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Sample records for mammary cancer progression

  1. Does Skeletal Muscle Mass Influence Breast Cancer? Evaluating Mammary Tumorigenesis and Progression Genetically Hyper-Muscular Mice

    DTIC Science & Technology

    2006-07-01

    1-0424 TITLE: Does Skeletal Muscle Mass Influence Breast Cancer ? Evaluating Mammary Tumorigenesis and Progression in...SUBTITLE Does Skeletal Muscle Mass Influence Breast Cancer ? Evaluating Mammary 5a. CONTRACT NUMBER Tumorigenesis and Progression in Genetically...activity independently reduce breast cancer . Conversely, obesity and insulin resistance are associated with increased breast cancer incidence

  2. Integrated extracellular matrix signaling in mammary gland development and breast cancer progression.

    PubMed

    Zhu, Jieqing; Xiong, Gaofeng; Trinkle, Christine; Xu, Ren

    2014-09-01

    Extracellular matrix (ECM), a major component of the cellular microenvironment, plays critical roles in normal tissue morphogenesis and disease progression. Binding of ECM to membrane receptor proteins, such as integrin, discoidin domain receptors, and dystroglycan, elicits biochemical and biomechanical signals that control cellular architecture and gene expression. These ECM signals cooperate with growth factors and hormones to regulate cell migration, differentiation, and transformation. ECM signaling is tightly regulated during normal mammary gland development. Deposition and alignment of fibrillar collagens direct migration and invasion of mammary epithelial cells during branching morphogenesis. Basement membrane proteins are required for polarized acinar morphogenesis and milk protein expression. Deregulation of ECM proteins in the long run is sufficient to promote breast cancer development and progression. Recent studies demonstrate that the integrated biophysical and biochemical signals from ECM and soluble factors are crucial for normal mammary gland development as well as breast cancer progression.

  3. Key signalling nodes in mammary gland development and cancer. Mitogen-activated protein kinase signalling in experimental models of breast cancer progression and in mammary gland development.

    PubMed

    Whyte, Jacqueline; Bergin, Orla; Bianchi, Alessandro; McNally, Sara; Martin, Finian

    2009-01-01

    Seven classes of mitogen-activated protein kinase (MAPK) intracellular signalling cascades exist, four of which are implicated in breast disease and function in mammary epithelial cells. These are the extracellular regulated kinase (ERK)1/2 pathway, the ERK5 pathway, the p38 pathway and the c-Jun N-terminal kinase (JNK) pathway. In some forms of human breast cancer and in many experimental models of breast cancer progression, signalling through the ERK1/2 pathway, in particular, has been implicated as being important. We review the influence of ERK1/2 activity on the organised three-dimensional association of mammary epithelial cells, and in models of breast cancer cell invasion. We assess the importance of epidermal growth factor receptor family signalling through ERK1/2 in models of breast cancer progression and the influence of ERK1/2 on its substrate, the oestrogen receptor, in this context. In parallel, we consider the importance of these MAPK-centred signalling cascades during the cycle of mammary gland development. Although less extensively studied, we highlight the instances of signalling through the p38, JNK and ERK5 pathways involved in breast cancer progression and mammary gland development.

  4. Macrophages promote the progression of premalignant mammary lesions to invasive cancer.

    PubMed

    Carron, Emily C; Homra, Samuel; Rosenberg, Jillian; Coffelt, Seth B; Kittrell, Frances; Zhang, Yiqun; Creighton, Chad J; Fuqua, Suzanne A; Medina, Daniel; Machado, Heather L

    2017-01-31

    Breast cancer initiation, progression and metastasis rely on a complex interplay between tumor cells and their surrounding microenvironment. Infiltrating immune cells, including macrophages, promote mammary tumor progression and metastasis; however, less is known about the role of macrophages in early stage lesions. In this study, we utilized a transplantable p53-null model of early progression to characterize the immune cell components of early stage lesions. We show that macrophages are recruited to ductal hyperplasias with a high tumor-forming potential where they are differentiated and polarized toward a tumor-promoting phenotype. These macrophages are a unique subset of macrophages, characterized by pro-inflammatory, anti-inflammatory and immunosuppressive factors. Macrophage ablation studies showed that macrophages are required for both early stage progression and primary tumor formation. These studies suggest that therapeutic targeting of tumor-promoting macrophages may not only be an effective strategy to block tumor progression and metastasis, but may also have critical implications for breast cancer prevention.

  5. Mammary cancers and pregnancy.

    PubMed Central

    Anderson, J M

    1979-01-01

    Uncertainties persist about management and prognosis of mammary cancers that occur during and after pregnancy and during lactation. Pathological features of mammary cancers occurring during pregnancy are the same as those in non-pregnant women and survival rates are comparable. Management should be the same as in non-pregnant patients. Termination of pregnancy does not improve survival but it should be advised if the prognosis is poor. Mastectomy apparently presents little danger to the fetus, though treatment such as chemotherapy and irradiation should be avoided. Women who have received treatment for mammary cancer need not be advised against subsequent pregnancy. Routine ovarian radiation in non-pregnant premenopausal women is not generally to be recommended, since it does not prolong survival and would deprive some of the chance of further pregnancy. In lactating women who develop mammary cancers survival is apparently not adversely affected. Lactation should be suppressed initially and followed by mastectomy. Regimens of immunotherapy, chemotherapy, or radiotherapy may then be begun. Until results of current trials of combined treatments of mammary cancers associated with pregnancy are available, management should be neither aggressive nor tentative. It should be based on a well-balanced concept of applying all available treatments, as in non-pregnant patients. PMID:376044

  6. Elimination of progressive mammary cancer by repeated administrations of chimeric antigen receptor-modified T cells.

    PubMed

    Globerson-Levin, Anat; Waks, Tova; Eshhar, Zelig

    2014-05-01

    Continuous oncogenic processes that generate cancer require an on-going treatment approach to eliminate the transformed cells, and prevent their further development. Here, we studied the ability of T cells expressing a chimeric antibody-based receptor (CAR) to offer a therapeutic benefit for breast cancer induced by erbB-2. We tested CAR-modified T cells (T-bodies) specific to erbB-2 for their antitumor potential in a mouse model overexpressing a human erbB-2 transgene that develops mammary tumors. Comparing the antitumor reactivity of CAR-modified T cells under various therapeutic settings, either prophylactic, prior to tumor development, or therapeutically. We found that repeated administration of CAR-modified T cells is required to eliminate spontaneously developing mammary cancer. Systemic, as well as intratumoral administered CAR-modified T cells accumulated at tumor sites and eventually eliminated the malignant cells. Interestingly, within a few weeks after a single CAR T cells' administration, and rejection of primary lesion, tumors usually relapsed both in treated mammary gland and at remote sites; however, repeated injections of CAR-modified T cells were able to control the secondary tumors. Since spontaneous tumors can arise repeatedly, especially in the case of syndromes characterized by specific susceptibility to cancer, multiple administrations of CAR-modified T cells can serve to control relapsing disease.

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

    SciTech Connect

    Weigelt, Britta; Bissell, Mina J.

    2008-06-26

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

  8. Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression.

    PubMed

    Benesch, Matthew G K; Tang, Xiaoyun; Dewald, Jay; Dong, Wei-Feng; Mackey, John R; Hemmings, Denise G; McMullen, Todd P W; Brindley, David N

    2015-09-01

    Compared to normal tissues, many cancer cells overexpress autotaxin (ATX). This secreted enzyme produces extracellular lysophosphatidate, which signals through 6 GPCRs to drive cancer progression. Our previous work showed that ATX inhibition decreases 4T1 breast tumor growth in BALB/c mice by 60% for about 11 d. However, 4T1 cells do not produce significant ATX. Instead, the ATX is produced by adjacent mammary adipose tissue. We investigated the molecular basis of this interaction in human and mouse breast tumors. Inflammatory mediators secreted by breast cancer cells increased ATX production in adipose tissue. The increased lysophosphatidate signaling further increased inflammatory mediator production in adipose tissue and tumors. Blocking ATX activity in mice bearing 4T1 tumors with 10 mg/kg/d ONO-8430506 (a competitive ATX inhibitor, IC90 = 100 nM; Ono Pharma Co., Ltd., Osaka, Japan) broke this vicious inflammatory cycle by decreasing 20 inflammatory mediators by 1.5-8-fold in cancer-inflamed adipose tissue. There was no significant decrease in inflammatory mediator levels in fat pads that did not bear tumors. ONO-8430506 also decreased plasma TNF-α and G-CSF cytokine levels by >70% and leukocyte infiltration in breast tumors and adjacent adipose tissue by >50%. Hence, blocking tumor-driven inflammation by ATX inhibition is effective in decreasing tumor growth in breast cancers where the cancer cells express negligible ATX.

  9. Transforming growth factor-(beta)s and mammary gland involution; functional roles and implications for cancer progression.

    PubMed

    Flanders, Kathleen C; Wakefield, Lalage M

    2009-06-01

    During rodent mammary gland involution there is a dramatic increase in the expression of the transforming growth factor-beta isoform, TGF-beta3. The TGF-betas are multifunctional cytokines which play important roles in wound healing and in carcinogenesis. The responses that are activated in the remodeling of the gland during involution have many similarities with the wound healing process and have been postulated to generate a mammary stroma that provides a microenvironment favoring tumor progression. In this review we will discuss the putative role of TGF-beta during involution, as well as its effects on the mammary microenvironment and possible implications for pregnancy-associated tumorigenesis.

  10. The importance of the microenvironment in breast cancer progression: recapitulation of mammary tumorigenesis using a unique human mammary epithelial cell model and a three-dimensional culture assay

    PubMed Central

    Weaver, V.M.; Fischer, A.H.; Peterson, O.W.; Bissell, M.J.

    2010-01-01

    The extracellular matrix (ECM) is a dominant regulator of tissue development and homeostasis. “Designer microenvironments” in culture and in vivo model systems have shown that the ECM regulates growth, differentiation, and apoptosis in murine and human mammary epithelial cells (MEC) through a hierarchy of transcriptional events involving the intricate interplay between soluble and physical signaling pathways. Furthermore, these studies have shown that these pathways direct and in turn are influenced by the tissue structure. Tissue structure is directed by the cooperative interactions of the cell–cell and cell–ECM pathways and can be modified by stromal factors. Not surprisingly then, loss of tissue structure and alterations in ECM components are associated with the appearance and dissemination of breast tumors, and malignancy is associated with perturbations in cell adhesion, changes in adhesion molecules, and a stromal reaction. Several lines of evidence now support the contention that the pathogenesis of breast cancer is determined (at least in part) by the dynamic interplay between the ductal epithelial cells, the microenvironment, and the tissue structure (acini). Thus, to understand the mechanisms involved in carcinogenesis, the role of the microenvironment (ECM as well as the stromal cells) with respect to tissue structure should be considered and studied. Towards this goal, we have established a unique human MEC model of tumorigenesis, which in concert with a three-dimensional assay, recapitulates many of the genetic and morphological changes observed in breast cancer in vivo. We are currently using this system to understand the role of the microenvironment and tissue structure in breast cancer progression. PMID:9164652

  11. P190-B, a Novel RhoGAP, in Mammary Gland Development and Breast Cancer Progression

    DTIC Science & Technology

    2005-09-01

    B overexpression during mammary gland involution, pl90-B/MMTV-rtTA bigenic female mice at eight weeks of age were bred to wildtype male mice. Age...for eight weeks at which time the mice were bred to wildtype FVB males . Three days after parturition mammary glands were collected and analyzed by H&E...overexpression during pregnancy and lactation, 12 week-old bigenic (n=6), and MTB (n=3) and wildtype littermate (n=3) control mice were bred to wildtype male

  12. Mammary Cancer and Activation of Transposable Elements

    DTIC Science & Technology

    2014-09-01

    AD_________________ Award Number: W81XWH-11-1-0402 TITLE: Mammary Cancer and Activation...TYPE Annual 3. DATES COVERED 1 Sep 2013 – 31 Aug 2014 4. TITLE AND SUBTITLE Mammary Cancer and Activation of Transposable Elements 5a. CONTRACT...investigate molecular events occurring in the preclinical stages of mammary cancer. Specifically, the project investigates the intersection between the

  13. Pathologic progression of mammary carcinomas in a C3(1)/SV40 T/t-antigen transgenic rat model of human triple-negative and Her2-positive breast cancer.

    PubMed

    Hoenerhoff, M J; Shibata, M A; Bode, A; Green, J E

    2011-04-01

    The C3(1) component of the rat prostate steroid binding protein has been used to target expression of the SV40 T/t-antigen to the mammary epithelium of mice resulting in pre-neoplastic lesions that progress to invasive and metastatic cancer with molecular features of human basal-type breast cancer. However, there are major differences in the histologic architecture of the stromal and epithelial elements between the mouse and human mammary glands. The rat mammary gland is more enriched with epithelial and stromal components than the mouse and more closely resembles the cellular composition of the human gland. Additionally, existing rat models of mammary cancer are typically estrogen receptor positive and hormone responsive, unlike most genetically engineered mouse mammary cancer models. In an attempt to develop a mammary cancer model that might more closely resemble the pathology of human breast cancer, we generated a novel C3(1)/SV40 T/t-antigen transgenic rat model that developed progressive mammary lesions leading to highly invasive adenocarcinomas. However, aggressive tumor development prevented the establishment of transgenic lines. Characterization of the tumors revealed that they were primarily estrogen receptor and progesterone receptor negative, and either her2/neu positive or negative, resembling human triple-negative or Her2 positive breast cancer. Tumors expressed the basal marker K14, as well as the luminal marker K18, and were negative for smooth muscle actin. The triple negative phenotype has not been previously reported in a rat mammary cancer model. Further development of a C3(1)SV40 T/t-antigen based model could establish valuable transgenic rat lines that develop basal-type mammary tumors.

