells in Metastatic Breast Cancer.

    Directory of Open Access Journals (Sweden)

    Helen Schneck

    Full Text Available Circulating tumor cells (CTCs are the potential precursors of metastatic disease. Most assays established for the enumeration of CTCs so far-including the gold standard CellSearch-rely on the expression of the cell surface marker epithelial cell adhesion molecule (EpCAM. But, these approaches may not detect CTCs that express no/low levels of EpCAM, e.g. by undergoing epithelial-to-mesenchymal transition (EMT. Here we present an enrichment strategy combining different antibodies specific for surface proteins and extracellular matrix (ECM components to capture an EpCAMlow/neg cell line and EpCAMneg CTCs from blood samples of breast cancer patients depleted for EpCAM-positive cells. The expression of respective proteins (Trop2, CD49f, c-Met, CK8, CD44, ADAM8, CD146, TEM8, CD47 was verified by immunofluorescence on EpCAMpos (e.g. MCF7, SKBR3 and EpCAMlow/neg (MDA-MB-231 breast cancer cell lines. To test antibodies and ECM proteins (e.g. hyaluronic acid (HA, collagen I, laminin for capturing EpCAMneg cells, the capture molecules were first spotted in a single- and multi-array format onto aldehyde-coated glass slides. Tumor cell adhesion of EpCAMpos/neg cell lines was then determined and visualized by Coomassie/MitoTracker staining. In consequence, marginal binding of EpCAMlow/neg MDA-MB-231 cells to EpCAM-antibodies could be observed. However, efficient adhesion/capturing of EpCAMlow/neg cells could be achieved via HA and immobilized antibodies against CD49f and Trop2. Optimal capture conditions were then applied to immunomagnetic beads to detect EpCAMneg CTCs from clinical samples. Captured CTCs were verified/quantified by immunofluorescence staining for anti-pan-Cytokeratin (CK-FITC/anti-CD45 AF647/DAPI. In total, in 20 out of 29 EpCAM-depleted fractions (69% from 25 metastatic breast cancer patients additional EpCAMneg CTCs could be identified [range of 1-24 CTCs per sample] applying Trop2, CD49f, c-Met, CK8 and/or HA magnetic enrichment. Ep

  1. Triple-negative breast cancer

    OpenAIRE

    Chacón, Reinaldo D; Costanzo, María V

    2010-01-01

    Perou's molecular classification defines tumors that neither express hormone receptors nor overexpress HER2 as triple-negative (TN) tumors. These tumors account for approximately 15% of breast cancers. The so-called basaloid tumors are not always synonymous with TN tumors; they differ in the fact that they express different molecular markers, have a higher histologic grade, and have a worse prognosis. Clinically they occur in younger women as interval cancer, and the risk of recurrence is hig...

  2. In Vivo Tumor Growth Rate Measured by US in Preoperative Period and Long Term Disease Outcome in Breast Cancer Patients

    National Research Council Canada - National Science Library

    Yoo, Tae-Kyung; Min, Jun Won; Kim, Min Kyoon; Lee, Eunshin; Kim, Jongjin; Lee, Han-Byoel; Kang, Young Joon; Kim, Yun-Gyoung; Moon, Hyeong-Gon; Moon, Woo Kyung; Cho, Nariya; Noh, Dong-Young; Han, Wonshik

    2015-01-01

    .... Breast cancer patients who received at least two serial breast ultrasonographies (US) in our institution during preoperative period and were surgically treated between 2002 and 2010 were reviewed...

  3. Caffeine Mediates Sustained Inactivation of Breast Cancer-Associated Myofibroblasts via Up-Regulation of Tumor Suppressor Genes

    Science.gov (United States)

    Al-Ansari, Mysoon M.; Aboussekhra, Abdelilah

    2014-01-01

    Background Active cancer-associated fibroblasts (CAFs) or myofibroblasts play important roles not only in the development and progression of breast carcinomas, but also in their prognosis and treatment. Therefore, targeting these cells through suppressing their supportive procarcinogenic paracrine effects is mandatory for improving the current therapies that are mainly targeting tumor cells. To this end, we investigated the effect of the natural and pharmacologically safe molecule, caffeine, on CAF cells and their various procarcinogenic effects. Methodology/Principal Findings We have shown here that caffeine up-regulates the tumor suppressor proteins p16, p21, p53 and Cav-1, and reduces the expression/secretion of various cytokines (IL-6, TGF-β, SDF-1 and MMP-2), and down-regulates α-SMA. Furthermore, caffeine suppressed the migratory/invasiveness abilities of CAF cells through PTEN-dependent Akt/Erk1/2 inactivation. Moreover, caffeine reduced the paracrine pro-invasion/−migration effects of CAF cells on breast cancer cells. These results indicate that caffeine can inactivate breast stromal myofibroblasts. This has been confirmed by showing that caffeine also suppresses the paracrine pro-angiogenic effect of CAF cells through down-regulating HIF-1αand its downstream effector VEGF-A. Interestingly, these effects were sustained in absence of caffeine. Conclusion/Significance The present findings provide a proof of principle that breast cancer myofibroblasts can be inactivated, and thereby caffeine may provide a safe and effective prevention against breast tumor growth/recurrence through inhibition of the procarcinogenic effects of active stromal fibroblasts. PMID:24595168

  4. Caffeine mediates sustained inactivation of breast cancer-associated myofibroblasts via up-regulation of tumor suppressor genes.

    Directory of Open Access Journals (Sweden)

    Mysoon M Al-Ansari

    Full Text Available BACKGROUND: Active cancer-associated fibroblasts (CAFs or myofibroblasts play important roles not only in the development and progression of breast carcinomas, but also in their prognosis and treatment. Therefore, targeting these cells through suppressing their supportive procarcinogenic paracrine effects is mandatory for improving the current therapies that are mainly targeting tumor cells. To this end, we investigated the effect of the natural and pharmacologically safe molecule, caffeine, on CAF cells and their various procarcinogenic effects. METHODOLOGY/PRINCIPAL FINDINGS: We have shown here that caffeine up-regulates the tumor suppressor proteins p16, p21, p53 and Cav-1, and reduces the expression/secretion of various cytokines (IL-6, TGF-β, SDF-1 and MMP-2, and down-regulates α-SMA. Furthermore, caffeine suppressed the migratory/invasiveness abilities of CAF cells through PTEN-dependent Akt/Erk1/2 inactivation. Moreover, caffeine reduced the paracrine pro-invasion/-migration effects of CAF cells on breast cancer cells. These results indicate that caffeine can inactivate breast stromal myofibroblasts. This has been confirmed by showing that caffeine also suppresses the paracrine pro-angiogenic effect of CAF cells through down-regulating HIF-1αand its downstream effector VEGF-A. Interestingly, these effects were sustained in absence of caffeine. CONCLUSION/SIGNIFICANCE: The present findings provide a proof of principle that breast cancer myofibroblasts can be inactivated, and thereby caffeine may provide a safe and effective prevention against breast tumor growth/recurrence through inhibition of the procarcinogenic effects of active stromal fibroblasts.

  5. Standardized assessment of tumor-infiltrating lymphocytes in breast cancer: an evaluation of inter-observer agreement between pathologists.

    Science.gov (United States)

    Tramm, Trine; Di Caterino, Tina; Jylling, Anne-Marie B; Lelkaitis, Giedrius; Lænkholm, Anne-Vibeke; Ragó, Péter; Tabor, Tomasz P; Talman, Maj-Lis M; Vouza, Emmanouela

    2018-01-01

    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 biomarker in the routine practice, and evaluation of the analytical validity is needed, including testing the reproducibility of decentralized assessment of TILs. The aim of this study was to evaluate the inter-observer agreement of TILs assessment using a standardized method, as proposed by the International TILs Working Group 2014, applied to a cohort of breast cancers reflecting an average breast cancer population. Stromal TILs were assessed using full slide sections from 124 breast cancers with varying histology, malignancy grade and ER- and HER2 status. TILs were estimated by nine dedicated breast pathologists using scanned hematoxylin-eosin stainings. TILs results were categorized using various cutoffs, and the inter-observer agreement was evaluated using the intraclass coefficient (ICC), Kappa statistics as well as individual overall agreements with the median value of TILs. Evaluation of TILs led to an ICC of 0.71 (95% CI: 0.65-0.77) corresponding to an acceptable agreement. Kappa values were in the range of 0.38-0.46 corresponding to a fair to moderate agreement. The individual agreements increased, when using only two categories ('high' vs. 'low' TILs) and a cutoff of 50-60%. The results of the present study are in accordance with previous studies, and shows that the proposed methodology for standardized evaluation of TILs renders an acceptable inter-observer agreement. The findings, however, indicate that assessment of TILs needs further refinement, and is in support of the latest St. Gallen Consensus, that routine reporting of TILs for early breast cancer is not ready for implementation in a clinical setting.