  14. Mammary development and breast cancer: the role of stem cells.

    PubMed

    Ercan, C; van Diest, P J; Vooijs, M

    2011-06-01

    The mammary gland is a highly regenerative organ that can undergo multiple cycles of proliferation, lactation and involution, a process controlled by stem cells. The last decade much progress has been made in the identification of signaling pathways that function in these stem cells to control self-renewal, lineage commitment and epithelial differentiation in the normal mammary gland. The same signaling pathways that control physiological mammary development and homeostasis are also often found deregulated in breast cancer. Here we provide an overview on the functional and molecular identification of mammary stem cells in the context of both normal breast development and breast cancer. We discuss the contribution of some key signaling pathways with an emphasis on Notch receptor signaling, a cell fate determination pathway often deregulated in breast cancer. A further understanding of the biological roles of the Notch pathway in mammary stem cell behavior and carcinogenesis might be relevant for the development of future therapies.

  15. Physiologically activated mammary fibroblasts promote postpartum mammary cancer

    PubMed Central

    Guo, Qiuchen; Burchard, Julja; Spellman, Paul

    2017-01-01

    Women diagnosed with breast cancer within 5 years of childbirth have poorer prognosis than nulliparous or pregnant women. Weaning-induced breast involution is implicated, as the collagen-rich, immunosuppressive microenvironment of the involuting mammary gland is tumor promotional in mice. To investigate the role of mammary fibroblasts, isolated mammary PDGFRα+ cells from nulliparous and postweaning mice were assessed for activation phenotype and protumorigenic function. Fibroblast activation during involution was evident by increased expression of fibrillar collagens, lysyl oxidase, Tgfb1, and Cxcl12 genes. The ability of mammary tumors to grow in an isogenic, orthotopic transplant model was increased when tumor cells were coinjected with involution-derived compared with nulliparous-derived mammary fibroblasts. Mammary tumors in the involution-fibroblast group had increased Ly6C+ monocytes at the tumor border, and decreased CD8+ T cell infiltration and tumor cell death. Ibuprofen treatment suppressed involution-fibroblast activation and tumor promotional capacity, concurrent with decreases in tumor Ly6C+ monocytes, and increases in intratumoral CD8+ T cell infiltration, granzyme levels, and tumor cell death. In total, our data identify a COX/prostaglandin E2 (PGE2)–dependent activated mammary fibroblast within the involuting mammary gland that displays protumorigenic, immunosuppressive activity, identifying fibroblasts as potential targets for the prevention and treatment of postpartum breast cancer. PMID:28352652

  16. p190-B, A Novel RhoGAP, In Mammary Gland Development and Breast Cancer Progression

    DTIC Science & Technology

    2006-09-01

    the membranes (data not shown). Acknowledgments We thank Shirley Small for her help with animal husbandry and colony management; Maria Gonzalez -Rimbau...buds and breast cancer. Cell Growth Differ 2000 11:343–354 13. Chakravarty G, Hadsell D, Buitrago W, Settleman J, Rosen JM 2003 p190-B RhoGAP regulates

  17. Enhanced mammary progesterone receptor-A isoform activity in the promotion of mammary tumor progression by dietary soy in rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dietary contribution to breast cancer risk, recurrence, and progression remains incompletely understood. Increased consumption of soy and soy isoflavones is associated with reduced mammary cancer susceptibility in women and in rodent models of carcinogenesis. In rats treated with N-Methyl-N-Nitrosou...

  18. Amphiregulin: role in mammary gland development and breast cancer.

    PubMed

    McBryan, Jean; Howlin, Jillian; Napoletano, Silvia; Martin, Finian

    2008-06-01

    Extensive epithelial cell proliferation underlies the ductal morphogenesis of puberty that generates the mammary tree that will eventually fill the fat pad. This estrogen-dependent process is believed to be essentially dependent on locally produced growth factors that act in a paracrine fashion. EGF-like growth factor ligands, acting through EGF receptors are some of the principal promoters of pubertal ductal morphogenesis. Amphiregulin is the most abundant EGF-like growth factor in the pubertal mammary gland. Its gene is transcriptionally regulated by ERalpha, and recent evidence identifies it as a key mediator of the estrogen-driven epithelial cell proliferation of puberty: The pubertal deficiency in mammary gland ductal morphogenesis in ERalpha, amphiregulin, and EGFR knockout mice phenocopy each other. As a prognostic indicator in human breast cancer, amphiregulin indicates an outcome identical to that predicted by ERalpha presence. Despite this, a range of studies both on preneoplastic human breast tissue and on cell culture based models of breast cancer, suggest a possibly significant role for amphiregulin in driving human breast cancer progression. Here we summarise our current understanding of amphiregulin's contribution to mammary gland development and breast cancer progression.

  19. The mammary cellular hierarchy and breast cancer.

    PubMed

    Oakes, Samantha R; Gallego-Ortega, David; Ormandy, Christopher J

    2014-11-01

    Advances in the study of hematopoietic cell maturation have paved the way to a deeper understanding the stem and progenitor cellular hierarchy in the mammary gland. The mammary epithelium, unlike the hematopoietic cellular hierarchy, sits in a complex niche where communication between epithelial cells and signals from the systemic hormonal milieu, as well as from extra-cellular matrix, influence cell fate decisions and contribute to tissue homeostasis. We review the discovery, definition and regulation of the mammary cellular hierarchy and we describe the development of the concepts that have guided our investigations. We outline recent advances in in vivo lineage tracing that is now challenging many of our assumptions regarding the behavior of mammary stem cells, and we show how understanding these cellular lineages has altered our view of breast cancer.

  20. Stromal Effects on Mammary Gland Development and Breast Cancer

    NASA Astrophysics Data System (ADS)

    Wiseman, Bryony S.; Werb, Zena

    2002-05-01

    Breast cancer manifests itself in the mammary epithelium, yet there is a growing recognition that mammary stromal cells also play an important role in tumorigenesis. During its developmental cycle, the mammary gland displays many of the properties associated with breast cancer, and many of the stromal factors necessary for mammary development also promote or protect against breast cancer. Here we review our present knowledge of the specific factors and cell types that contribute to epithelial-stromal crosstalk during mammary development. To find cures for diseases like breast cancer that rely on epithelial-stromal crosstalk, we must understand how these different cell types communicate with each other.

  1. Mammary Cancer and Activation of Transposable Elements

    DTIC Science & Technology

    2014-09-01

    AD_________________ AWARD NUMBER: W81XWH-11-1-0401 TITLE: Mammary Cancer and Activation of Transposable Elements PRINCIPAL INVESTIGATOR...way as transcripts from the regular gene promoter. Transcriptional activation of retrotransposons is strongly linked with their CpG DNA methylation

  2. Human mammary microenvironment better regulates the biology of human breast cancer in humanized mouse model.

    PubMed

    Zheng, Ming-Jie; Wang, Jue; Xu, Lu; Zha, Xiao-Ming; Zhao, Yi; Ling, Li-Jun; Wang, Shui

    2015-02-01

    During the past decades, many efforts have been made in mimicking the clinical progress of human cancer in mouse models. Previously, we developed a human breast tissue-derived (HB) mouse model. Theoretically, it may mimic the interactions between "species-specific" mammary microenvironment of human origin and human breast cancer cells. However, detailed evidences are absent. The present study (in vivo, cellular, and molecular experiments) was designed to explore the regulatory role of human mammary microenvironment in the progress of human breast cancer cells. Subcutaneous (SUB), mammary fat pad (MFP), and HB mouse models were developed for in vivo comparisons. Then, the orthotopic tumor masses from three different mouse models were collected for primary culture. Finally, the biology of primary cultured human breast cancer cells was compared by cellular and molecular experiments. Results of in vivo mouse models indicated that human breast cancer cells grew better in human mammary microenvironment. Cellular and molecular experiments confirmed that primary cultured human breast cancer cells from HB mouse model showed a better proliferative and anti-apoptotic biology than those from SUB to MFP mouse models. Meanwhile, primary cultured human breast cancer cells from HB mouse model also obtained the migratory and invasive biology for "species-specific" tissue metastasis to human tissues. Comprehensive analyses suggest that "species-specific" mammary microenvironment of human origin better regulates the biology of human breast cancer cells in our humanized mouse model of breast cancer, which is more consistent with the clinical progress of human breast cancer.

  3. Leukocytes in Mammary Development and Cancer

    PubMed Central

    Coussens, Lisa M.; Pollard, Jeffrey W.

    2011-01-01

    Leukocytes, of both the innate and adaptive lineages, are normal cellular components of all tissues. These important cells not only are critical for regulating normal tissue homeostasis, but also are significant paracrine regulators of all physiologic and pathologic tissue repair processes. This article summarizes recent insights regarding the trophic roles of leukocytes at each stage of mammary gland development and during cancer development, with a focus on Murids and humans. PMID:21123394

  4. Inbreeding and canine mammary cancer: a retrospective study.

    PubMed

    Dorn, C R; Schneider, R

    1976-09-01

    Using files of the Animal Neoplasm Registry (ANR) in Alameda and Contra Costa Counties, California, we conducted a retrospective study to compare the degree of inbreeding in the ancestry of purebred dogs with mammary and other cancers, and of those without tumors. Wright's coefficients of inbreeding, calculated for all animals in the three groups, ranged from 0.000 to 0.535. The median inbreeding coefficients of the mammary cancer and comparison groups (consisting of other cancers) were approximately twice that of the nonneoplastic group, but neither difference was statistically significant. Dogs with mammary adenocarcinoma and mixed mammary cancer had similar degrees of inbreeding.

  5. Stem cells in normal mammary gland and breast cancer.

    PubMed

    Luo, Jie; Yin, Xin; Ma, Tao; Lu, Jun

    2010-04-01

    The mammary gland is a structurally dynamic organ that undergoes dramatic alterations with age, menstrual cycle, and reproductive status. Mammary gland stem cells, the minor cell population within the mature organ, are thought to have multiple functions in regulating mammary gland development, tissue maintenance, major growth, and structural remodeling. In addition, accumulative evidence suggests that breast cancers are initiated and maintained by a subpopulation of tumor cells with stem cell features (called cancer stem cells). A variety of methods have been developed to identify and characterize mammary stem cells, and several signal transduction pathways have been identified to be essential for the self-renewal and differentiation of mammary gland stem cells. Understanding the origin of breast cancer stem cells, their relationship to breast cancer development, and the differences between normal and cancer stem cells may lead to novel approaches to breast cancer diagnosis, prevention, and treatment.

  6. MMTV-PyMT and Derived Met-1 Mouse Mammary Tumor Cells as Models for Studying the Role of the Androgen Receptor in Triple-Negative Breast Cancer Progression.

    PubMed

    Christenson, Jessica L; Butterfield, Kiel T; Spoelstra, Nicole S; Norris, John D; Josan, Jatinder S; Pollock, Julie A; McDonnell, Donald P; Katzenellenbogen, Benita S; Katzenellenbogen, John A; Richer, Jennifer K

    2017-04-01

    Triple-negative breast cancer (TNBC) has a faster rate of metastasis compared to other breast cancer subtypes, and no effective targeted therapies are currently FDA-approved. Recent data indicate that the androgen receptor (AR) promotes tumor survival and may serve as a potential therapeutic target in TNBC. Studies of AR in disease progression and the systemic effects of anti-androgens have been hindered by the lack of an AR-positive (AR+) immunocompetent preclinical model. In this study, we identified the transgenic MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mouse mammary gland carcinoma model of breast cancer and Met-1 cells derived from this model as tools to study the role of AR in breast cancer progression. AR protein expression was examined in late-stage primary tumors and lung metastases from MMTV-PyMT mice as well as in Met-1 cells by immunohistochemistry (IHC). Sensitivity of Met-1 cells to the AR agonist dihydrotestosterone (DHT) and anti-androgen therapy was examined using cell viability, migration/invasion, and anchorage-independent growth assays. Late-stage primary tumors and lung metastases from MMTV-PyMT mice and Met-1 cells expressed abundant nuclear AR protein, while negative for estrogen and progesterone receptors. Met-1 sensitivity to DHT and AR antagonists demonstrated a reliance on AR for survival, and AR antagonists inhibited invasion and anchorage-independent growth. These data suggest that the MMTV-PyMT model and Met-1 cells may serve as valuable tools for mechanistic studies of the role of AR in disease progression and how anti-androgens affect the tumor microenvironment.

  7. Positional variations in mammary gland development and cancer.

    PubMed

    Veltmaat, Jacqueline M; Ramsdell, Ann F; Sterneck, Esta

    2013-06-01

    Most mammals develop their mammary glands in pairs of which the two counterparts are symmetrically displaced away from the ventral midline. Based on this symmetry and the same functional outcome as a milk-producing organ, the mammary glands are easily presumed to be mere copies of one another. Based on our analysis of published data with inclusion of new results related to mammary development and pathology in mice, we argue that this presumption is incorrect: Between and within pairs, mammary glands differ from one another, and tumor incidence and biology depend on the position along the anterior-posterior and the left-right axis as well. This insight has implications for experimental designs with mouse models and for data extrapolation between mammary glands within and between species. We suggest that improved documentation of location-specific mammary gland features will lead to more insights into the molecular mechanisms of mammary gland development and cancer biology in both mice and humans.

  8. Mammary gland stem cells and their application in breast cancer.

    PubMed

    Yang, Xing; Wang, Hui; Jiao, Baowei

    2017-02-07

    The mammary gland is an organ comprising two primary lineages, specifically the inner luminal and the outer myoepithelial cell layers. Mammary gland stem cells (MaSCs) are highly dynamic and self-renewing, and can give rise to these mammary gland lineages. The lineages are responsible for gland generation during puberty as well as expansion during pregnancy. In recent years, researchers have focused on understanding how MaSCs are regulated during mammary gland development and transformation of breast cancer. Here, we summarize the identification of MaSCs, and how they are regulated by the signaling transduction pathways, mammary gland microenvironment, and non-coding RNAs (ncRNAs). Moreover, we debate the evidence for their serving as the origin of breast cancer, and discuss the therapeutic perspectives of targeting breast cancer stem cells (BCSCs). In conclusion, a better understanding of the key regulators of MaSCs is crucial for the clinical treatment of breast cancer.

  9. Genetic Susceptibility to Estrogen-Induced Mammary Cancers

    DTIC Science & Technology

    2000-11-01

    mammary glands were reflected in mammary histology. (A and E) Thin sections from Fig. 3. E2 induced pituitary growth and hyperprolactinemia similarly in...with E2 5 (33%) exhibited a normal DNA profile where the great for 12 wk induced pituitary growth and hyperprolactinemia in majority of cells displayed...etal. , " terone, or PRL. Hyperprolactinemia has been shown to be sufficient to induce mammary cancer in certain strains of mouse 1 , (29-31) and rat

  10. Wound healing-like immune program facilitates postpartum mammary gland involution and tumor progression.

    PubMed

    Martinson, Holly A; Jindal, Sonali; Durand-Rougely, Clarissa; Borges, Virginia F; Schedin, Pepper

    2015-04-15

    Women diagnosed with breast cancer within 5 years postpartum have poor survival rates. The process of postpartum mammary gland involution, whereby the lactating gland remodels to its prepregnant state, promotes breast cancer progression in xenograft models. Macrophage influx occurs during mammary gland involution, implicating immune modulation in the promotion of postpartum breast cancer. Herein, we characterize the postpartum murine mammary gland and find an orchestrated influx of immune cells similar to that which occurs during wound healing. Further, the normal involuting gland may be in an immunosuppressed state as discerned by the transient presence of Foxp3(+) regulatory T cells and IL-10(+) macrophages with T cell suppressive function. To determine the influence of the postpartum immune microenvironment on mammary tumor promotion, we developed an immune-competent model. In this model, mammary tumors in the involution group are sixfold larger than nulliparous group tumors, have decreased CD4(+) and CD8(+) T cell infiltrates and contain a greater number of macrophages with the ability to inhibit T cell activation. Targeting involution with a neutralizing antibody against the immunosuppressive cytokine IL-10 reduces tumor growth in involution group mice but not in nulliparous mice, implicating the involution microenvironment as the primary target of αIL-10 treatment. Relevance to women is implicated, as we find postlactational human breast tissue has transient high IL-10(+) and Foxp3(+) immune cell infiltrate. These data show an immune modulated microenvironment within the normal involuting mammary gland suggestive of immunosuppression, that when targeted reduces tumor promotion, revealing possible immune-based strategies for postpartum breast cancer.

  11. Hippo pathway in mammary gland development and breast cancer.

    PubMed

    Shi, Peiguo; Feng, Jing; Chen, Ceshi

    2015-01-01

    Accumulated evidence suggests that the Hippo signaling pathway plays crucial roles in mammary gland development and breast cancer. Key components of the Hippo pathway regulate breast epithelial cell proliferation, migration, invasion, and stemness. Additionally, the Hippo pathway regulates breast tumor growth, metastasis, and drug resistance. It is expected that the Hippo pathway will provide novel therapeutic targets for breast cancer. This review will discuss and summarize the roles of several core components of the Hippo pathway in mammary gland development and breast cancer.

  12. Modeling mechanical interactions between cancerous mammary acini

    NASA Astrophysics Data System (ADS)

    Wang, Jeffrey; Liphardt, Jan; Rycroft, Chris

    2015-03-01

    The rules and mechanical forces governing cell motility and interactions with the extracellular matrix of a tissue are often critical for understanding the mechanisms by which breast cancer is able to spread through the breast tissue and eventually metastasize. Ex vivo experimentation has demonstrated the the formation of long collagen fibers through collagen gels between the cancerous mammary acini responsible for milk production, providing a fiber scaffolding along which cancer cells can disorganize. We present a minimal mechanical model that serves as a potential explanation for the formation of these collagen fibers and the resultant motion. Our working hypothesis is that cancerous cells induce this fiber formation by pulling on the gel and taking advantage of the specific mechanical properties of collagen. To model this system, we employ a new Eulerian, fixed grid simulation method to model the collagen as a nonlinear viscoelastic material subject to various forces coupled with a multi-agent model to describe individual cancer cells. We find that these phenomena can be explained two simple ideas: cells pull collagen radially inwards and move towards the tension gradient of the collagen gel, while being exposed to standard adhesive and collision forces.

  13. Effects of Recurrent Stress and a Music Intervention on Tumor Progression and Indices of Distress in an MNU-induced Mammary Cancer in Rats

    DTIC Science & Technology

    2011-03-04

    of Thesis: The effects of recurrent stress and a music intervention on tumor progression and indices of distress in an...2009). Cancer patients already have poorer immune systems than persons without disease (Andersen, 2003), and the effects of stress on breast...Pharmacology, Biochemistry and Behavior, 66, 375-381. Ferrer, A.J. (2007). The effect of live music on

  14. Breast cancer detection using mammary ductoscopy.

    PubMed

    Sauter, Edward

    2005-06-01

    Mammary ductoscopy (MD) has been used as a tool to evaluate the breast for cancer for over 10 years. MD allows the direct visualization of the duct lumen, providing a more targeted approach to the diagnosis of disease arising in the ductal system, since the lesion can be visualized and samples collected in the area of interest. Initial studies of MD evaluated women with pathologic spontaneous nipple discharge (PND), while more recent reports are also using MD to assess women without PND for the presence of breast cancer. Cytologic assessment of MD is highly specific but less sensitive in the detection of breast cancer. Nonetheless, a MD sample from a breast with PND may rarely undergo cytologic review and be interpreted as consistent with malignancy, only later to undergo surgical resection demonstrating benign pathology. For this reason, PND specimens interpreted as malignant on cytologic review require histopathologic confirmation prior to instituting therapy. Additional sample evaluation using image or molecular analysis may improve the sensitivity and specificity of MD in breast cancer detection.

  15. A Comparative Approach of Tumor-Associated Inflammation in Mammary Cancer between Humans and Dogs.

    PubMed

    Carvalho, Maria Isabel; Silva-Carvalho, Ricardo; Pires, Isabel; Prada, Justina; Bianchini, Rodolfo; Jensen-Jarolim, Erika; Queiroga, Felisbina L

    2016-01-01

    Infiltrating cells of the immune system are widely accepted to be generic constituents of tumor microenvironment. It has been well established that the development of mammary cancer, both in humans and in dogs, is associated with alterations in numbers and functions of immune cells at the sites of tumor progression. These tumor infiltrating immune cells seem to exhibit exclusive phenotypic and functional characteristics and mammary cancer cells can take advantage of signaling molecules released by them. Cancer related inflammation has an important role in mammary carcinogenesis, contributing to the acquisition of core hallmark capabilities that allow cancer cells to survive, proliferate, and disseminate. Indeed, recent studies in human breast cancer and in canine mammary tumors have identified a growing list of signaling molecules released by inflammatory cells that serve as effectors of their tumor-promoting actions. These include the COX-2, the tumor EGF, the angiogenic VEGF, other proangiogenic factors, and a large variety of chemokines and cytokines that amplify the inflammatory state. This review describes the intertwined signaling pathways shared by T-lymphocytic/macrophage infiltrates and important tissue biomarkers in both human and dog mammary carcinogenesis.

  16. A Comparative Approach of Tumor-Associated Inflammation in Mammary Cancer between Humans and Dogs

    PubMed Central

    Silva-Carvalho, Ricardo; Pires, Isabel; Bianchini, Rodolfo; Jensen-Jarolim, Erika

    2016-01-01

    Infiltrating cells of the immune system are widely accepted to be generic constituents of tumor microenvironment. It has been well established that the development of mammary cancer, both in humans and in dogs, is associated with alterations in numbers and functions of immune cells at the sites of tumor progression. These tumor infiltrating immune cells seem to exhibit exclusive phenotypic and functional characteristics and mammary cancer cells can take advantage of signaling molecules released by them. Cancer related inflammation has an important role in mammary carcinogenesis, contributing to the acquisition of core hallmark capabilities that allow cancer cells to survive, proliferate, and disseminate. Indeed, recent studies in human breast cancer and in canine mammary tumors have identified a growing list of signaling molecules released by inflammatory cells that serve as effectors of their tumor-promoting actions. These include the COX-2, the tumor EGF, the angiogenic VEGF, other proangiogenic factors, and a large variety of chemokines and cytokines that amplify the inflammatory state. This review describes the intertwined signaling pathways shared by T-lymphocytic/macrophage infiltrates and important tissue biomarkers in both human and dog mammary carcinogenesis. PMID:28053982

  17. A review of mammary ductoscopy in breast cancer.

    PubMed

    Yamamoto, Daigo; Tanaka, Kanji

    2004-01-01

    Breast carcinoma and hyperplasia are thought to start in the lining of the breast duct. Mammary ductoscopy is an emerging technique allowing direct visual access of the ductal system of the breast through the nipple. This article reviews and discusses the utility of mammary ductoscopy. Abnormalities can be identified successfully by mammary ductoscopy, and intraductal biopsy can be used when the tumor is a polypoid type. Ductal lavage using microcatheters is effective in identifying malignant cells in high-risk women and this has stimulated interest in exploring the role of mammary ductoscopy in breast cancer screening. Mammary ductoscopy combined with ductal lavage may have a role in the management of patients with nipple discharge, the guiding of breast-conserving surgery for cancer, and in screening for high-risk women. The addition of molecular and genetic analysis of cells obtained by mammary ductoscopy are likely to enhance the use of this technique. Mammary ductoscopy techniques are safe and appear useful for detecting abnormalities in the breast. The additional molecular biologic study or ductal lavage may enhance the ability to direct and limit subsequent surgery when removing the offending lesions.

  18. Notch in mammary gland development and breast cancer.

    PubMed

    Politi, Katerina; Feirt, Nikki; Kitajewski, Jan

    2004-10-01

    Notch signaling has been implicated in many processes including cell fate determination and oncogenesis. In mice, the Notch1 and Notch4 genes are both targets for insertion and rearrangement by the mouse mammary tumor virus and these mutations promote epithelial mammary tumorigenesis. Moreover, expression of a constitutively active form of Notch4 in mammary epithelial cells inhibits epithelial differentiation and leads to tumor formation in this organ. These data implicate the Notch pathway in breast tumorigenesis and provide the foundation for future experiments that will aid in our understanding of the role of Notch in human breast cancer development. Here, we review studies of mammary tumorigenesis induced by Notch in mouse and in vitro culture models providing evidence that Notch activation is a causal factor in human breast cancer.

  19. Nitric Oxide in Mammary Tumor Progression

    DTIC Science & Technology

    1998-07-01

    and endothelial cells, and poor cent work utilizing live videomicroscopy has dem- in human macrophages [24]. onstrated that even after successful...AC: Steps in tumor metastasis: New tion. concepts in intravital videomicroscopy . Cancer Met Rev 14: 2. How universal is the phenomenon of NO-medi- 1279... videomicroscopy . It is shown phokine (IL-2) activated killer (LAK) cells can in- that endogenous NO (derived from tumor vascular flict direct damage to

  20. Anti-influenza neuraminidase inhibitor oseltamivir phosphate induces canine mammary cancer cell aggressiveness.

    PubMed

    de Oliveira, Joana T; Santos, Ana L; Gomes, Catarina; Barros, Rita; Ribeiro, Cláudia; Mendes, Nuno; de Matos, Augusto J; Vasconcelos, M Helena; Oliveira, Maria José; Reis, Celso A; Gärtner, Fátima

    2015-01-01

    Oseltamivir phosphate is a widely used anti-influenza sialidase inhibitor. Sialylation, governed by sialyltransferases and sialidases, is strongly implicated in the oncogenesis and progression of breast cancer. In this study we evaluated the biological behavior of canine mammary tumor cells upon oseltamivir phosphate treatment (a sialidase inhibitor) in vitro and in vivo. Our in vitro results showed that oseltamivir phosphate impairs sialidase activity leading to increased sialylation in CMA07 and CMT-U27 canine mammary cancer cells. Surprisingly, oseltamivir phosphate stimulated, CMT-U27 cell migration and invasion capacity in vitro, in a dose-dependent manner. CMT-U27 tumors xenograft of oseltamivir phosphate-treated nude mice showed increased sialylation, namely α2,6 terminal structures and SLe(x) expression. Remarkably, a trend towards increased lung metastases was observed in oseltamivir phosphate-treated nude mice. Taken together, our findings revealed that oseltamivir impairs canine mammary cancer cell sialidase activity, altering the sialylation pattern of canine mammary tumors, and leading, surprisingly, to in vitro and in vivo increased mammary tumor aggressiveness.