  6. Suppressive effects of a proton beam on tumor growth and lung metastasis through the inhibition of metastatic gene expression in 4T1 orthotopic breast cancer model.

    Science.gov (United States)

    Kwon, Yun-Suk; Lee, Kyu-Shik; Chun, So-Young; Jang, Tae Jung; Nam, Kyung-Soo

    2016-07-01

    A proton beam is a next generation tool to treat intractable cancer. Although the therapeutic effects of a proton beam are well known, the effect on tumor metastasis is not fully described. Here, we investigated the effects of a proton beam on metastasis in highly invasive 4T1 murine breast cancer cells and their orthotopic breast cancer model. Cells were irradiated with 2, 4, 8 or 16 Gy proton beam, and changes in cell proliferation, survival, and migration were observed by MTT, colony forming and wound healing assays. 4T1 breast cancer cell-implanted BALB/c mice were established and the animals were randomly divided into 4 groups when tumor size reached 200 mm3. Breast tumors were selectively irradiated with 10, 20 or 30 Gy proton beam. Breast tumor sizes were measured twice a week, and breast tumor and lung tissues were pathologically observed. Metastasis-regulating gene expression was assessed with quantitative RT-PCR. A proton beam dose-dependently decreased cell proliferation, survival and migration in 4T1 murine breast cancer cells. Also, growth of breast tumors in the 4T1 orthotopic breast cancer model was significantly suppressed by proton beam irradiation without significant change of body weight. Furthermore, fewer tumor nodules metastasized from breast tumor into lung in mice irradiated with 30 Gy proton beam, but not with 10 and 20 Gy, than in control. We observed correspondingly lower expression levels of urokinase plasminogen activator (uPA), uPA receptor, cyclooxygenase (COX)-2, and vascular endothelial growth factor (VEGF), which are important factors in cancer metastasis, in breast tumor irradiated with 30 Gy proton beam. Proton beam irradiation did not affect expressions of matrix metalloproteinase (MMP)-9 and MMP-2. Taken together, the data suggest that, although proton beam therapy is an effective tool for breast cancer treatment, a suitable dose is necessary to prevent metastasis-linked relapse and poor prognosis.

  7. Hypomethylation of the MMP7 promoter and increased expression of MMP7 distinguishes the basal-like breast cancer subtype from other triple-negative tumors.

    Science.gov (United States)

    Sizemore, Steven T; Sizemore, Gina M; Booth, Christine N; Thompson, Cheryl L; Silverman, Paula; Bebek, Gurkan; Abdul-Karim, Fadi W; Avril, Stefanie; Keri, Ruth A

    2014-07-01

    Identification of novel targets for the treatment of basal-like breast cancer is essential for improved outcomes in patients with this disease. This study investigates the association of MMP7 expression and MMP7 promoter methylation with subtype and outcome in breast cancer patient cohorts. Immunohistochemical analysis was performed on a breast cancer tissue microarray and validated in independent histological samples. MMP7 expression significantly correlated with patient age, tumor size, triple-negative (TN) status, and recurrence. Analysis of publically available datasets confirmed MMP7 gene expression as a prognostic marker of breast cancer metastasis, particularly metastasis to the brain and lungs. Methylation of the MMP7 promoter was assessed by methylation-specific PCR in a panel of breast cancer cell lines and patient tumor samples. Hypomethylation of the MMP7 promoter significantly correlated with TN status in DNA from patient tumor samples, and this association was confirmed using The Cancer Genome Atlas (TCGA) dataset. Evaluation of a panel of breast cancer cell lines and data from the Curtis and TCGA breast carcinoma datasets revealed that elevated MMP7 expression and MMP7 promoter hypomethylation are specific biomarkers of the basal-like molecular subtype which shares considerable, but not complete, overlap with the clinical TN subtype. Importantly, MMP7 expression was identified as an independent predictor of pathological complete response in a large breast cancer patient cohort. Combined, these data suggest that MMP7 expression and MMP7 promoter methylation may be useful as prognostic biomarkers. Furthermore, MMP7 expression and promoter methylation analysis may be effective mechanisms to distinguish basal-like breast cancers from other triple-negative subtypes. Finally, these data implicate MMP7 as a potential therapeutic target for the treatment of basal-like breast cancers.

  8. Adenoid cystic breast cancer.

    Science.gov (United States)

    McClenathan, James H; de la Roza, Gustavo

    2002-06-01

    Adenoid cystic carcinoma is a rare type of breast cancer that is generally reported in individual case reports or as series from major referral centers. To characterize early diagnostic criteria for adenoid cystic carcinoma and to determine whether breast-preserving surgery with radiotherapy is as effective as mastectomy for eradicating the disease, we reviewed clinical records of a large series of patients treated for adenoid cystic carcinoma of the breast at a large health maintenance organization (HMO) that includes primary care facilities and referral centers. Using the data bank of the Northern California Cancer Registry of the Kaiser Permanente Northern California Region (KPNCR), we retrospectively reviewed medical records of patients treated for adenoid cystic carcinoma of the breast. Follow-up also was done for these patients. Adenoid cystic carcinoma of the breast was diagnosed in 22 of 27,970 patients treated for breast cancer at KPNCR from 1960 through 2000. All 22 patients were female and were available for follow-up. Mean age of patients at diagnosis was 61 years (range, 37 to 94 years). In 17 (77%) of the women, a lump in the breast led to initial suspicion of a tumor; in 4 (23%) of the 22 patients, mammography led to suspicion of a tumor. Median tumor size was 20 mm. Pain was a prominent symptom. Surgical management evolved from radical and modified radical mastectomy to simple mastectomy or lumpectomy during the study period, during which time 1 patient died of previous ordinary ductal carcinoma of the contralateral breast, and 7 died of unrelated disease. At follow-up, 12 of the 13 remaining patients were free of disease; 1 patient died of the disease; and 1 patient remained alive despite late occurrence of lymph node and pulmonary metastases. Whether breast-preserving surgery with radiotherapy is as effective as mastectomy for treating adenoid cystic carcinoma of the breast has not been determined.

  9. Hereditary breast cancer

    DEFF Research Database (Denmark)

    Larsen, Martin J; Thomassen, Mads; Gerdes, Anne-Marie

    2014-01-01

    Pathogenic mutations in BRCA1 or BRCA2 are only detected in 25% of families with a strong history of breast cancer, though hereditary factors are expected to be involved in the remaining families with no recognized mutation. Molecular characterization is expected to provide new insight...... into the tumor biology to guide the search of new high-risk alleles and provide better classification of the growing number of BRCA1/2 variants of unknown significance (VUS). In this review, we provide an overview of hereditary breast cancer, its genetic background, and clinical implications, before focusing...... on the pathologically and molecular features associated with the disease. Recent transcriptome and genome profiling studies of tumor series from BRCA1/2 mutation carriers as well as familial non-BRCA1/2 will be discussed. Special attention is paid to its association with molecular breast cancer subtypes as well...

  10. Risk of mortality of node-negative, ER/PR/HER2 breast cancer subtypes in T1, T2, and T3 tumors.

    Science.gov (United States)

    Parise, Carol A; Caggiano, Vincent

    2017-10-01

    The purpose of this study was to assess differences in breast cancer-specific mortality within tumors of the same size when breast cancer was defined using the three tumor markers estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). We identified 104,499 cases of node-negative primary female invasive breast cancer from the California Cancer Registry. Tumor size was categorized as T1a, T1b, T1c, T2, and T3. Breast cancer was defined using ER, PR, and HER2. Kaplan-Meier Survival analysis was conducted and Cox Regression was used to compute the adjusted risk of mortality for the ER+/PR+/HER2+, ER-/PR-/HER2- (TNBC), and ER-/PR-/HER2+ (HER2-overexpressing) subtypes when compared with the ER+/PR+/HER2-. Separate models were computed for each tumor size. Unadjusted survival analysis showed that for all tumor sizes, the ER+/PR+ subtypes regardless of HER status have better breast cancer-specific survival than ER-/PR- subtypes. Subtype was not an important factor for risk of mortality for T1a tumors. The ER+/PR+/HER2+ subtype was only a risk for mortality in T1b tumors that were unadjusted for treatment. For all other tumor sizes, the ER+/PR+/HER2+ had the same mortality as the ER+/PR+/HER2- subtype regardless of adjustment for treatment. The HER2-overexpressing subtype had a higher risk of mortality than the ER+/PR+/HER2- subtype except for T1b tumors that were adjusted for treatment. For all tumor sizes, the TNBC had higher hazard ratios than all other subtypes. T1a tumors have the same risk of mortality regardless of ER/PR/HER2 subtype, and ER and PR negativity plays a stronger role in survival than HER2 positivity for tumors of all size.

  11. Deregulation of the Pit-1 transcription factor in human breast cancer cells promotes tumor growth and metastasis

    Science.gov (United States)

    Ben-Batalla, Isabel; Seoane, Samuel; Garcia-Caballero, Tomas; Gallego, Rosalia; Macia, Manuel; Gonzalez, Luis O.; Vizoso, Francisco; Perez-Fernandez, Roman

    2010-01-01

    The Pit-1 transcription factor (also know as POU1F1) plays a critical role in cell differentiation during organogenesis of the anterior pituitary in mammals and is a transcriptional activator for pituitary gene transcription. Increased expression of Pit-1 has been reported in human tumorigenic breast cells. Here, we found that Pit-1 overexpression or knockdown in human breast cancer cell lines induced profound phenotypic changes in the expression of proteins involved in cell proliferation, apoptosis, and invasion. Some of these protumorigenic effects of Pit-1 were mediated by upregulation of Snai1, an inductor of the epithelial-mesenchymal transition. In immunodeficient mice, Pit-1 overexpression induced tumoral growth and promoted metastasis in lung. In patients with invasive ductal carcinoma of the breast and node-positive tumor, high expression of Pit-1 was significantly correlated with Snai1 positivity. Notably, in these patients elevated expression of Pit-1 was significantly and independently associated with the occurrence of distant metastasis. These findings suggest that Pit-1 could help to make a more accurate prognosis in patients with node-positive breast cancer and may represent a new therapeutic target. PMID:21060149

  12. Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors.

    Science.gov (United States)

    Zhao, Yuechao; Laws, Mary J; Guillen, Valeria Sanabria; Ziegler, Yvonne; Min, Jian; Sharma, Abhishek; Kim, Sung Hoon; Chu, David; Park, Ben Ho; Oesterreich, Steffi; Mao, Chengjian; Shapiro, David J; Nettles, Kendall W; Katzenellenbogen, John A; Katzenellenbogen, Benita S

    2017-10-15

    Many estrogen receptor α (ERα)-positive breast cancers develop resistance to endocrine therapy via mutation of ERs whose constitutive activation is associated with shorter patient survival. Because there is now a clinical need for new antiestrogens (AE) against these mutant ERs, we describe here our development and characterization of three chemically novel AEs that effectively suppress proliferation of breast cancer cells and tumors. Our AEs are effective against wild-type and Y537S and D538G ERs, the two most commonly occurring constitutively active ERs. The three new AEs suppressed proliferation and estrogen target gene expression in WT and mutant ER-containing cells and were more effective in D538G than in Y537S cells and tumors. Compared with WT ER, mutants exhibited approximately 10- to 20-fold lower binding affinity for AE and a reduced ability to be blocked in coactivator interaction, likely contributing to their relative resistance to inhibition by AE. Comparisons between mutant ER-containing MCF7 and T47D cells revealed that AE responses were compound, cell-type, and ERα-mutant dependent. These new ligands have favorable pharmacokinetic properties and effectively suppressed growth of WT and mutant ER-expressing tumor xenografts in NOD/SCID-γ mice after oral or subcutaneous administration; D538G tumors were more potently inhibited by AE than Y537S tumors. These studies highlight the differential responsiveness of the mutant ERs to different AEs and make clear the value of having a toolkit of AEs for treatment of endocrine therapy-resistant tumors driven by different constitutively active ERs. Cancer Res; 77(20); 5602-13. ©2017 AACR. ©2017 American Association for Cancer Research.

  13. Tumor suppressor genes are frequently methylated in lymph node metastases of breast cancers

    Directory of Open Access Journals (Sweden)

    Xu Jia

    2010-07-01

    Full Text Available Abstract Introduction Metastasis represents a major adverse step in the progression of breast carcinoma. Lymph node invasion is the most relevant prognostic factor; however little is known on the molecular events associated with lymph node metastasis process. This study is to investigate the status and role of methylation in lymph node metastatic tumors. Materials and methods Bisulfite pyrosequencing is used to screen 6 putative tumor suppressor genes (HIN-1, RASSF1A, RIL, CDH13, RARβ2 and E-cadherin in 38 pairs of primary breast tumors and lymph node metastases. Results We found that HIN-1, CDH13, RIL, RASSF1A and RARβ2 were frequently methylated both in primary and metastatic tissues (range: 55.3%~89.5%. E-cadherin was not frequently methylated in either setting (range: 18.4%~23.7%. The methylation status of HIN-1, CDH13, RIL, and RARβ2 in lymph nodes metastasis were correlated with that in primary tumors. The Pearson correlation values ranged from 0.624 to 0.472 (p values HIN-1 methylation and hormone status in metastatic lymph nodes. Hypermethylation of HIN-1 in metastasis lymph nodes was significantly associated with expression of ER (odds ratio, 1.070; P = 0.024 and with PR (odds ratio, 1.046; P = 0.026. Conclusions This study suggests that hypermethylation of tumor suppressor genes is extended from primary to metastatic tumors during tumor progression.

  14. Induction of interleukin-1β by mouse mammary tumor irradiation promotes triple negative breast cancer cells invasion and metastasis development.

    Science.gov (United States)

    Bouchard, Gina; Therriault, Hélène; Bujold, Rachel; Saucier, Caroline; Paquette, Benoit

    2017-05-01

    Radiotherapy increases the level of inflammatory cytokines, some of which are known to promote metastasis. In a mouse model of triple negative breast cancer (TNBC), we determined whether irradiation of the mammary tumor increases the level of key cytokines and favors the development of lung metastases. D2A1 TNBC cells were implanted in the mammary glands of a Balb/c mouse and then 7 days old tumors were irradiated (4 × 6 Gy). The cytokines IL-1β, IL-4, IL-6, IL-10, IL-17 and MIP-2 were quantified in plasma before, midway and after irradiation. The effect of tumor irradiation on the invasion of cancer cells, the number of circulating tumor cells (CTC) and lung metastases were also measured. TNBC tumor irradiation significantly increased the plasma level of IL-1β, which was associated with a greater number of CTC (3.5-fold) and lung metastases (2.3-fold), compared to sham-irradiated animals. Enhancement of D2A1 cell invasion in mammary gland was associated with an increase of the matrix metalloproteinases-2 and -9 activity (MMP-2, -9). The ability of IL-1β to stimulate the invasiveness of irradiated D2A1 cells was confirmed by in vitro invasion chamber assays. Irradiation targeting a D2A1 tumor and its microenvironment increased the level of the inflammatory cytokine IL-1β and was associated with the promotion of cancer cell invasion and lung metastasis development.

  15. Breast tumor cell-specific knockout ofTwist1inhibits cancer cell plasticity, dissemination, and lung metastasis in mice.

    Science.gov (United States)

    Xu, Yixiang; Lee, Dong-Kee; Feng, Zhen; Xu, Yan; Bu, Wen; Li, Yi; Liao, Lan; Xu, Jianming

    2017-10-24

    Twist1 is an epithelial-mesenchymal transition (EMT)-inducing transcription factor (TF) that promotes cell migration and invasion. To determine the intrinsic role of Twist1 in EMT and breast cancer initiation, growth, and metastasis, we developed mouse models with an oncogene-induced mammary tumor containing wild-type (WT) Twist1 or tumor cell-specific Twist1 knockout (Twist1 TKO ). Twist1 knockout showed no effects on tumor initiation and growth. In both models with early-stage tumor cells, Twist1, and mesenchymal markers were not expressed, and lung metastasis was absent. Twist1 expression was detected in ∼6% of the advanced WT tumor cells. Most of these Twist1 + cells coexpressed several other EMT-inducing TFs (Snail, Slug, Zeb2), lost ERα and luminal marker K8, acquired basal cell markers (K5, p63), and exhibited a partial EMT plasticity (E-cadherin + /vimentin + ). In advanced Twist1 TKO tumor cells, Twist1 knockout largely diminished the expression of the aforementioned EMT-inducing TFs and basal and mesenchymal markers, but maintained the expression of the luminal markers. Circulating tumor cells (CTCs) were commonly detected in mice with advanced WT tumors, but not in mice with advanced Twist1 TKO tumors. Nearly all WT CTCs coexpressed Twist1 with other EMT-inducing TFs and both epithelial and mesenchymal markers. Mice with advanced WT tumors developed extensive lung metastasis consisting of luminal tumor cells with silenced Twist1 and mesenchymal marker expression. Mice with advanced Twist1 TKO tumors developed very little lung metastasis. Therefore, Twist1 is required for the expression of other EMT-inducing TFs in a small subset of tumor cells. Together, they induce partial EMT, basal-like tumor progression, intravasation, and metastasis. Published under the PNAS license.