  1. Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate Induces Canine Mammary Cancer Cell Aggressiveness

    PubMed Central

    de Oliveira, Joana T.; Santos, Ana L.; Gomes, Catarina; Barros, Rita; Ribeiro, Cláudia; Mendes, Nuno; de Matos, Augusto J.; Vasconcelos, M. Helena; Oliveira, Maria José; Reis, Celso A.; Gärtner, Fátima

    2015-01-01

    Oseltamivir phosphate is a widely used anti-influenza sialidase inhibitor. Sialylation, governed by sialyltransferases and sialidases, is strongly implicated in the oncogenesis and progression of breast cancer. In this study we evaluated the biological behavior of canine mammary tumor cells upon oseltamivir phosphate treatment (a sialidase inhibitor) in vitro and in vivo. Our in vitro results showed that oseltamivir phosphate impairs sialidase activity leading to increased sialylation in CMA07 and CMT-U27 canine mammary cancer cells. Surprisingly, oseltamivir phosphate stimulated, CMT-U27 cell migration and invasion capacity in vitro, in a dose-dependent manner. CMT-U27 tumors xenograft of oseltamivir phosphate-treated nude mice showed increased sialylation, namely α2,6 terminal structures and SLe(x) expression. Remarkably, a trend towards increased lung metastases was observed in oseltamivir phosphate-treated nude mice. Taken together, our findings revealed that oseltamivir impairs canine mammary cancer cell sialidase activity, altering the sialylation pattern of canine mammary tumors, and leading, surprisingly, to in vitro and in vivo increased mammary tumor aggressiveness. PMID:25850034

  2. On the possible role of mammary-derived growth hormone in human breast cancer.

    PubMed

    Thijssen, Jos H H

    2009-12-01

    The incidence of breast cancer has risen worldwide, especially in countries where it used to be low, very probably as a result of economic prosperity and changes in life-style. In women, the available data have resulted in the concept of progression from normal breast development to cancer through precursor lesions sensitive to hormones and growth factors that can be produced locally in the mammary gland, acting as paracrine or autocrine stimulating agents. The local endocrine environment in the breast can be different from the situation in the circulation. In the dog, growth hormone (GH) can be produced locally in the mammary glands and its production can be stimulated by progestins. This GH probably plays a paracrine role in the progesterone-induced proliferation and differentiation of mammary epithelium. There is increasing evidence that the local mammary progestin/GH-axis is operational not only in dogs but also in human breast cancer. No data are yet available on the production of mammary-derived GH in women.

  3. Endocrine-active chemicals in mammary cancer causation and prevention.

    PubMed

    Jenkins, Sarah; Betancourt, Angela M; Wang, Jun; Lamartiniere, Coral A

    2012-04-01

    Endocrine-active chemicals alter or mimic physiological hormones. These compounds are reported to originate from a wide variety of sources, and recent studies have shown widespread human exposure to several of these compounds. Given the role of the sex steroid hormone, estradiol, in human breast cancer causation, endocrine-active chemicals which interfere with estrogen signaling constitute one potential factor contributing to the high incidence of breast cancer. Thus, the aim of this review is to examine several common endocrine-active chemicals and their respective roles in breast cancer causation or prevention. The plastic component, bisphenol A (BPA), the synthetic estrogen, diethylstilbestrol (DES), the by-product of organic combustion, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the soy component, genistein, and the red grape phytoalexin, resveratrol, have some degree of structural similarities to each other and estradiol. However, despite these structural similarities, the in vitro and in vivo properties of each of these chemicals vary greatly in terms of breast cancer causation and prevention. Early life exposure to BPA and DES increases rodent susceptibility to chemically induced mammary carcinogenesis, presumably through retardation of normal mammary gland maturation and/or disrupting the ratio of cell proliferation and apoptosis in the mammary gland. On the other hand, early exposures to genistein and resveratrol protect rodents against chemically induced and spontaneous mammary cancers. This is reported to occur through the ability of genistein and resveratrol to accelerate mammary gland maturation. Interestingly, TCDD, which is the most structurally dissimilar to the above chemicals and functions as an anti-estrogen, also increases chemically induced mammary carcinogenesis through retardation of mammary gland maturation. This article is part of a Special Issue entitled 'Endocrine disruptors'.

  4. Proteomic Analysis of Genistein Mammary Cancer

    DTIC Science & Technology

    2005-07-01

    pathways we found up-regulated P-ERK-1, but no significant short-term changes in the tyrosine hydroxylase and iNOS protein expressions in mammary glands...of 21 day old rats. At day 50, there was significant up-regulation of tyrosine hydroxylase and VEGF-R2. This and previous work suggests that early...mammary glands of 21 day old rats only. In 50 day old rats, mammary tyrosine hydroxylase protein expression was up- regulated and now we report that

  5. A Multifaceted Role for Myd88-Dependent Signaling in Progression of Murine Mammary Carcinoma

    PubMed Central

    Higgins, Mary J.; Serrano, Antonio; Boateng, Kofi Y.; Parsons, Victoria A.; Phuong, Tiffany; Seifert, Alyssa; Ricca, Jacob M.; Tucker, Kyle C.; Eidelman, Alec S.; Carey, Maureen A.; Kurt, Robert A.

    2016-01-01

    Previous data obtained in our laboratory suggested that there may be constitutive signaling through the myeloid differentiation primary response gene 88 (Myd88)-dependent signaling cascade in murine mammary carcinoma. Here, we extended these findings by showing that, in the absence of an added Toll-like receptor (TLR) agonist, the myddosome complex was preformed in 4T1 tumor cells, and that Myd88 influenced cytoplasmic extracellular signal–regulated kinase (Erk)1/Erk2 levels, nuclear levels of nuclear factor-kappaB (NFκB) and signal transducer and activator of transcription 5 (STAT5), tumor-derived chemokine (C–C motif) ligand 2 (CCL2) expression, and in vitro and in vivo tumor growth. In addition, RNA-sequencing revealed that Myd88-dependent signaling enhanced the expression of genes that could contribute to breast cancer progression and genes previously associated with poor outcome for patients with breast cancer, in addition to suppressing the expression of genes capable of inhibiting breast cancer progression. Yet, Myd88-dependent signaling in tumor cells also suppressed expression of genes that could contribute to tumor progression. Collectively, these data revealed a multifaceted role for Myd88-dependent signaling in murine mammary carcinoma. PMID:27812285

  6. The role of neutralizing antibodies for mouse mammary tumor virus transmission and mammary cancer development

    NASA Astrophysics Data System (ADS)

    Finke, Daniela; Luther, Sanjiv A.; Acha-Orbea, Hans

    2003-01-01

    Mouse mammary tumor virus (MMTV) infection establishes chronic germinal centers and a lifelong neutralizing Ab response. We show that removal of the draining lymph node after establishment of the germinal center reaction led to complete loss of neutralizing Abs despite comparable infection levels in peripheral lymphocytes. Importantly, in the absence of neutralization, only the exocrine organs mammary gland, salivary gland, pancreas, and skin showed strikingly increased infection, resulting in accelerated mammary tumor development. Induction of stronger neutralization did not influence chronic infection levels of peripheral lymphoid organs but strongly inhibited mammary gland infection and virus transmission to the next generation. Taken together, we provide evidence that a tight equilibrium in virus neutralization allows limited infection of exocrine organs and controls cancer development in susceptible mouse strains. These experiments show that a strong neutralizing Ab response induced after infection is not able to control lymphoid MMTV infection. Strong neutralization, however, is capable of blocking amplification of mammary gland infection, tumor development, and virus transmission to the next generation. The results also indicate a role of neutralization in natural resistance to MMTV infection.

  7. The role of mammary ductoscopy in breast cancer: a review of the literature.

    PubMed

    Kapenhas-Valdes, Edna; Feldman, Sheldon M; Boolbol, Susan K

    2008-12-01

    Breast cancer is the most frequently diagnosed malignancy among American women. It is the second most common cause of cancer death. Genetic analysis using comparative genetic hybridization (CGH) has shown evidence that the majority of breast cancers, approximately 85%, begin in the ductal epithelium with normal cells progressing to atypia and finally to carcinoma. Mammary ductoscopy, also referred to as the intraductal approach, is a new tool that allows direct visualization of the breast ductal system. It enables one to sample the ductal epithelium and may allow identification of early changes cytologically as well as potentially play an important role in aiding surgical excision. This may aid in detection of breast masses long before they are palpable or visible via mammography. Mammary ductoscopy may have a role in the evaluation of women with nipple discharge, high-risk women, or limiting the amount of tissue removed in breast conservation surgery for cancer.

  8. Differentiation of the mammary epithelial cell during involution: implications for breast cancer.

    PubMed

    Monks, Jenifer; Henson, Peter M

    2009-06-01

    That milk secretion is not the final differentiated state of the mammary alveolar cells is a relatively new concept. Recent work has suggested that secreting, mammary epithelial cells (MECs) have another function to perform before they undergo cell death in the involuting mammary gland. That is, they help in the final clearance and breakdown of their neighboring cells (and likely residual milk as well.) They become, for a short time, amateur phagocytes, or efferocytes, and then are believed to die and be cleared themselves. Although relatively little study has been made of this change in the functional state of the MEC, nevertheless we may speculate from the involution literature, and extend findings from other systems of apoptotic cell clearance, on some of the mechanisms involved. And with the finding that involution may represent a unique susceptibility window for the progression of metastatic breast cancer, we may suggest areas for future research along these lines as well.

  9. Elf5 inhibits the epithelial-mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2.

    PubMed

    Chakrabarti, Rumela; Hwang, Julie; Andres Blanco, Mario; Wei, Yong; Lukačišin, Martin; Romano, Rose-Anne; Smalley, Kirsten; Liu, Song; Yang, Qifeng; Ibrahim, Toni; Mercatali, Laura; Amadori, Dino; Haffty, Bruce G; Sinha, Satrajit; Kang, Yibin

    2012-11-01

    The epithelial-mesenchymal transition (EMT) is a complex process that occurs during organogenesis and in cancer metastasis. Despite recent progress, the molecular pathways connecting the physiological and pathological functions of EMT need to be better defined. Here we show that the transcription factor Elf5, a key regulator of mammary gland alveologenesis, controls EMT in both mammary gland development and metastasis. We uncovered this role for Elf5 through analyses of Elf5 conditional knockout animals, various in vitro and in vivo models of EMT and metastasis, an MMTV-neu transgenic model of mammary tumour progression and clinical breast cancer samples. Furthermore, we demonstrate that Elf5 suppresses EMT by directly repressing the transcription of Snail2, a master regulator of mammary stem cells and a known inducer of EMT. These findings establish Elf5 not only as a key cell lineage regulator during normal mammary gland development, but also as a suppressor of EMT and metastasis in breast cancer.

  10. Macrophages: Regulators of the Inflammatory Microenvironment during Mammary Gland Development and Breast Cancer

    PubMed Central

    Brady, Nicholas J.; Chuntova, Pavlina; Schwertfeger, Kathryn L.

    2016-01-01

    Macrophages are critical mediators of inflammation and important regulators of developmental processes. As a key phagocytic cell type, macrophages evolved as part of the innate immune system to engulf and process cell debris and pathogens. Macrophages produce factors that act directly on their microenvironment and also bridge innate immune responses to the adaptive immune system. Resident macrophages are important for acting as sensors for tissue damage and maintaining tissue homeostasis. It is now well-established that macrophages are an integral component of the breast tumor microenvironment, where they contribute to tumor growth and progression, likely through many of the mechanisms that are utilized during normal wound healing responses. Because macrophages contribute to normal mammary gland development and breast cancer growth and progression, this review will discuss both resident mammary gland macrophages and tumor-associated macrophages with an emphasis on describing how macrophages interact with their surrounding environment during normal development and in the context of cancer. PMID:26884646

  11. Macrophages: Regulators of the Inflammatory Microenvironment during Mammary Gland Development and Breast Cancer.

    PubMed

    Brady, Nicholas J; Chuntova, Pavlina; Schwertfeger, Kathryn L

    2016-01-01

    Macrophages are critical mediators of inflammation and important regulators of developmental processes. As a key phagocytic cell type, macrophages evolved as part of the innate immune system to engulf and process cell debris and pathogens. Macrophages produce factors that act directly on their microenvironment and also bridge innate immune responses to the adaptive immune system. Resident macrophages are important for acting as sensors for tissue damage and maintaining tissue homeostasis. It is now well-established that macrophages are an integral component of the breast tumor microenvironment, where they contribute to tumor growth and progression, likely through many of the mechanisms that are utilized during normal wound healing responses. Because macrophages contribute to normal mammary gland development and breast cancer growth and progression, this review will discuss both resident mammary gland macrophages and tumor-associated macrophages with an emphasis on describing how macrophages interact with their surrounding environment during normal development and in the context of cancer.

  12. The hedgehog signaling network, mammary stem cells, and breast cancer: connections and controversies.

    PubMed

    Lewis, M T; Visbal, A P

    2006-01-01

    Several signal transduction networks have been implicated in the regulation of mammary epithelial stem cell self-renewal and maintenance (Kalirai and Clarke 2006; Liu et al. 2005). These signaling networks include those of the Wnt, Notch, TGFO, EGF, FGF, IGF, and most recently, the Hedgehog (Hh) families of secreted ligands. However, we currently know very little about the cellular and molecular mechanisms by which these signaling pathways function to regulate normal epithelial stem/progenitor cells. What is clear is that the regulatory signaling networks thought to control normal stem/progenitor cell self-renewal and maintenance are, with the current sole exception of the hedgehog network, well-documented to have contributory roles in mammary cancer development and disease progression when misregulated. In this review, genetic regulation of mammary gland development by hedgehog network genes is outlined, highlighting a developing controversy as to whether activated hedgehog signaling regulates normal regenerative mammary epithelial stem cells or, indeed, whether activated hedgehog signaling functions at all in ductal development. In addition, the question of whether inappropriate hedgehog network activation influences breast cancer development is addressed, with emphasis on the prospects for using hedgehog signaling antagonists clinically for breast cancer treatment or prevention.