  16. Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling.

    Science.gov (United States)

    Dave, Bhuvanesh; Granados-Principal, Sergio; Zhu, Rui; Benz, Stephen; Rabizadeh, Shahrooz; Soon-Shiong, Patrick; Yu, Ke-Da; Shao, Zhimin; Li, Xiaoxian; Gilcrease, Michael; Lai, Zhao; Chen, Yidong; Huang, Tim H-M; Shen, Haifa; Liu, Xuewu; Ferrari, Mauro; Zhan, Ming; Wong, Stephen T C; Kumaraswami, Muthiah; Mittal, Vivek; Chen, Xi; Gross, Steven S; Chang, Jenny C

    2014-06-17

    We previously described a gene signature for breast cancer stem cells (BCSCs) derived from patient biopsies. Selective shRNA knockdown identified ribosomal protein L39 (RPL39) and myeloid leukemia factor 2 (MLF2) as the top candidates that affect BCSC self-renewal. Knockdown of RPL39 and MLF2 by specific siRNA nanoparticles in patient-derived and human cancer xenografts reduced tumor volume and lung metastases with a concomitant decrease in BCSCs. RNA deep sequencing identified damaging mutations in both genes. These mutations were confirmed in patient lung metastases (n = 53) and were statistically associated with shorter median time to pulmonary metastasis. Both genes affect the nitric oxide synthase pathway and are altered by hypoxia. These findings support that extensive tumor heterogeneity exists within primary cancers; distinct subpopulations associated with stem-like properties have increased metastatic potential.

  17. Breast Cancer Overview

    Science.gov (United States)

    ... are here Home > Types of Cancer > Breast Cancer Breast Cancer This is Cancer.Net’s Guide to Breast Cancer. Use the menu below to choose the Overview/ ... social workers, and patient advocates. Cancer.Net Guide Breast Cancer Introduction Statistics Medical Illustrations Risk Factors and Prevention ...

  18. Breast Cancer -- Male

    Science.gov (United States)

    ... Home > Types of Cancer > Breast Cancer in Men Breast Cancer in Men This is Cancer.Net’s Guide to Breast Cancer in Men. Use the menu below to choose ... social workers, and patient advocates. Cancer.Net Guide Breast Cancer in Men Introduction Statistics Risk Factors and Prevention ...

  19. Anti-MUC1 Antibody in Nipple Aspirate Fluids Correlates with Tumor Aggressiveness in Breast Cancer: A Feasibility Study

    Directory of Open Access Journals (Sweden)

    Ebru Menekse

    2015-01-01

    Full Text Available Antibodies against MUC1 are found in circulation of breast cancer (BC patients. We hypothesized that anti-MUC1 antibodies might be present in even a higher concentration in nipple aspirate fluid (NAF and could be used to predict aggressiveness of BC. Serum and NAF samples were collected from high risk lesions, BC, and healthy contralateral breasts. ELISA was used to measure the amount of IgG, IgM, and IgA against a tumor-specific MUC1 peptide derived from the extracellular tandem repeat domain of MUC1. Tumor characteristics were recorded prospectively; 120 NAF samples were obtained from a total of 77 women in the study. There was no significant difference of anti-MUC1 antibody levels compared to BC with other lesions. Anti-MUC1 IgG level in NAF was higher in triple negative tumors (P=0.02; serum anti-MUC1 IgG levels were significantly higher in patients with ER (− tumor and recurrent disease (P=0.01; NAF anti-MUC1 IgA levels were significantly higher in patients with LVI and Her2-neu (+ tumors (P<0.05. These results show that NAF could be a reliable biomarker to predict tumor aggressiveness in BC. A larger study will be needed to confirm these data and to investigate the potential of anti-MUC1 antibodies in NAF and serum to predict disease outcome.

  20. Breast Cancer

    Science.gov (United States)

    ... the Mediterranean diet choose healthy fats, such as olive oil, over butter and fish instead of red meat. Breast cancer risk reduction for women with a high risk If your doctor has assessed your family history and determined that you have other factors, such ...

  1. Feasibility of collecting tumor samples of breast cancer patients diagnosed up to 50 years ago in the Child Health and Development Studies.

    Science.gov (United States)

    Krigbaum, N Y; Rubin, R A; Cirillo, P M; Terry, M B; Habel, L A; Morris, C; Cohn, B A

    2017-06-01

    Environmental exposures during pregnancy may increase breast cancer risk for mothers and female offspring. Tumor tissue assays may provide insight regarding the mechanisms. This study assessed the feasibility of obtaining tumor samples and pathology reports from mothers (F0) who were enrolled in the Child Health and Development Studies during pregnancy from 1959 to 1967 and their daughters (F1) who developed breast cancer over more than 50 years of follow-up. Breast cancer cases were identified through linkage to the California Cancer Registry and self-report. Written consent was obtained from 116 F0 and 95 F1 breast cancer survivors to access their pathology reports and tumor blocks. Of those contacted, 62% consented, 13% refused and 24% did not respond. We obtained tissue samples for 57% and pathology reports for 75%, and if diagnosis was made ⩽10 years we obtained tissue samples and pathology reports for 91% and 79%, respectively. Obtaining pathology reports and tumor tissues of two generations is feasible and will support investigation of the relationship between early-life exposures and molecular tumor markers. However, we found that more recent diagnosis increased the accessibility of tumor tissue. We recommend that cohorts request consent for obtaining future tumor tissues at study enrollment and implement real-time tissue collection to enhance success of collecting tumor samples and data.

  2. Olive phenolics as c-Met inhibitors: (--Oleocanthal attenuates cell proliferation, invasiveness, and tumor growth in breast cancer models.

    Directory of Open Access Journals (Sweden)

    Mohamed R Akl

    Full Text Available Dysregulation of the Hepatocyte growth factor (HGF/c-Met signaling axis upregulates diverse tumor cell functions, including cell proliferation, survival, scattering and motility, epithelial-to-mesenchymal transition (EMT, angiogenesis, invasion, and metastasis. (--Oleocanthal is a naturally occurring secoiridoid from extra-virgin olive oil, which showed antiproliferative and antimigratory activity against different cancer cell lines. The aim of this study was to characterize the intracellular mechanisms involved in mediating the anticancer effects of (--oleocanthal treatment and the potential involvement of c-Met receptor signaling components in breast cancer. Results showed that (--oleocanthal inhibits the growth of human breast cancer cell lines MDA-MB-231, MCF-7 and BT-474 while similar treatment doses were found to have no effect on normal human MCF10A cell growth. In addition, (--oleocanthal treatment caused a dose-dependent inhibition of HGF-induced cell migration, invasion and G1/S cell cycle progression in breast cancer cell lines. Moreover, (--oleocanthal treatment effects were found to be mediated via inhibition of HGF-induced c-Met activation and its downstream mitogenic signaling pathways. This growth inhibitory effect is associated with blockade of EMT and reduction in cellular motility. Further results from in vivo studies showed that (--oleocanthal treatment suppressed tumor cell growth in an orthotopic model of breast cancer in athymic nude mice. Collectively, the findings of this study suggest that (--oleocanthal is a promising dietary supplement lead with potential for therapeutic use to control malignancies with aberrant c-Met activity.

  3. KISS1 tumor suppressor restricts angiogenesis of breast cancer brain metastases and sensitizes them to oncolytic virotherapy in vitro.

    Science.gov (United States)

    Platonov, Mikhail E; Borovjagin, Anton V; Kaverina, Natalya; Xiao, Ting; Kadagidze, Zaira; Lesniak, Maciej; Baryshnikova, Marya; Ulasov, Ilya V

    2018-03-28

    KISS1 tumor suppressor protein regulates cancer cell invasion via MMP9 metalloproteinase. Downregulation of KISS1 gene expression promotes progression of breast cancer and melanoma, resulting in the development of distant metastases. In the current study, we investigated whether restoration of KISS1 expression in KISS1-deficient human metastatic breast cancer cells holds potential as an advanced anticancer strategy. To this end we engineered an infectivity-enhanced conditionally-replicative human adenovirus type 5 encoding KISS1 as an "arming" transgene in the Ad5 E3 region for an ectopic KISS1 expression in transduced cancer cells. The oncolytic potential of the vector was examined using brain-invading metastatic clones of CN34 and MDA-MB-231 breast cancer cells, which supported high levels of AdKISS1 replication, correlating with a robust CRAd-mediated cytotoxicity. Secretion of cellular factors responsible for tumor angiogenesis, cell-to-cell communication and anti-tumoral immune responses upon KISS1 expression in breast cancer cells was analyzed by a RayBiotech Kiloplex Quantibody array. Overall, our results indicate that KISS1 transgene expression provides an important benefit for CRAd-mediated cytotoxicity in breast cancer cells and holds potential as an anticancer treatment in conjunction with oncolytic virotherapy of breast and other metastatic cancers. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. mTOR in breast cancer: differential expression in triple-negative and non-triple-negative tumors.

    LENUS (Irish Health Repository)

    Walsh, S

    2012-04-01

    Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptors (ER), progesterone receptors (PR) and overexpression of HER2. Targeted therapy is currently unavailable for this subgroup of breast cancer patients. mTOR controls cancer cell growth, survival and invasion and is thus a potential target for the treatment of patients with TNBC. Using immunohistochemistry, mTOR and p-mTOR were measured in 89 TNBCs and 99 non-TNBCs. While mTOR expression was confined to tumor cell cytoplasm, p-mTOR staining was located in the nucleus, perinuclear area and in the cytoplasm. Potentially important, was our finding that nuclear p-mTOR was found more frequently in triple-negative than non triple-negative cancers (p < 0.001). These results suggest that mTOR may play a more important role in the progression of TNBC compared to non-TNBC. Based on these findings, we conclude that mTOR may be a new target for the treatment of triple-negative breast cancer.

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

    Science.gov (United States)

    Muranen, Taru A; Blomqvist, Carl; Dörk, Thilo; Jakubowska, Anna; Heikkilä, Päivi; Fagerholm, Rainer; Greco, Dario; Aittomäki, Kristiina; Bojesen, Stig E; Shah, Mitul; Dunning, Alison M; Rhenius, Valerie; Hall, Per; Czene, Kamila; Brand, Judith S; Darabi, Hatef; Chang-Claude, Jenny; Rudolph, Anja; Nordestgaard, Børge G; Couch, Fergus J; Hart, Steven N; Figueroa, Jonine; García-Closas, Montserrat; Fasching, Peter A; Beckmann, Matthias W; Li, Jingmei; Liu, Jianjun; Andrulis, Irene L; Winqvist, Robert; Pylkäs, Katri; Mannermaa, Arto; Kataja, Vesa; Lindblom, Annika; Margolin, Sara; Lubinski, Jan; Dubrowinskaja, Natalia; Bolla, Manjeet K; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Easton, Douglas F; Pharoah, Paul D P; Schmidt, Marjanka K; Nevanlinna, Heli

    2016-10-03

    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. 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. Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO: GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature. P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly

  6. A tumor DNA complex aberration index is an independent predictor of survival in breast and ovarian cancer.

    Science.gov (United States)

    Vollan, Hans Kristian Moen; Rueda, Oscar M; Chin, Suet-Feung; Curtis, Christina; Turashvili, Gulisa; Shah, Sohrab; Lingjærde, Ole Christian; Yuan, Yinyin; Ng, Charlotte K; Dunning, Mark J; Dicks, Ed; Provenzano, Elena; Sammut, Stephen; McKinney, Steven; Ellis, Ian O; Pinder, Sarah; Purushotham, Arnie; Murphy, Leigh C; Kristensen, Vessela N; Brenton, James D; Pharoah, Paul D P; Børresen-Dale, Anne-Lise; Aparicio, Samuel; Caldas, Carlos

    2015-01-01

    Complex focal chromosomal rearrangements in cancer genomes, also called "firestorms", can be scored from DNA copy number data. The complex arm-wise aberration index (CAAI) is a score that captures DNA copy number alterations that appear as focal complex events in tumors, and has potential prognostic value in breast cancer. This study aimed to validate this DNA-based prognostic index in breast cancer and test for the first time its potential prognostic value in ovarian cancer. Copy number alteration (CNA) data from 1950 breast carcinomas (METABRIC cohort) and 508 high-grade serous ovarian carcinomas (TCGA dataset) were analyzed. Cases were classified as CAAI positive if at least one complex focal event was scored. Complex alterations were frequently localized on chromosome 8p (n = 159), 17q (n = 176) and 11q (n = 251). CAAI events on 11q were most frequent in estrogen receptor positive (ER+) cases and on 17q in estrogen receptor negative (ER-) cases. We found only a modest correlation between CAAI and the overall rate of genomic instability (GII) and number of breakpoints (r = 0.27 and r = 0.42, p Breast cancer specific survival (BCSS), overall survival (OS) and ovarian cancer progression free survival (PFS) were used as clinical end points in Cox proportional hazard model survival analyses. CAAI positive breast cancers (43%) had higher mortality: hazard ratio (HR) of 1.94 (95%CI, 1.62-2.32) for BCSS, and of 1.49 (95%CI, 1.30-1.71) for OS. Representations of the 70-gene and the 21-gene predictors were compared with CAAI in multivariable models and CAAI was independently significant with a Cox adjusted HR of 1.56 (95%CI, 1.23-1.99) for ER+ and 1.55 (95%CI, 1.11-2.18) for ER- disease. None of the expression-based predictors were prognostic in the ER- subset. We found that a model including CAAI and the two expression-based prognostic signatures outperformed a model including the 21-gene and 70-gene signatures but excluding CAAI. Inclusion of CAAI in the clinical

  7. Viruses and Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lawson, James S., E-mail: james.lawson@unsw.edu.au; Heng, Benjamin [School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney (Australia)

    2010-04-30

    Viruses are the accepted cause of many important cancers including cancers of the cervix and anogenital area, the liver, some lymphomas, head and neck cancers and indirectly human immunodeficiency virus associated cancers. For over 50 years, there have been serious attempts to identify viruses which may have a role in breast cancer. Despite these efforts, the establishment of conclusive evidence for such a role has been elusive. However, the development of extremely sophisticated new experimental techniques has allowed the recent development of evidence that human papilloma virus, Epstein-Barr virus, mouse mammary tumor virus and bovine leukemia virus may each have a role in the causation of human breast cancers. This is potentially good news as effective vaccines are already available to prevent infections from carcinogenic strains of human papilloma virus, which causes cancer of the uterine cervix.

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

    Science.gov (United States)

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

    2011-01-01

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

  9. Nilotinib Enhances Tumor Angiogenesis and Counteracts VEGFR2 Blockade in an Orthotopic Breast Cancer Xenograft Model with Desmoplastic Response

    Directory of Open Access Journals (Sweden)

    Sara Zafarnia

    2017-11-01

    Full Text Available Vascular endothelial growth factor (VEGF/VEGF receptor (VEGFR-targeted therapies predominantly affect nascent, immature tumor vessels. Since platelet-derived growth factor receptor (PDGFR blockade inhibits vessel maturation and thus increases the amount of immature tumor vessels, we evaluated whether the combined PDGFR inhibition by nilotinib and VEGFR2 blockade by DC101 has synergistic therapy effects in a desmoplastic breast cancer xenograft model. In this context, besides immunohistological evaluation, molecular ultrasound imaging with BR55, the clinically used VEGFR2-targeted microbubbles, was applied to monitor VEGFR2-positive vessels noninvasively and to assess the therapy effects on tumor angiogenesis. DC101 treatment alone inhibited tumor angiogenesis, resulting in lower tumor growth and in significantly lower vessel density than in the control group after 14 days of therapy. In contrast, nilotinib inhibited vessel maturation but enhanced VEGFR2 expression, leading to markedly increased tumor volumes and a significantly higher vessel density. The combination of both drugs led to an almost similar tumor growth as in the DC101 treatment group, but VEGFR2 expression and microvessel density were higher and comparable to the controls. Further analyses revealed significantly higher levels of tumor cell–derived VEGF in nilotinib-treated tumors. In line with this, nilotinib, especially in low doses, induced an upregulation of VEGF and IL-6 mRNA in the tumor cells in vitro, thus providing an explanation for the enhanced angiogenesis observed in nilotinib-treated tumors in vivo. These findings suggest that nilotinib inhibits vessel maturation but counteracts the effects of antiangiogenic co-therapy by enhancing VEGF expression by the tumor cells and stimulating tumor angiogenesis.