  13. A mammary stem cell population identified and characterized in late embryogenesis reveals similarities to human breast cancer.

    PubMed

    Spike, Benjamin T; Engle, Dannielle D; Lin, Jennifer C; Cheung, Samantha K; La, Justin; Wahl, Geoffrey M

    2012-02-03

    Gene expression signatures relating mammary stem cell populations to breast cancers have focused on adult tissue. Here, we identify, isolate, and characterize the fetal mammary stem cell (fMaSC) state since the invasive and proliferative processes of mammogenesis resemble phases of cancer progression. fMaSC frequency peaks late in embryogenesis, enabling more extensive stem cell purification than achieved with adult tissue. fMaSCs are self-renewing, multipotent, and coexpress multiple mammary lineage markers. Gene expression, transplantation, and in vitro analyses reveal putative autocrine and paracrine regulatory mechanisms, including ErbB and FGF signaling pathways impinging on fMaSC growth. Expression profiles from fMaSCs and associated stroma exhibit significant similarities to basal-like and Her2+ intrinsic breast cancer subtypes. Our results reveal links between development and cancer and provide resources to identify new candidates for diagnosis, prognosis, and therapy.

  14. Genetic Susceptibility to Estrogen-Induced Mammary Cancers

    DTIC Science & Technology

    2001-11-01

    Susceptibility to Estrogen -Induced Mammary Cancers PRINCIPAL INVESTIGATOR: Dr. James D. Shull CONTRACTING ORGANIZATION: University of Nebraska Medical Center Omaha...DATES COVERED blank) November 2001 Final (01 Oct 98 - 01 Oct 01) 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS Genetic Susceptibility to Estrogen -Induced...Street, Fort Detrick, Maryland 21702-5012. 13. ABSTRACT (Maximum 200 Words) Estrogens are important in the etiology of breast cancer. We have developed

  15. Field cancerization in mammary carcinogenesis - Implications for prevention and treatment of breast cancer.

    PubMed

    Rivenbark, Ashley G; Coleman, William B

    2012-12-01

    The natural history of breast cancer unfolds with the development of ductal carcinoma in situ (DCIS) in normal breast tissue, and evolution of this pre-invasive neoplasm into invasive cancer. The mechanisms that drive these processes are poorly understood, but evidence from the literature suggests that mammary carcinogenesis may occur through the process of field cancerization. Clinical observations are consistent with the idea that (i) DCIS may arise in a field of altered breast epithelium, (ii) narrow surgical margins do not remove the entire altered field (contributing to recurrence and/or disease progression), and (iii) whole-breast radiation therapy is effective in elimination of the residual field of altered cells adjacent to the resected DCIS. Molecular studies suggest that the field of altered breast epithelial cells may carry cancer-promoting genetic mutations (or other molecular alterations) or cancer promoting epimutations (oncogenic alterations in the epigenome). In fact, most breast cancers develop through a succession of molecular events involving both genetic mutations and epimutations. Hence, in hereditary forms of breast cancer, the altered field reflects the entire breast tissue which is composed of cells with a predisposing molecular lesion (such as a BRCA1 mutation). In the example of a BRCA1-mutant patient, it is evident that local resection of a DCIS lesion or localized but invasive cancer will not result in elimination of the altered field. In sporadic breast cancer patients, the mechanistic basis for the altered field may not be so easily recognized. Nonetheless, identification of the nature of field cancerization in a given patient may guide clinical intervention. Thus, patients with DCIS that develops in response to an epigenetic lesion (such as a hypermethylation defect affecting the expression of tumor suppressor genes) might be treated with epigenetic therapy to normalize the altered field and reduce the risk of secondary occurrence of

  16. RUNX2 in mammary gland development and breast cancer.

    PubMed

    Ferrari, Nicola; McDonald, Laura; Morris, Joanna S; Cameron, Ewan R; Blyth, Karen

    2013-06-01

    Runx2 is best known as an essential factor in osteoblast differentiation and bone development but, like many other transcription factors involved in development, is known to operate over a much wider tissue range. Our understanding of these other aspects of Runx2 function is still at a relatively early stage and the importance of its role in cell fate decisions and lineage maintenance in non-osseous tissues is only beginning to emerge. One such tissue is the mammary gland, where Runx2 is known to be expressed and participate in the regulation of mammary specific genes. Furthermore, differential and temporal expression of this gene is observed during mammary epithelial differentiation in vivo, strongly indicative of an important functional role. Although the precise nature of that role remains elusive, preliminary evidence hints at possible involvement in the regulation of mammary stem and/or progenitor cells. As with many genes important in regulating cell fate, RUNX2 has also been linked to metastatic cancer where in some established breast cell lines, retention of expression is associated with a more invasive phenotype. More recently, expression analysis has been extended to primary breast cancers where high levels of RUNX2 align with a specific subtype of the disease. That RUNX2 expression correlates with the so called "Triple Negative" subtype is particularly interesting given the known cross talk between Runx2 and estrogen receptor signaling pathways. This review summaries our current understanding of Runx2 in mammary gland development and cancer, and postulates a role that may link both these processes.

  17. Mammary Cancer and Activation of Transposable Elements

    DTIC Science & Technology

    2013-09-01

    cytes and ADS-derived induced pluripotent stem cells (ADS-iPSCs) (19) and primary mouse ES cells to isolated sperm and oocytes (20). We selected an...051 59 5 92% H9-IMR90 5875 7 669 782 605 58 91% oocyte - ES cell (mouse) 4727 1 204 883 334 25 93% sperm - ES cell (mouse) 4580 4 364 748 1027 104 91...collaborator, Dr. Anne Peaston, developed a genetically engineered mouse model in which a specific mammary cell population is fluorescently marked upon

  18. Mouse Mammary Cancer Models - Mechanisms and Markers

    DTIC Science & Technology

    2001-08-01

    Wipl knockout mouse model and have shown defects in cell cycle control in cells derived from Wipl null animals. We are crossing these mice to mammary...compartment of the testes (13,14). Mice lacking Wipl are viable, but males show a reduced longevity and frequent runting (14). Wipl null males also show...predominates and thus the other TG/p53 mouse . Wnt-1 TG mice contain several copies nontumor components should not obscure any strong of a germline Wnt-1

  19. Hypothyroidism reduces mammary tumor progression via Β-catenin-activated intrinsic apoptotic pathway in rats.

    PubMed

    López Fontana, C M; Zyla, L E; Santiano, F E; Sasso, C V; Cuello-Carrión, F D; Pistone Creydt, V; Fanelli, M A; Carón, R W

    2017-02-13

    Experimental hypothyroidism retards mammary carcinogenesis promoting apoptosis of tumor cells. β-catenin plays a critical role in cell adhesion and intracellular signaling pathways conditioning the prognosis of breast cancer. However, the mechanistic connections associated with the expression of β-catenin in thyroid status and breast cancer are not known. Therefore, we studied the relationship between the expression and localization of β-catenin and apoptosis in mammary tumors induced by 7,12-dimethylbenz(a)anthracene (DMBA) in hypothyroid (Hypot) and euthyroid (EUT) rats. Female Sprague Dawley rats were treated with a dose of DMBA (15 mg/rat) at 55 days of age and were then divided into two groups: HypoT (0.01% 6-N-propyl-2-thiouracil in drinking water, n = 54) and EUT (untreated control, n = 43). Latency, incidence and progression of tumors were determined. At sacrifice, tumors were obtained for immunohistological studies and Western Blot. The latency was longer (p < 0.05), the incidence was lower (p < 0.0001) and tumor growth was slower (p < 0.01) in HypoT rats compared to EUT. The expression of Bax, cleaved caspase-9 and caspase-3 was significantly higher in tumors of HypoT than in EUT (p < 0.05) indicating the activation of the intrinsic pathway. In this group, β-catenin was expressed in the plasma membrane and with less intensity, while its expression was nuclear and with greater intensity in the EUT (p < 0.05). Moreover, the expression of survivin was reduced in tumors of HypoT rats (p < 0.05). In conclusion, decreased expression of β-catenin and its normal location in membrane of mammary tumors are associated with augmented apoptosis via activation of the intrinsic pathway in HypoT rats.

  20. Radiogenic neoplasia in thyroid and mammary clonogens. Progress report, January 1, 1993--December 31, 1993

    SciTech Connect

    Clifton, K.H.

    1993-07-30

    The induction of cancer by ionizing radiation is a matter of great practical importance to the nuclear industry, to national defense, to radiological medicine and to the general public. It is increasingly apparent that carcinogenesis is one of the leading dose-limiting effects of radiation exposure (Co90). Quantitative information at the cellular level is essential to an understanding of the mechanisms of radiogenic neoplastic initiation and the stages of promotion and progression to overt neoplasia. We have developed two experimental models, the rat thyroid and rat mammary clonogen transplant systems, for the quantitative study of radiation carcinogenesis at the cellular level in vivo (C185). The most important steps taken or completed during the current grant year include: (a) demonstration of the high age-dependent radiosensitivity of prepubertal rat mammary clonogens to radiogenic damage which may influence their susceptibility to neoplastic initiation, and (b) demonstration of the feasibility of using a molecular test for clonogenicity in which Simple Sequence Repeats in the DNA serve as identifying signals of the genotypic origin of the cells. We have also (c) set up a large carcinogenesis experiment to test the effect of close intercellular contact in thyroid glands in situ on promotion-progression of radiogenically initiated clonogens, (d) achieved considerable further concentration of thyroid clonogens, and (e) begun to explore whether thyroid cells can be induced to give rise to three dimensional multicellular structures in culture in reconstituted basement membrane. These are discussed in this report.

  1. Social isolation induces autophagy in the mouse mammary gland: link to increased mammary cancer risk.

    PubMed

    Sumis, Allison; Cook, Katherine L; Andrade, Fabia O; Hu, Rong; Kidney, Emma; Zhang, Xiyuan; Kim, Dominic; Carney, Elissa; Nguyen, Nguyen; Yu, Wei; Bouker, Kerrie B; Cruz, Idalia; Clarke, Robert; Hilakivi-Clarke, Leena

    2016-10-01

    Social isolation is a strong predictor of early all-cause mortality and consistently increases breast cancer risk in both women and animal models. Because social isolation increases body weight, we compared its effects to those caused by a consumption of obesity-inducing diet (OID) in C57BL/6 mice. Social isolation and OID impaired insulin and glucose sensitivity. In socially isolated, OID-fed mice (I-OID), insulin resistance was linked to reduced Pparg expression and increased neuropeptide Y levels, but in group-housed OID fed mice (G-OID), it was linked to increased leptin and reduced adiponectin levels, indicating that the pathways leading to insulin resistance are different. Carcinogen-induced mammary tumorigenesis was significantly higher in I-OID mice than in the other groups, but cancer risk was also increased in socially isolated, control diet-fed mice (I-C) and G-OID mice compared with that in controls. Unfolded protein response (UPR) signaling (GRP78; IRE1) was upregulated in the mammary glands of OID-fed mice, but not in control diet-fed, socially isolated I-C mice. In contrast, expression of BECLIN1, ATG7 and LC3II were increased, and p62 was downregulated by social isolation, indicating increased autophagy. In the mammary glands of socially isolated mice, but not in G-OID mice, mRNA expressions of p53 and the p53-regulated autophagy inducer Dram1 were upregulated, and nuclear p53 staining was strong. Our findings further indicated that autophagy and tumorigenesis were not increased in Atg7(+/-) mice kept in social isolation and fed OID. Thus, social isolation may increase breast cancer risk by inducing autophagy, independent of changes in body weight.

  2. Tracing anti-cancer and cancer-promoting actions of all-trans retinoic acid in breast cancer to a RARα epigenetic mechanism of mammary epithelial cell fate.

    PubMed

    Rossetti, Stefano; Ren, MingQiang; Visconti, Nicolo; Corlazzoli, Francesca; Gagliostro, Vincenzo; Somenzi, Giulia; Yao, Jin; Sun, Yijun; Sacchi, Nicoletta

    2016-12-27

    A hallmark of cancer cells is the ability to evade the growth inhibitory/pro-apoptotic action of physiological all-trans retinoic acid (RA) signal, the bioactive derivative of Vitamin A. However, as we and others reported, RA can also promote cancer cell growth and invasion. Here we show that anticancer and cancer-promoting RA actions in breast cancer have roots in a mechanism of mammary epithelial cell morphogenesis that involves both transcriptional (epigenetic) and non-transcriptional RARα (RARA) functions. We found that the mammary epithelial cell-context specific degree of functionality of the RARA transcriptional (epigenetic) component of this mechanism, by tuning the effects of the non-transcriptional RARA component, determines different cell fate decisions during mammary morphogenesis. Indeed, factors that hamper the RARA epigenetic function make physiological RA drive aberrant morphogenesis via non-transcriptional RARA, thus leading to cell transformation. Remarkably, also the cell context-specific degree of functionality of the RARA epigenetic component retained by breast cancer cells is critical to determine cell fate decisions in response to physiological as well as supraphysiological RA variation. Overall this study supports the proof of principle that the epigenetic functional plasticity of the mammary epithelial cell RARA mechanism, which is essential for normal morphogenetic processes, is necessary to deter breast cancer onset/progression consequent to the insidious action of physiological RA.