  10. WISP3 (CCN6 Is a Secreted Tumor-Suppressor Protein that Modulates IGF Signaling in Inflammatory Breast Cancer

    Directory of Open Access Journals (Sweden)

    Celina G. Kleer

    2004-03-01

    Full Text Available Inflammatory breast cancer (IBC is the most lethal form of locally advanced breast cancer. We have found that WISP3 is lost in 80% of human IBC tumors and that it has growth- and angiogenesis-inhibitory functions in breast cancer in vitro and in vivo. WISP3 is a cysteine-rich, putatively secreted protein that belongs to the CCN family. It contains a signal peptide at the N-terminus and four highly conserved motifs. Here, for the first time, we investigate the function of WISP3 protein in relationship to its structural features. We found that WISP3 is secreted into the conditioned media and into the lumens of normal breast ducts. Once secreted, WISP3 was able to decrease, directly or through induction of other molecule(s, the IGF-1-induced activation of the IGF-IR, and two of its main downstream signaling molecules, IRS1 and ERK-1/2, in SUM149 IBC cells. Furthermore, WISP3 containing conditioned media decreased the growth rate of SUM149 cells. This work sheds light into the mechanism of WISP3 function by demonstrating that it is secreted and that, once in the extracellular media, it induces a series of molecular events that leads to modulation of IGF-IR signaling pathways and cellular growth in IBC cells.

  11. High expression of miR-21 in tumor stroma correlates with increased cancer cell proliferation in human breast cancer

    DEFF Research Database (Denmark)

    Rask, Lene; Balslev, Eva; Jørgensen, Stine

    2011-01-01

    features, we performed in situ hybridization and semi-quantitative assessment of the miR-21 signal on 12 LN negative grade I (assumed low risk), and 12 LN positive grade II (high risk) breast cancers. miR-21 was predominantly seen in cancer associated fibroblast-like cells, with no difference in expression......Low-risk and high-risk breast cancer patients are stratified primarily according to their lymph node (LN) status and grading. However, some low-risk patients relapse, and some high-risk patients have a favorable clinical outcome, implying a need for better prognostic and predictive tests. Micro...... RNAs are often aberrantly expressed in cancer and microRNA-21 is upregulated in a variety of cancers, including breast cancer. High miR-21 levels have been associated with poor prognosis. To determine the cellular localization of miR-21 and to compare its expression levels with histopathological...

  12. [Pregnancy and breast cancer].

    Science.gov (United States)

    Ramírez-Torres, Nicolás; Asbun-Bojalil, Juan; Hernández-Valencia, Marcelino

    2013-01-01

    association of breast cancer and pregnancy is not common. The objective of this investigation was to evaluate the pregnancy, young age, stage, treatment, prognosis and mortality of women with breast cancer during pregnancy. retrospective analysis from March 1992 to February 2009, 16 patients were included with breast cancer and pregnancy. They were analized: histological characteristic of tumor, therapeutic response of the oncological treatment, evolution of the pregnancy. From of baby born: Apgar and weight. The woman's mortality with breast cancer during pregnancy was evaluated for age group and for interval of time between late pregnancy and diagnosis posterior of breast cancer and pregnancy. characteristic predominant clinicohistological: stage III (81.2%), T3-T4 (75%), N+ 93.7%, invasive ductal carcinoma (87.5%), histological grade 2-3 (93.7%), receptor estrogeno positive (43.7%); RPpositive (25%); HER-2/neu positive (31.2%). 27 chemotherapy cycles were applied with 5-fluorouracil, epirubicin and cyclophosphamide during the second or third trimester of the pregnancy, there were not severe adverse effects for the mothers and the baby born exposed to chemotherapy. The mean time to disease recurrence was 18.8 months (range, 6-62 months). The rate of mortality for specific age (breast cancer and pregnancy.

  13. Genetic mapping in mice identifies DMBT1 as a candidate modifier of mammary tumors and breast cancer risk

    DEFF Research Database (Denmark)

    Blackburn, Anneke C; Hill, Linda Z; Roberts, Amy L

    2007-01-01

    Low-penetrance breast cancer susceptibility alleles seem to play a significant role in breast cancer risk but are difficult to identify in human cohorts. A genetic screen of 176 N2 backcross progeny of two Trp53(+/-) strains, BALB/c and C57BL/6, which differ in their susceptibility to mammary...... tumors, identified a modifier of mammary tumor susceptibility in an approximately 25-Mb interval on mouse chromosome 7 (designated SuprMam1). Relative to heterozygotes, homozygosity for BALB/c alleles of SuprMam1 significantly decreased mammary tumor latency from 70.7 to 61.1 weeks and increased risk...... twofold (P = 0.002). Dmbt1 (deleted in malignant brain tumors 1) was identified as a candidate modifier gene within the SuprMam1 interval because it was differentially expressed in mammary tissues from BALB/c-Trp53(+/-) and C57BL/6-Trp53(+/-) mice. Dmbt1 mRNA and protein was reduced in mammary glands...

  14. Real-Time MRI Navigated Ultrasound for Preoperative Tumor Evaluation in Breast Cancer Patients: Technique and Clinical Implementation

    Energy Technology Data Exchange (ETDEWEB)

    Park, Ah Young; Seo, Bo Kyoung [Department of Radiology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan 15355 (Korea, Republic of)

    2016-11-01

    Real-time magnetic resonance imaging (MRI) navigated ultrasound is an image fusion technique to display the results of both MRI and ultrasonography on the same monitor. This system is a promising technique to improve lesion detection and analysis, to maximize advantages of each imaging modality, and to compensate the disadvantages of both MRI and ultrasound. In evaluating breast cancer stage preoperatively, MRI and ultrasound are the most representative imaging modalities. However, sometimes difficulties arise in interpreting and correlating the radiological features between these two different modalities. This pictorial essay demonstrates the technical principles of the real-time MRI navigated ultrasound, and clinical implementation of the system in preoperative evaluation of tumor extent, multiplicity, and nodal status in breast cancer patients.

  15. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay.

    Science.gov (United States)

    Baccelli, Irène; Schneeweiss, Andreas; Riethdorf, Sabine; Stenzinger, Albrecht; Schillert, Anja; Vogel, Vanessa; Klein, Corinna; Saini, Massimo; Bäuerle, Tobias; Wallwiener, Markus; Holland-Letz, Tim; Höfner, Thomas; Sprick, Martin; Scharpff, Martina; Marmé, Frederik; Sinn, Hans Peter; Pantel, Klaus; Weichert, Wilko; Trumpp, Andreas

    2013-06-01

    It has been hypothesized that carcinoma metastasis is initiated by a subpopulation of circulating tumor cells (CTCs) found in the blood of patients. However, although the presence of CTCs is an indicator of poor prognosis in several carcinoma entities, the existence and phenotype of metastasis-initiating cells (MICs) among CTCs has not been experimentally demonstrated. Here we developed a xenograft assay and used it to show that primary human luminal breast cancer CTCs contain MICs that give rise to bone, lung and liver metastases in mice. These MIC-containing CTC populations expressed EPCAM, CD44, CD47 and MET. In a small cohort of patients with metastases, the number of EPCAM(+)CD44(+)CD47(+)MET(+) CTCs, but not of bulk EPCAM(+) CTCs, correlated with lower overall survival and increased number of metastasic sites. These data describe functional circulating MICs and associated markers, which may aid the design of better tools to diagnose and treat metastatic breast cancer.

  16. Real-time MRI navigated ultrasound for preoperative tumor evaluation in breast cancer patients: Technique and clinical implementation

    Energy Technology Data Exchange (ETDEWEB)

    Park, Ah Young; Seo, Bo Kyoung [Dept. of Radiology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan (Korea, Republic of)

    2016-09-15

    Real-time magnetic resonance imaging (MRI) navigated ultrasound is an image fusion technique to display the results of both MRI and ultrasonography on the same monitor. This system is a promising technique to improve lesion detection and analysis, to maximize advantages of each imaging modality, and to compensate the disadvantages of both MRI and ultrasound. In evaluating breast cancer stage preoperatively, MRI and ultrasound are the most representative imaging modalities. However, sometimes difficulties arise in interpreting and correlating the radiological features between these two different modalities. This pictorial essay demonstrates the technical principles of the real-time MRI navigated ultrasound, and clinical implementation of the system in preoperative evaluation of tumor extent, multiplicity, and nodal status in breast cancer patients.