  3. Tracing anti-cancer and cancer-promoting actions of all-trans retinoic acid in breast cancer to a RARa epigenetic mechanism of mammary epithelial cell fate

    PubMed Central

    Rossetti, Stefano; Ren, MingQiang; Visconti, Nicolo; Corlazzoli, Francesca; Gagliostro, Vincenzo; Somenzi, Giulia; Yao, Jin; Sun, Yijun; Sacchi, Nicoletta

    2016-01-01

    A hallmark of cancer cells is the ability to evade the growth inhibitory/pro-apoptotic action of physiological all-trans retinoic acid (RA) signal, the bioactive derivative of Vitamin A. However, as we and others reported, RA can also promote cancer cell growth and invasion. Here we show that anticancer and cancer-promoting RA actions in breast cancer have roots in a mechanism of mammary epithelial cell morphogenesis that involves both transcriptional (epigenetic) and non-transcriptional RARα (RARA) functions. We found that the mammary epithelial cell-context specific degree of functionality of the RARA transcriptional (epigenetic) component of this mechanism, by tuning the effects of the non-transcriptional RARA component, determines different cell fate decisions during mammary morphogenesis. Indeed, factors that hamper the RARA epigenetic function make physiological RA drive aberrant morphogenesis via non-transcriptional RARA, thus leading to cell transformation. Remarkably, also the cell context-specific degree of functionality of the RARA epigenetic component retained by breast cancer cells is critical to determine cell fate decisions in response to physiological as well as supraphysiological RA variation. Overall this study supports the proof of principle that the epigenetic functional plasticity of the mammary epithelial cell RARA mechanism, which is essential for normal morphogenetic processes, is necessary to deter breast cancer onset/progression consequent to the insidious action of physiological RA. PMID:27894085

  4. Mammary Stem/Progenitor Cells and Cancer Susceptibility

    DTIC Science & Technology

    2012-06-01

    dependent mammary cancer; and 2) Brown Norway (BN), which is highly resistant. Major findings: ACI and BN rats likely exhibit significant differences in...stimulated states in two well characterized inbred rat strains: 1) ACI, which is highly susceptible to 17β-estradiol (E2)-induced/progesterone (P...MaSC number and/or responsiveness to hormone. Technical issues and loss of commercial source of BN rats led to revision of Aims. The data generated

  5. MicroRNA expression in canine mammary cancer.

    PubMed

    Boggs, R Michelle; Wright, Zachary M; Stickney, Mark J; Porter, Weston W; Murphy, Keith E

    2008-08-01

    MicroRNAs (miRNAs) are 18-22-nt noncoding RNAs that are involved in post-transcriptional regulation of genes. Oncomirs, a subclass of miRNAs, include genes whose expression, or lack thereof, are associated with cancers. Until the last decade, the domestic dog was an underused model for the study of various human diseases that have genetic components. The dog exhibits marked genetic and physiologic similarity to the human, thereby making it an excellent model for study and treatment of various hereditary diseases. Furthermore, because the dog presents with distinct, spontaneously occurring mammary tumors, it may serve as a model for genetic analysis and treatments of humans with malignant breast tumors. Because miRNAs have been found to act as both tumor suppressors and oncogenes in several different cancers, expression patterns of ten miRNAs (miR-15a, miR-16, miR-17-5p, miR-21, miR-29b, miR-125b, miR-145, miR-155, miR-181b, let-7f) known to be associated with human breast cancers were compared to malignant canine mammary tumors (n = 6) and normal canine mammary tissue (n = 10). Resulting data revealed miR-29b and miR-21 to have a statistically significant (p < 0.05 by MANOVA analysis) upregulation in cancerous samples. The ten canine miRNAs follow the same pattern of expression as in the human, except for miR-145 which does not show a difference in expression between the normal and cancerous canine samples. In addition, when analyzed according to specific cancer phenotypes, miR-15a and miR-16 show a significant downregulation in canine ductal carcinomas while miRsR-181b, -21, -29b, and let-7f show a significant upregulation in canine tubular papillary carcinomas.

  6. Inhibition of Breast Cancer Progression by Blocking Heterocellular Contact between Epithelial Cells and Fibroblasts

    DTIC Science & Technology

    2012-04-01

    between MCF-DCIS cells and human mammary fibroblasts (HMFs) in breast cancer progression by employing a microfluidic -based compartmentalized 3D co-culture platform enabling both contact-free and contact-associated co-cultures.

  7. Mammary Cancer and Activation of Transposable Elements

    DTIC Science & Technology

    2015-03-01

    propose that the wide-spread remodeling of DNA methylation patterns found in tumors may begin at this early pre-clinical stages modeled in this study...elucidating relationships between DNA methylation and expression. These tools have broad potential to affect our understanding of the functions of DNA ...methylation in breast cancer and may impact cancer prevention in the future. 15. SUBJECT TERMS Breast cancer, epigenetic, DNA methylation

  8. Vitamin D receptor regulates autophagy in the normal mammary gland and in luminal breast cancer cells

    PubMed Central

    Tavera-Mendoza, Luz E.; Westerling, Thomas; Libby, Eric; Marusyk, Andriy; Cato, Laura; Cassani, Raymundo; Cameron, Lisa A.; Ficarro, Scott B.; Marto, Jarrod A.; Klawitter, Jelena; Brown, Myles

    2017-01-01

    Women in North America have a one in eight lifetime risk of developing breast cancer (BC), and a significant proportion of these individuals will develop recurrent BC and will eventually succumb to the disease. Metastatic, therapy-resistant BC cells are refractory to cell death induced by multiple stresses. Here, we document that the vitamin D receptor (VDR) acts as a master transcriptional regulator of autophagy. Activation of the VDR by vitamin D induces autophagy and an autophagic transcriptional signature in BC cells that correlates with increased survival in patients; strikingly, this signature is present in the normal mammary gland and is progressively lost in patients with metastatic BC. A number of epidemiological studies have shown that sufficient vitamin D serum levels might be protective against BC. We observed that dietary vitamin D supplementation in mice increases basal levels of autophagy in the normal mammary gland, highlighting the potential of vitamin D as a cancer-preventive agent. These findings point to a role of vitamin D and the VDR in modulating autophagy and cell death in both the normal mammary gland and BC cells. PMID:28242709

  9. Vitamin D receptor regulates autophagy in the normal mammary gland and in luminal breast cancer cells.

    PubMed

    Tavera-Mendoza, Luz E; Westerling, Thomas; Libby, Eric; Marusyk, Andriy; Cato, Laura; Cassani, Raymundo; Cameron, Lisa A; Ficarro, Scott B; Marto, Jarrod A; Klawitter, Jelena; Brown, Myles

    2017-03-14

    Women in North America have a one in eight lifetime risk of developing breast cancer (BC), and a significant proportion of these individuals will develop recurrent BC and will eventually succumb to the disease. Metastatic, therapy-resistant BC cells are refractory to cell death induced by multiple stresses. Here, we document that the vitamin D receptor (VDR) acts as a master transcriptional regulator of autophagy. Activation of the VDR by vitamin D induces autophagy and an autophagic transcriptional signature in BC cells that correlates with increased survival in patients; strikingly, this signature is present in the normal mammary gland and is progressively lost in patients with metastatic BC. A number of epidemiological studies have shown that sufficient vitamin D serum levels might be protective against BC. We observed that dietary vitamin D supplementation in mice increases basal levels of autophagy in the normal mammary gland, highlighting the potential of vitamin D as a cancer-preventive agent. These findings point to a role of vitamin D and the VDR in modulating autophagy and cell death in both the normal mammary gland and BC cells.

  10. 14-3-3ζ Orchestrates Mammary Tumor Onset and Progression via miR221-Mediated Cell Proliferation

    PubMed Central

    Wyszomierski, Shannon L.; Wang, Qingfei; Li, Ping; Sahin, Ozgur; Xiao, Yi; Zhang, Siyuan; Xiong, Yan; Yang, Jun; Wang, Hai; Guo, Hua; Zhang, Jitao D.; Medina, Daniel; Muller, William J.; Yu, Dihua

    2013-01-01

    14-3-3ζ is overexpressed in over 40% of breast cancers but its pathophysiological relevance to tumorigenesis has not been established. Here we show that 14-3-3ζ overexpression is sufficient to induce tumorigenesis in a transgenic mouse model of breast cancer. MMTV-LTR promoter driven HA-14-3-3ζ transgenic mice (MMTV-HA-14-3-3ζ) developed mammary tumors whereas control mice did not. Whey acidic protein promoter driven HA-14-3-3ζ transgenic mice (WAP-HA-14-3-3ζ) developed hyperplastic lesions and showed increased susceptibility to carcinogen-induced tumorigenesis. When crossed with MMTV-neu transgenic mice, 14-3-3ζ.neu transgenic mice exhibited accelerated mammary tumorigenesis and metastasis compared to MMTV-neu mice. Mechanistically, 14-3-3ζ overexpression enhanced MAPK/c-Jun signaling leading to increased miR-221 transcription, which inhibited p27 CDKI translation, and consequently, promoted cell proliferation. Importantly, this 14-3-3ζ/miR-221/p27/proliferation axis is also functioning in patients' breast tumors and associates with high grade cancers. Taken together, our findings show that 14-3-3ζ overexpression has a causal role in mammary tumorigenesis and progression, acting through miR-221 in cooperation with known oncogenic events to drive neoplastic cell proliferation. PMID:24197133

  11. Intraductal approach to breast cancer: the role of mammary ductoscopy.

    PubMed

    Deshmane, Vinay

    2010-09-01

    Mammary ductoscopy is a recent advance enabling direct visualisation and sampling of human mammary ducts using a micro endoscope. The majority of pre malignant and malignant changes in the breast arise from the epithelium lining the duct lobular unit, and access to this region by ductoscopy has the potential to revolutionise breast cancer diagnosis and treatment. The ability to sample ductal epithelium may allow identification of early malignant and pre-malignant cytological changes and assist surgical excision, facilitating diagnosis of non palpable cancer before detection on current imaging modalities. Presently, there are three main indications for ductoscopy in clinical practice viz. determining extent of resection for breast cancer, assessment of high risk individuals and in the management of patients with pathological nipple discharge. Our initial experience with ductoscopy in patients with nipple discharge undergoing surgery has been rewarding. Ductoscopy was feasible in 92% of patients. Abnormal findings on ductoscopy were associated with DCIS in 37% and DCIS with early invasive breast cancer in 21%, while normal ductoscopy correlated with a normal pathological assessment.

  12. Dietary compound isoliquiritigenin prevents mammary carcinogenesis by inhibiting breast cancer stem cells through WIF1 demethylation

    PubMed Central

    Wang, Yu; Xie, Xiaoming; Shen, Jiangang; Peng, Cheng; You, Jieshu; Peng, Fu; Tang, Hailin; Guan, Xinyuan; Chen, Jianping

    2015-01-01

    Breast cancer stem cells (CSCs) are considered as the root of mammary tumorigenesis. Previous studies have demonstrated that ISL efficiently limited the activities of breast CSCs. However, the cancer prevention activities of ISL and its precise molecular mechanisms remain largely unknown. Here, we report a novel function of ISL as a natural demethylation agent targeting WIF1 to prevent breast cancer. ISL administration suppressed in vivo breast cancer initiation and progression, accompanied by reduced CSC-like populations. A global gene expression profile assay further identified WIF1 as the main response gene of ISL treatment, accompanied by the simultaneous downregulation of β-catenin signaling and G0/G1 phase arrest in breast CSCs. In addition, WIF1 inhibition significantly relieved the CSC-limiting effects of ISL and methylation analysis further revealed that ISL enhanced WIF1 gene expression via promoting the demethylation of its promoter, which was closely correlated with the inhibition of DNMT1 methyltransferase. Molecular docking analysis finally revealed that ISL could stably dock into the catalytic domain of DNMT1. Taken together, our findings not only provide preclinical evidence to demonstrate the use of ISL as a dietary supplement to inhibit mammary carcinogenesis but also shed novel light on WIF1 as an epigenetic target for breast cancer prevention. PMID:25918249

  13. Beneficial bacteria stimulate host immune cells to counteract dietary and genetic predisposition to mammary cancer in mice

    PubMed Central

    Lakritz, Jessica R; Poutahidis, Theofilos; Levkovich, Tatiana; Varian, Bernard J; Ibrahim, Yassin M; Chatzigiagkos, Antonis; Mirabal, Sheyla; Alm, Eric J; Erdman, Susan E

    2014-01-01

    Recent studies suggest health benefits including protection from cancer after eating fermented foods such as probiotic yogurt, though the mechanisms are not well understood. Here we tested mechanistic hypotheses using two different animal models: the first model studied development of mammary cancer when eating a Westernized diet, and the second studied animals with a genetic predilection to breast cancer. For the first model, outbred Swiss mice were fed a Westernized chow putting them at increased risk for development of mammary tumors. In this Westernized diet model, mammary carcinogenesis was inhibited by routine exposure to Lactobacillus reuteri ATCC-PTA-6475 in drinking water. The second model was FVB strain erbB2 (HER2) mutant mice, genetically susceptible to mammary tumors mimicking breast cancers in humans, being fed a regular (non-Westernized) chow diet. We found that oral supplement with these purified lactic acid bacteria alone was sufficient to inhibit features of mammary neoplasia in both models. The protective mechanism was determined to be microbially-triggered CD4+CD25+ lymphocytes. When isolated and transplanted into other subjects, these L. reuteri-stimulated lymphocytes were sufficient to convey transplantable anti-cancer protection in the cell recipient animals. These data demonstrate that host immune responses to environmental microbes significantly impact and inhibit cancer progression in distal tissues such as mammary glands, even in genetically susceptible mice. This leads us to conclude that consuming fermentative microbes such as L. reuteri may offer a tractable public health approach to help counteract the accumulated dietary and genetic carcinogenic events integral in the Westernized diet and lifestyle. What's new? Can eating fermented foods like yogurt ward off cancer? Recent studies have suggested it's possible. To find out how, these authors isolated the probiotic bacteria involved in fermentation and fed them to mice that were

  14. Remodeling of endogenous mammary epithelium by breast cancer stem cells.

    PubMed

    Parashurama, Natesh; Lobo, Neethan A; Ito, Ken; Mosley, Adriane R; Habte, Frezghi G; Zabala, Maider; Smith, Bryan R; Lam, Jessica; Weissman, Irving L; Clarke, Michael F; Gambhir, Sanjiv S

    2012-10-01

    Poorly regulated tissue remodeling results in increased breast cancer risk, yet how breast cancer stem cells (CSC) participate in remodeling is unknown. We performed in vivo imaging of changes in fluorescent, endogenous duct architecture as a metric for remodeling. First, we quantitatively imaged physiologic remodeling of primary branches of the developing and regenerating mammary tree. To assess CSC-specific remodeling events, we isolated CSC from MMTV-Wnt1 (mouse mammary tumor virus long-term repeat enhancer driving Wnt1 oncogene) breast tumors, a well studied model in which tissue remodeling affects tumorigenesis. We confirm that CSC drive tumorigenesis, suggesting a link between CSC and remodeling. We find that normal, regenerating, and developing gland maintain a specific branching pattern. In contrast, transplantation of CSC results in changes in the branching patterns of endogenous ducts while non-CSC do not. Specifically, in the presence of CSC, we identified an increased number of branches, branch points, ducts which have greater than 40 branches (5/33 for CSC and 0/39 for non-CSC), and histological evidence of increased branching. Moreover, we demonstrate that only CSC implants invade into surrounding stroma with structures similar to developing mammary ducts (nine for CSC and one for non-CSC). Overall, we demonstrate a novel approach for imaging physiologic and pathological remodeling. Furthermore, we identify unique, CSC-specific, remodeling events. Our data suggest that CSC interact with the microenvironment differently than non-CSC, and that this could eventually be a therapeutic approach for targeting CSC.

  15. Aurora kinase-A overexpression in mouse mammary epithelium induces mammary adenocarcinomas harboring genetic alterations shared with human breast cancer.

    PubMed

    Treekitkarnmongkol, Warapen; Katayama, Hiroshi; Kai, Kazuharu; Sasai, Kaori; Jones, Jennifer Carter; Wang, Jing; Shen, Li; Sahin, Aysegul A; Gagea, Mihai; Ueno, Naoto T; Creighton, Chad J; Sen, Subrata

    2016-12-01

    Recent data from The Cancer Genome Atlas analysis have revealed that Aurora kinase A (AURKA) amplification and overexpression characterize a distinct subset of human tumors across multiple cancer types. Although elevated expression of AURKA has been shown to induce oncogenic phenotypes in cells in vitro, findings from transgenic mouse models of Aurora-A overexpression in mammary glands have been distinct depending on the models generated. In the present study, we report that prolonged overexpression of AURKA transgene in mammary epithelium driven by ovine β-lactoglobulin promoter, activated through multiple pregnancy and lactation cycles, results in the development of mammary adenocarcinomas with alterations in cancer-relevant genes and epithelial-to-mesenchymal transition. The tumor incidence was 38.9% (7/18) in Aurora-A transgenic mice at 16 months of age following 4-5 pregnancy cycles. Aurora-A overexpression in the tumor tissues accompanied activation of Akt, elevation of Cyclin D1, Tpx2 and Plk1 along with downregulation of ERα and p53 proteins, albeit at varying levels. Microarray comparative genomic hybridization (CGH) analyses of transgenic mouse mammary adenocarcinomas revealed copy gain of Glp1r and losses of Ercc5, Pten and Tcf7l2 loci. Review of human breast tumor transcriptomic data sets showed association of these genes at varying levels with Aurora-A gain of function alterations. Whole exome sequencing of the mouse tumors also identified gene mutations detected in Aurora-A overexpressing human breast cancers. Our findings demonstrate that prolonged overexpression of Aurora-A can be a driver somatic genetic event in mammary adenocarcinomas associated with deregulated tumor-relevant pathways in the Aurora-A subset of human breast cancer.

  16. Cell Polarity Proteins in Breast Cancer Progression.

    PubMed

    Rejon, Carlis; Al-Masri, Maia; McCaffrey, Luke

    2016-10-01

    Breast cancer, one of the leading causes of cancer related death in women worldwide, is a heterogeneous disease with diverse subtypes that have different properties and prognoses. The developing mammary gland is a highly proliferative and invasive tissue, and some of the developmental programs may be aberrantly activated to promote breast cancer progression. In the breast, luminal epithelial cells exhibit apical-basal polarity, and the failure to maintain this organizational structure, due to disruption of polarity complexes, is implicated in promoting hyperplasia and tumors. Therefore, understanding the mechanisms underlying loss of polarity will contribute to our knowledge of the early stages leading to the pathogenesis of the disease. In this review, we will discuss recent findings that support the idea that loss of apical-basal cell polarity is a crucial step in the acquisition of the malignant phenotype. Oncogene induced loss of tissue organization shares a conserved cellular mechanism with developmental process, we will further describe the role of the individual polarity complexes, the Par, Crumbs, and Scribble, to couple cell division orientation and cell growth. We will examine symmetric or asymmetric cell divisions in mammary stem cell and their contribution to the development of breast cancer subtypes and cancer stem cells. Finally, we will highlight some of the recent advances in our understanding of the molecular mechanisms by which changes in epithelial polarity programs promote invasion and metastasis through single cell and collective cell modes. J. Cell. Biochem. 117: 2215-2223, 2016. © 2016 Wiley Periodicals, Inc.

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

    PubMed

    Wu, Xiaoting; Gallo, Kathleen A

    2013-01-01

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

  18. Interplay between progesterone and prolactin in mammary development and implications for breast cancer.

    PubMed

    Lee, Heather J; Ormandy, Christopher J

    2012-06-24

    Progesterone and prolactin remodel mammary morphology during pregnancy by acting on the mammary epithelial cell hierarchy. The roles of each hormone in mammary development have been well studied, but evidence of signalling cross-talk between progesterone and prolactin is still emerging. Factors such as receptor activator of NFkB ligand (RANKL) may integrate signals from both hormones to orchestrate their joint actions on the epithelial cell hierarchy. Common targets of progesterone and prolactin signalling are also likely to integrate their pro-proliferative actions in breast cancer. Therefore, a thorough understanding of the interplay between progesterone and prolactin in mammary development may reveal therapeutic targets for breast cancer. This review summarises our understanding of Pg and PRL action in mammary gland development before focusing on molecular mechanisms of signalling cross-talk and the implications for breast cancer.

  19. Development of new therapy for canine mammary cancer with recombinant measles virus

    PubMed Central

    Shoji, Koichiro; Yoneda, Misako; Fujiyuki, Tomoko; Amagai, Yosuke; Tanaka, Akane; Matsuda, Akira; Ogihara, Kikumi; Naya, Yuko; Ikeda, Fusako; Matsuda, Hiroshi; Sato, Hiroki; Kai, Chieko

    2016-01-01

    Oncolytic virotherapy is a promising treatment strategy for cancer. We previously generated a recombinant measles virus (rMV-SLAMblind) that selectively uses a poliovirus receptor-related 4 (PVRL4/Nectin4) receptor, but not signaling lymphocyte activation molecule (SLAM). We demonstrated that the virus exerts therapeutic effects against human breast cancer cells. Here, we examined the applicability of rMV-SLAMblind to treating canine mammary cancers (CMCs). We found that the susceptibilities of host cells to rMV-SLAMblind were dependent on canine Nectin-4 expression. Nectin-4 was detected in four of nine CMC cell lines. The rMV-SLAMblind efficiently infected those four Nectin-4-positive cell lines and was cytotoxic for three of them (CF33, CHMm, and CTBm). In vivo experiment showed that the administration of rMV-SLAMblind greatly suppressed the progression of tumors in mice xenografted with a CMC cell line (CF33). Immunohistochemistry revealed that canine Nectin-4 was expressed in 45% of canine mammary tumors, and the tumor cells derived from one clinical specimen were efficiently infected with rMV-SLAMblind. These results suggest that rMV-SLAMblind infects CMC cells and displays antitumor activity in vitro, in xenografts, and ex vivo. Therefore, oncolytic virotherapy with rMV-SLAMblind can be a novel method for treating CMCs. PMID:27119113

  20. Radiogenic neoplasia in thyroid and mammary clonogens. Progress report, January 1, 1991--December 31, 1991

    SciTech Connect

    Clifton, K.H.

    1991-05-31

    We have developed rat thyroid and mammary clonogen transplantation systems for the study of radiogenic cancer induction at the target cell level in vivo. The epithelial cell populations of both glands contain small subpopulations of cells which are capable of giving rise to monoclonal glandular structures when transplanted and stimulated with appropriate hormones. During the end of the last grant year and the first half of the current grant year, we have completed analyses and summarized for publication: investigations on the relationship between grafted thyroid cell number and the rapidity and degree of reestablishment of the thyroid-hypothalamicpituitary axis in thyroidectomized rats maintained on a normal diet or an iodine deficient diet; studies of the persistence of, and the differentiation potential and functional characteristics of, the TSH- (thyrotropin-) responsive sub-population of clonogens during goitrogenesis, the plateau-phase of goiter growth, and goiter involution; studies of changes in the size of the clonogen sub-population during goitrogenesis, goiter involution and the response to goitrogen rechallenge; and the results of the large carcinogenesis experiment on the nature of the grafted thyroid cell number-dependent suppression of promotion/progression to neoplasia in grafts of radiation-initiated thyroid cells. We are testing new techniques for the culture, cytofluorescent analysis and characterization mammary epithelial cells and of clonogens in a parallel project, and plan to apply similar technology to the thyroid epithelial cells and clonogen population. Data from these studies will be used in the design of future carcinogenesis experiments on neoplastic initiation by high and low LET radiations and on cells interactions during the neoplastic process.

  1. Development and characterization of a novel rat model of estrogen-induced mammary cancer.

    PubMed

    Dennison, Kirsten L; Samanas, Nyssa Becker; Harenda, Quincy Eckert; Hickman, Maureen Peters; Seiler, Nicole L; Ding, Lina; Shull, James D

    2015-04-01

    The ACI rat model of 17β-estradiol (E2)-induced mammary cancer is highly relevant for use in establishing the endocrine, genetic, and environmental bases of breast cancer etiology and identifying novel agents and strategies for preventing breast cancer. E2 treatment rapidly induces mammary cancer in female ACI rats and simultaneously induces pituitary lactotroph hyperplasia and adenoma. The pituitary tumors can result in undesired morbidity, which compromises long-term studies focused on mammary cancer etiology and prevention. We have defined the genetic bases of susceptibility to E2-induced mammary cancers and pituitary tumors and have utilized the knowledge gained in these studies to develop a novel inbred rat strain, designated ACWi, that retains the high degree of susceptibility to E2-induced mammary cancer exhibited by ACI rats, but lacks the treatment-related morbidity associated with pituitary lactotroph hyperplasia/adenoma. When treated with E2, female ACWi rats developed palpable mammary cancer at a median latency of 116 days, an incidence of 100% by 161 days and exhibited an average of 15.6 mammary tumors per rat following 196 days of treatment. These parameters did not differ from those observed for contemporaneously treated ACI rats. None of the E2-treated ACWi rats were killed before the intended experimental end point due to any treatment-related morbidity other than mammary cancer burden, whereas 20% of contemporaneously treated ACI rats exhibited treatment-related morbidity that necessitated premature killing. The ACWi rat strain is well suited for use by those in the research community, focusing on breast cancer etiology and prevention.

  2. The biology of progesterone receptor in the normal mammary gland and in breast cancer.

    PubMed

    Obr, Alison E; Edwards, Dean P

    2012-06-24

    This paper reviews work on progesterone and the progesterone receptor (PR) in the mouse mammary gland that has been used extensively as an experimental model. Studies have led to the concept that progesterone controls proliferation and morphogenesis of the luminal epithelium in a tightly orchestrated manner at distinct stages of development by paracrine signaling pathways, including receptor activator of nuclear factor κB ligand (RANKL) as a major paracrine factor. Progesterone also drives expansion of stem cells by paracrine signals to generate progenitors required for alveologenesis. During mid-to-late pregnancy, progesterone has another role to suppress secretory activation until parturition mediated in part by crosstalk between PR and prolactin/Stat5 signaling to inhibit induction of milk protein gene expression, and by inhibiting tight junction closure. In models of hormone-dependent mouse mammary tumors, the progesterone/PR signaling axis enhances pre-neoplastic progression by a switch from a paracrine to an autocrine mode of proliferation and dysregulation of the RANKL signaling pathway. Limited experiments with normal human breast show that progesterone/PR signaling also stimulates epithelial cell proliferation by a paracrine mechanism; however, the signaling pathways and whether RANKL is a major mediator remains unknown. Work with human breast cancer cell lines, patient tumor samples and clinical studies indicates that progesterone is a risk factor for breast cancer and that alteration in progesterone/PR signaling pathways contributes to early stage human breast cancer progression. However, loss of PR expression in primary tumors is associated with a less differentiated more invasive phenotype and worse prognosis, suggesting that PR may limit later stages of tumor progression.