  17. Mammographic findings of breast cancer: Emphasis on the tumor and microcalcifications

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Tae Myon; Choi, Hye Young; Baek, Seung Yon; Choi, Su Na Mi [Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    1993-07-15

    Most of the breast cancer revealed mass and/or microcalcifications on mammography. We analyzed morphologic characteristic of the masses and microcalcifications on mammography which confirmed as breast cancer pathologically. Of all 54 cases, 4 patients (7%) showed microcalcification only, 27 patients (50%), mass only, and the other 23 patients (43%), both micro calcification and mass on the mammography. The margin of the breast mass were ill-defined in 37 cases, well-defined in 8 cases, and well-defined with surrounding infiltration in 5 cases. The morphologic characteristics of the microcalcification were punctuate-liner-V shape in 11 patients, punctuate-linear shape in 9 patients, and punctuate shape in 7 patients.

  18. The prognostic role of tumor-infiltrating CD4 and CD8 T lymphocytes in breast cancer.

    Science.gov (United States)

    Matkowski, Rafal; Gisterek, Iwona; Halon, Agnieszka; Lacko, Aleksandra; Szewczyk, Krzysztof; Staszek, Urszula; Pudelko, Marek; Szynglarewicz, Bartlomiej; Szelachowska, Jolanta; Zolnierek, Andrzej; Kornafel, Jan

    2009-07-01

    The aim of the study was to assess the prognostic role of CD4 and CD8 expression and the type, density, localization and distribution of tumor infiltrating lymphocytes (TILs) in patients with breast cancer. Tissue samples were obtained from 88 breast cancer patients with operable disease and ductal histology. Forty-three women had pathologically confirmed axillary lymph node involvement. The TILs and expression of CD8 (cytotoxic T-cells) and CD4 (T-helper cells) were evaluated in the tumor samples using mouse monoclonal antibodies. Thirteen patients relapsed; nine of them had strong expression of CD4 and CD8, which was statistically significant. The patients with high expression of CD4 or CD8 had distinctly worse cancer specific overall survival (OS). High correlations between CD4 and CD8 expression and lymph node status and intensity of lymphatic infiltrate as well as between both markers were found. The analysis of tumor-infiltrating immune cells may be a valuable prognostic tool and a marker of lymph node involvement.

  19. Tumor cryoablation in combination with natural killer cells therapy and Herceptin in patients with HER2-overexpressing recurrent breast cancer.

    Science.gov (United States)

    Liang, Shuzhen; Niu, Lizhi; Xu, Kecheng; Wang, Xiaohua; Liang, Yingqing; Zhang, Mingjie; Chen, Jibing; Lin, Mao

    2017-12-01

    In this study, we investigated the clinical benefits of a combination of tumor cryoablation with natural killer (NK) cells therapy and Herceptin for human epidermal growth factor (HER) 2-overexpressing recurrent breast cancer. From May 2015 to May 2016, 48 patients who met the enrollment criteria were assigned to three groups (n=16): cryoablation group (group I), cryoablation-NK cells therapy group (group II) and cryoablation-NK cells therapy-Herceptin group (group III). Safety and short-term effects were evaluated. All the adverse effects were manageable and acceptable. The three-therapy combination treatment not only yielded good clinical efficacy, it also improved the quality of life; reduced levels of circulating tumor cells (CTCs); reduced carcino-embryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) expression; enhanced immune function significantly. Furthermore, it can resulte in significant prolongation of progression free survival (PFS). This is the first clinical study to demonstrate the benefit of the three-therapy combination of tumor cryoablation, NK cells therapy, and Herceptin for HER2-overexpressing recurrent breast cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Tumor Angiogenesis Therapy Using Targeted Delivery of Paclitaxel to the Vasculature of Breast Cancer Metastases

    Directory of Open Access Journals (Sweden)

    Shijun Zhu

    2014-01-01

    Full Text Available Breast cancer aberrantly expresses tissue factor (TF in cancer tissues and cancer vascular endothelial cells (VECs. TF plays a central role in cancer angiogenesis, growth, and metastasis and, as such, is a target for therapy and drug delivery. TF is the cognate receptor of factor VIIa (fVIIa. We have coupled PTX (paclitaxel, also named Taxol with a tripeptide, phenylalanine-phenylalanine-arginine chloromethyl ketone (FFRck and conjugated it with fVIIa. The key aim of the work is to evaluate the antiangiogenic effects of PTX-FFRck-fVIIa against a PTX-resistant breast cancer cell line. Matrigel mixed with VEGF and MDA-231 was injected subcutaneously into the flank of athymic nude mice. Animals were treated by tail vein injection of the PTX-FFRck-fVIIa conjugate, unconjugated PTX, or PBS. The PTX-FFRck-fVIIa conjugate significantly reduces microvessel density in matrigel (p<0.01–0.05 compared to PBS and unconjugated PTX. The breast cancer lung metastasis model in athymic nude mice was developed by intravenous injection of MDA-231 cells expressing luciferase. Animals were similarly treated intravenously with the PTX-FFRck-fVIIa conjugate or PBS. The conjugate significantly inhibits lung metastasis as compared to the control, highlighting its potential to antagonize angiogenesis in metastatic carcinoma. In conclusion, PTX conjugated to fVIIa is a promising therapeutic approach for improving selective drug delivery and inhibiting angiogenesis.

  1. Genome-wide epigenetic profiling of breast cancer tumors treated with aromatase inhibitors

    NARCIS (Netherlands)

    Nevedomskaya, E.; Wessels, L.; Zwart, W.

    2014-01-01

    Aromatase inhibitors (AI) are extensively used in the treatment of estrogen receptor-positive breast cancers, however resistance to AI treatment is commonly observed. Apart from Estrogen receptor (ER?) expression, no predictive biomarkers for response to AI treatment are clinically applied. Yet,

  2. Sentinel Lymph Node Biopsy and Isolated Tumor Cells in Invasive Lobular Versus Ductal Breast Cancer

    NARCIS (Netherlands)

    Truin, Wilfred; Roumen, Rudi M.; Siesling, Sabine; van der Heiden-van der Loo, Margriet; Lobbezoo, Dorien J.; Tjan-Heijnen, Vivianne C.G.; Voogd, Adri C.

    2016-01-01

    Background Sentinel lymph node (SLN) biopsy is the standard of care for axillary staging in invasive breast cancer. The introduction of SLN biopsy with an extensive pathology examination, in addition to the introduction of the 2002 TNM classification, led to different axillary classification

  3. EGF receptor-targeted synthetic double-stranded RNA eliminates glioblastoma, breast cancer, and adenocarcinoma tumors in mice.

    Directory of Open Access Journals (Sweden)

    Alexei Shir

    2006-01-01

    Full Text Available BACKGROUND: Glioblastoma multiforme (GBM is the most lethal form of brain cancer. With the available treatments, survival does not exceed 12-14 mo from the time of diagnosis. We describe a novel strategy to selectively induce the death of glioblastoma cells and other cancer cells that over-express the EGF receptor. Using a non-viral delivery vector that homes to the EGF receptor, we target synthetic anti-proliferative dsRNA (polyinosine-cytosine [poly IC], a strong activator of apoptosis, selectively to cancer cells. METHODS AND FINDINGS: Poly IC was delivered by means of a non-viral vector: 25kDa polyethylenimine-polyethyleneglycol-EGF (PEI25-PEG-EGF. EGFR-targeted poly IC induced rapid apoptosis in the target cells in vitro and in vivo. Expression of several cytokines and "bystander killing" of untransfected tumor cells was detected in vitro and in vivo. Intra-tumoral delivery of the EGFR-targeted poly IC induced the complete regression of pre-established intracranial tumors in nude mice, with no obvious adverse toxic effects on normal brain tissue. A year after treatment completion the treated mice remain cancer-free and healthy. Similarly, non-viral delivery of poly IC completely eliminated pre-established breast cancer and adenocarcinoma xenografts derived from EGFR over-expressing cancer cell lines, suggesting that the strategy is applicable to other EGFR-over-expressing tumors. CONCLUSION: The strategy described has yielded an effective treatment of EGFR over-expressing GBM in an animal model. If this strategy is translated successfully to the clinical setting, it may actually offer help to GBM patients. Moreover the elimination of two additional EGFR over-expressing cancers in vivo suggests that in principle this strategy can be applied to treat other tumors that over-express EGFR.

  4. Rare copy number variants observed in hereditary breast cancer cases disrupt genes in estrogen signaling and TP53 tumor suppression network.

    Directory of Open Access Journals (Sweden)

    Katri Pylkäs

    Full Text Available Breast cancer is the most common cancer in women in developed countries, and the contribution of genetic susceptibility to breast cancer development has been well-recognized. However, a great proportion of these hereditary predisposing factors still remain unidentified. To examine the contribution of rare copy number variants (CNVs in breast cancer predisposition, high-resolution genome-wide scans were performed on genomic DNA of 103 BRCA1, BRCA2, and PALB2 mutation negative familial breast cancer cases and 128 geographically matched healthy female controls; for replication an independent cohort of 75 similarly mutation negative young breast cancer patients was used. All observed rare variants were confirmed by independent methods. The studied breast cancer cases showed a consistent increase in the frequency of rare CNVs when compared to controls. Furthermore, the biological networks of the disrupted genes differed between the two groups. In familial cases the observed mutations disrupted genes, which were significantly overrepresented in cellular functions related to maintenance of genomic integrity, including DNA double-strand break repair (P = 0.0211. Biological network analysis in the two independent breast cancer cohorts showed that the disrupted genes were closely related to estrogen signaling and TP53 centered tumor suppressor network. These results suggest that rare CNVs represent an alternative source of genetic variation influencing hereditary risk for breast cancer.

  5. Rare copy number variants observed in hereditary breast cancer cases disrupt genes in estrogen signaling and TP53 tumor suppression network.

    Science.gov (United States)

    Pylkäs, Katri; Vuorela, Mikko; Otsukka, Meeri; Kallioniemi, Anne; Jukkola-Vuorinen, Arja; Winqvist, Robert

    2012-01-01

    Breast cancer is the most common cancer in women in developed countries, and the contribution of genetic susceptibility to breast cancer development has been well-recognized. However, a great proportion of these hereditary predisposing factors still remain unidentified. To examine the contribution of rare copy number variants (CNVs) in breast cancer predisposition, high-resolution genome-wide scans were performed on genomic DNA of 103 BRCA1, BRCA2, and PALB2 mutation negative familial breast cancer cases and 128 geographically matched healthy female controls; for replication an independent cohort of 75 similarly mutation negative young breast cancer patients was used. All observed rare variants were confirmed by independent methods. The studied breast cancer cases showed a consistent increase in the frequency of rare CNVs when compared to controls. Furthermore, the biological networks of the disrupted genes differed between the two groups. In familial cases the observed mutations disrupted genes, which were significantly overrepresented in cellular functions related to maintenance of genomic integrity, including DNA double-strand break repair (P = 0.0211). Biological network analysis in the two independent breast cancer cohorts showed that the disrupted genes were closely related to estrogen signaling and TP53 centered tumor suppressor network. These results suggest that rare CNVs represent an alternative source of genetic variation influencing hereditary risk for breast cancer.

  6. Breast cancer cell behaviors on staged tumorigenesis-mimicking matrices derived from tumor cells at various malignant stages.

    Science.gov (United States)

    Hoshiba, Takashi; Tanaka, Masaru

    2013-09-20

    Extracellular matrix (ECM) has been focused to understand tumor progression in addition to the genetic mutation of cancer cells. Here, we prepared "staged tumorigenesis-mimicking matrices" which mimic in vivo ECM in tumor tissue at each malignant stage to understand the roles of ECM in tumor progression. Breast tumor cells, MDA-MB-231 (invasive), MCF-7 (non-invasive), and MCF-10A (benign) cells, were cultured to form their own ECM beneath the cells and formed ECM was prepared as staged tumorigenesis-mimicking matrices by decellularization treatment. Cells showed weak attachment on the matrices derived from MDA-MB-231 cancer cells. The proliferations of MDA-MB-231 and MCF-7 was promoted on the matrices derived from MDA-MB-231 cancer cells whereas MCF-10A cell proliferation was not promoted. MCF-10A cell proliferation was promoted on the matrices derived from MCF-10A cells. Chemoresistance of MDA-MB-231 cells against 5-fluorouracil increased on only matrices derived from MDA-MB-231 cells. Our results showed that the cells showed different behaviors on staged tumorigenesis-mimicking matrices according to the malignancy of cell sources for ECM preparation. Therefore, staged tumorigenesis-mimicking matrices might be a useful in vitro ECM models to investigate the roles of ECM in tumor progression. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Co-treatment of breast cancer cells with pharmacologic doses of 2-deoxy-D-glucose and metformin: Starving tumors.

    Science.gov (United States)

    Wokoun, Ulrike; Hellriegel, Martin; Emons, Günter; Gründker, Carsten

    2017-04-01

    A characteristic of tumor cells is the increased aerobic glycolysis for energy production. Thus, inhibition of glycolysis represents a selective therapeutic option. It has been shown that glycolysis inhibitor 2-deoxy-D-glucose (2DG) induces apoptotic cell death in different tumor entities. In addition, the antitumor activity of the anti-diabetic drug metformin has been demonstrated. In the present study, we aimed to ascertain whether the combination of pharmacologic doses of 2DG with metformin increases the antitumor efficacy. Cell viability of MDA-MB-231 and HCC1806 triple-negative breast cancer (TNBC) cells treated without or with 2DG or with metformin alone or with the combination of both agents was measured using Alamar Blue assay. Induction of apoptosis was quantified by measurement of the loss of mitochondrial membrane potential and cleavage of PARP. Treatment of breast cancer cells with glycolysis inhibitor 2DG or with the anti-diabetic drug metformin resulted in a significant decrease in cell viability and an increase in apoptosis. Treatment with 2DG in combination with metformin resulted in significantly reduced viability compared with the single agent treatments. The observed reduction in viability was due to induction of apoptosis. In addition, in regards to apoptosis induction a stronger effect in the case of co-treatment compared with single agent treatments was observed. The glycolytic phenotype of human breast cancer cells can be targeted for therapeutic intervention. Co-treatment with doses of the glycolysis inhibitor 2DG and anti-diabetic drug metformin is tolerable in humans and may be a suitable therapy for human breast cancers.

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

    DEFF Research Database (Denmark)

    Kim, Jiyoung; Villadsen, René; Sørlie, Therese

    2012-01-01

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

  9. SLIT2, a human homologue of the Drosophila Slit2 gene, has tumor suppressor activity and is frequently inactivated in lung and breast cancers.

    Science.gov (United States)

    Dallol, Ashraf; Da Silva, Nancy Fernandes; Viacava, Paolo; Minna, John D; Bieche, Ivan; Maher, Eamonn R; Latif, Farida

    2002-10-15

    Slit2 plays a vital role in axon guidance by signaling through Robo receptors. Recent evidence suggests that Slit2 protein may function in other settings because human and Xenopus Slit2 has been shown to inhibit leukocyte chemotaxis. SLIT2 protein is a putative ligand for the ROBO receptors. We recently demonstrated that ROBO1 is inactivated by promoter region hypermethylation in cancers; furthermore, tumor suppressor activity has not been shown. Thus, the importance of ROBO1 inactivation in human cancer is uncertain. Therefore, we investigated the status of SLIT2 located at 4p15.2 in lung and breast cancers. Although somatic SLIT2 mutations were not detected, epigenetic inactivation was common. SLIT2 promoter methylation was detected in 59% of breast cancer, 77% of non-small cell lung cancer, and 55% of small cell lung cancer cell lines. In these tumor lines, SLIT2 expression was restored by treatment with a demethylating agent. SLIT2 promoter methylation was detected in 43% of breast cancer, 53% of non-small cell lung cancer, and 36% of small cell lung cancer primary tumors. The majority of methylated tumors demonstrated allelic loss at 4p15.2. In addition, SLIT2 expression was down-regulated in methylated breast tumors, relative to normal control, as demonstrated by quantitative real-time reverse transcription-PCR. Overexpression of SLIT2 suppressed >70% of colony growth in each of three breast tumor lines (with either absent or low SLIT2 expression). Because SLIT2 is primarily a secreted protein, SLIT2-conditioned medium suppressed the growth of several breast cancer lines (with absent or weak SLIT2expression) by 26-51% but had no significant effect on a breast tumor cell line that expresses normal levels of SLIT2. These findings demonstrate that SLIT2 is frequently inactivated in lung and breast cancer by promoter region hypermethylation and allele loss and is an excellent candidate for the lung and breast tumor suppressor gene previously mapped to 4p15.2.