  3. Tumor Microenvironment Regulates Metastasis and Metastasis Genes of Mouse MMTV-PymT Mammary Cancer Cells In Vivo

    PubMed Central

    Werbeck, J. L.; Thudi, N. K.; Martin, C. K.; Premanandan, C.; Yu, L.; Ostrowksi, M. C.; Rosol, T. J.

    2014-01-01

    Metastasis is the primary cause of death in breast cancer patients, yet there are challenges to modeling this process in vivo. The goal of this study was to analyze the effects of injection site on tumor growth and metastasis and gene expression of breast cancer cells in vivo using the MMTV-PymT breast cancer model (Met-1 cells). Met-1 cells were injected into 5 sites (subcutaneous, mammary fat pad, tail vein, intracardiac, and intratibial), and tumors and metastases were monitored using bioluminescent imaging and confirmed with gross necropsy and histopathology. Met-1 tumors were analyzed based on morphology and changes in gene expression in each tissue microenvironment. There were 6 permissible sites of Met-1 tumor growth (mammary gland, subcutis, lung, adrenal gland, ovary, bone). Met-1 cells grew faster in the subcutis compared to mammary fat pad tumors (highest Ki-67 index). Morphologic differences were evident in each tumor microenvironment. Finally, 7 genes were differentially expressed in the Met-1 tumors in the 6 sites of growth or metastasis. This investigation demonstrates that breast cancer progression and metastasis are regulated by not only the tumor cells but also the experimental model and unique molecular signals from the tumor microenvironment. PMID:24091811

  4. Tumor microenvironment regulates metastasis and metastasis genes of mouse MMTV-PymT mammary cancer cells in vivo.

    PubMed

    Werbeck, J L; Thudi, N K; Martin, C K; Premanandan, C; Yu, L; Ostrowksi, M C; Rosol, T J

    2014-07-01

    Metastasis is the primary cause of death in breast cancer patients, yet there are challenges to modeling this process in vivo. The goal of this study was to analyze the effects of injection site on tumor growth and metastasis and gene expression of breast cancer cells in vivo using the MMTV-PymT breast cancer model (Met-1 cells). Met-1 cells were injected into 5 sites (subcutaneous, mammary fat pad, tail vein, intracardiac, and intratibial), and tumors and metastases were monitored using bioluminescent imaging and confirmed with gross necropsy and histopathology. Met-1 tumors were analyzed based on morphology and changes in gene expression in each tissue microenvironment. There were 6 permissible sites of Met-1 tumor growth (mammary gland, subcutis, lung, adrenal gland, ovary, bone). Met-1 cells grew faster in the subcutis compared to mammary fat pad tumors (highest Ki-67 index). Morphologic differences were evident in each tumor microenvironment. Finally, 7 genes were differentially expressed in the Met-1 tumors in the 6 sites of growth or metastasis. This investigation demonstrates that breast cancer progression and metastasis are regulated by not only the tumor cells but also the experimental model and unique molecular signals from the tumor microenvironment.

  5. Use of a Novel Embryonic Mammary Stem Cell Gene Signature to Improve Human Breast Cancer Diagnostics and Therapeutic Decision Making

    DTIC Science & Technology

    2014-10-01

    sorting data coming from human and mouse adult mammary gland , and coming from the fetal mammary rudiment, to define gene expression profiles of...AD_____________ Award Number: W81XWH-12-1-0106 TITLE: Use of a Novel Embryonic Mammary Stem Cell Gene Signature to Improve Human...SUBTITLE Use of a Novel Embryonic Mammary Stem Cell Gene Signature to Improve Human Breast Cancer Diagnostics and Therapeutic Decision Making Improve

  6. Use of a Novel Embryonic Mammary Stem Cell Gene Signature to Improve Human Breast Cancer Diagnostics and Therapeutic Decision Making

    DTIC Science & Technology

    2014-10-01

    Conclusion. We have used FAC sorting data coming from human and mouse adult mammary gland , and coming from the fetal mammary rudiment, to define gene...AD_____________ Award Number: W81XWH-12-1-0107 TITLE: Use of a Novel Embryonic Mammary Stem Cell Gene Signature to Improve Human...4. TITLE AND SUBTITLE Use of a Novel Embryonic Mammary Stem Cell Gene Signature to Improve Human Breast Cancer Diagnostics and Therapeutic

  7. Interstitial Fluid Sphingosine-1-Phosphate in Murine Mammary Gland and Cancer and Human Breast Tissue and Cancer Determined by Novel Methods.

    PubMed

    Nagahashi, Masayuki; Yamada, Akimitsu; Miyazaki, Hiroshi; Allegood, Jeremy C; Tsuchida, Junko; Aoyagi, Tomoyoshi; Huang, Wei-Ching; Terracina, Krista P; Adams, Barbara J; Rashid, Omar M; Milstien, Sheldon; Wakai, Toshifumi; Spiegel, Sarah; Takabe, Kazuaki

    2016-06-01

    The tumor microenvironment is a determining factor for cancer biology and progression. Sphingosine-1-phosphate (S1P), produced by sphingosine kinases (SphKs), is a bioactive lipid mediator that regulates processes important for cancer progression. Despite its critical roles, the levels of S1P in interstitial fluid (IF), an important component of the tumor microenvironment, have never previously been measured due to a lack of efficient methods for collecting and quantifying IF. The purpose of this study is to clarify the levels of S1P in the IF from murine mammary glands and its tumors utilizing our novel methods. We developed an improved centrifugation method to collect IF. Sphingolipids in IF, blood, and tissue samples were measured by mass spectrometry. In mice with a deletion of SphK1, but not SphK2, levels of S1P in IF from the mammary glands were greatly attenuated. Levels of S1P in IF from mammary tumors were reduced when tumor growth was suppressed by oral administration of FTY720/fingolimod. Importantly, sphingosine, dihydro-sphingosine, and S1P levels, but not dihydro-S1P, were significantly higher in human breast tumor tissue IF than in the normal breast tissue IF. To our knowledge, this is the first reported S1P IF measurement in murine normal mammary glands and mammary tumors, as well as in human patients with breast cancer. S1P tumor IF measurement illuminates new aspects of the role of S1P in the tumor microenvironment.

  8. Evaluation of Leucocyte Functions Six Years after Tumour Autograft in Human Mammary Cancer

    PubMed Central

    Anderson, J. Maxwell; Kelly, F.; Wood, Suzanne E.; Rodger, K. D.; Freshney, R. Ian

    1973-01-01

    Mammary cancer directed and nonspecific immunoassays were made in 3 groups of female patients. One group had primary mammary cancer treated by mastectomy and postoperative radiotherapy plus an autograft of irradiated tumour (AIT) 40-66 months previously. A second age-matched group had mammary cancer comparable to the first group in clinical presentation and treatment except that no AIT was given. The third group consisted of non-cancer-bearing age-matched females. The migration of leucocytes from autografted patients was significantly inhibited in the presence of allogeneic mammary cancer cells from a standardized panel, compared with leucocytes from either non-autograft patients or non-cancer bearers. Selected data from a lymphocyte cytotoxicity test revealed a significantly greater kill of allogeneic mammary cancer target cells by autograft lymphocytes than by those of other groups. These indications of increased cancer directed cell mediated immunity in respect of sensitivity and toxicity in association with AIT require further elucidation under strictly controlled conditions. PMID:4807858

  9. Mammary epithelial morphogenesis and early breast cancer. Evidence of involvement of basal components of the RNA Polymerase I transcription machinery.

    PubMed

    Rossetti, Stefano; Wierzbicki, Andrzej J; Sacchi, Nicoletta

    2016-09-16

    Upregulation of RNA Polymerase (Pol I)-mediated transcription of rRNA and increased ribogenesis are hallmarks of breast cancer. According to several datasets, including The Cancer Genome Atlas (TCGA), amplification/upregulation of genes encoding for basal components of the Pol I transcriptional machinery is frequent at different breast cancer stages. Here we show that knock down of the RNA polymerase I-specific transcription initiation factor RRN3 (TIF-IA) in breast cancer cells is sufficient to reduce rRNA synthesis and inhibit cell proliferation, and second that stable ectopic expression of RRN3 in human mammary epithelial (HME1) cells, by increasing rRNA transcription, confers increased sensitivity to the anti-proliferative effects of a selective Pol I inhibitor. Further, RRN3-overexpressing HME1 cells, when grown in in vitro 3-dimensional (3D) culture, develop into morphologically aberrant acinar structures lacking a lumen and filled with proliferative cells, thus acquiring a morphology resembling in situ ductal breast cancer lesions (DCIS). Consequently, interference with RRN3 control of Pol I transcription seems capable of both compromising mammary epithelial morphogenetic processes at early breast cancer stages, and driving breast cancer progression by fostering proliferation.

  10. Radiogenic neoplasia in thyroid and mammary clonogens. Progress report, January 1, 1990--December 31, 1992

    SciTech Connect

    Clifton, K.H.

    1992-05-20

    We have developed rat thyroid and mammary clonogen transplantation systems for the study of radiogenic cancer induction at the target cell level in vivo. The epithelial cell populations of both glands contain small subpopulations of cells which are capable of giving rise to monoclonal glandular structures when transplanted and stimulated with appropriate hormones. Previous results indicated that these clonogens are the precursor cells of radiogenic cancer, and that initiation, is common event at the clonegenic cell level. Detailed information on the physiologic control of clonogen proliferation, differentiation, and total numbers is thus essential to an understanding of the carcinogenic process. We report here studies on investigations on the relationships between grafted thyroid cell number and the rapidity and degree of reestablishment of the thyroid-hypothalamus-pituitary feedback axis in thyroidectomized rats maintained on a normal diet or an iodine deficient diet; studies of the persistence of, and the differentiation potential and functional characteristics of, the TSH-(thyrotropin-) responsive sub- population of clonogens during goitrogenesis, the plateau-phase of goiter growth, and goiter involution; studies of changes in the size of the clonogen sub-population during goitrogenesis, goiter involution and the response to goitrogen rechallenge; and a large carcinogenesis experiment on the nature of the grafted thyroid cell number-dependent suppression of promotion/progression to neoplasia in grafts of radiation-initiated thyroid cells. Data from these studies will be used in the design of future carcinogenesis experiments on neoplastic initiation by high and low LET radiations and on cell interactions during the neoplastic process.

  11. Mammary Fat of Breast Cancer: Gene Expression Profiling and Functional Characterization

    PubMed Central

    Chen, Fei; Fu, Ziyi; Yin, Hong; Lu, Xun; Yu, Jing; Lu, Cheng

    2014-01-01

    Mammary fat is the main composition of breast, and is the most probable candidate to affect tumor behavior because the fat produces hormones, growth factors and adipokines, a heterogeneous group of signaling molecules. Gene expression profiling and functional characterization of mammary fat in Chinese women has not been reported. Thus, we collected the mammary fat tissues adjacent to breast tumors from 60 subjects, among which 30 subjects had breast cancer and 30 had benign lesions. We isolated and cultured the stromal vascular cell fraction from mammary fat. The expression of genes related to adipose function (including adipogenesis and secretion) was detected at both the tissue and the cellular level. We also studied mammary fat browning. The results indicated that fat tissue close to malignant and benign lesions exhibited distinctive gene expression profiles and functional characteristics. Although the mammary fat of breast tumors atrophied, it secreted tumor growth stimulatory factors. Browning of mammary fat was observed and browning activity of fat close to malignant breast tumors was greater than that close to benign lesions. Understanding the diversity between these two fat depots may possibly help us improve our understanding of breast cancer pathogenesis and find the key to unlock new anticancer therapies. PMID:25291184

  12. Mammary fat of breast cancer: gene expression profiling and functional characterization.

    PubMed

    Wang, Fengliang; Gao, Sheng; Chen, Fei; Fu, Ziyi; Yin, Hong; Lu, Xun; Yu, Jing; Lu, Cheng

    2014-01-01

    Mammary fat is the main composition of breast, and is the most probable candidate to affect tumor behavior because the fat produces hormones, growth factors and adipokines, a heterogeneous group of signaling molecules. Gene expression profiling and functional characterization of mammary fat in Chinese women has not been reported. Thus, we collected the mammary fat tissues adjacent to breast tumors from 60 subjects, among which 30 subjects had breast cancer and 30 had benign lesions. We isolated and cultured the stromal vascular cell fraction from mammary fat. The expression of genes related to adipose function (including adipogenesis and secretion) was detected at both the tissue and the cellular level. We also studied mammary fat browning. The results indicated that fat tissue close to malignant and benign lesions exhibited distinctive gene expression profiles and functional characteristics. Although the mammary fat of breast tumors atrophied, it secreted tumor growth stimulatory factors. Browning of mammary fat was observed and browning activity of fat close to malignant breast tumors was greater than that close to benign lesions. Understanding the diversity between these two fat depots may possibly help us improve our understanding of breast cancer pathogenesis and find the key to unlock new anticancer therapies.

  13. Sphingosylphosphorylcholine in cancer progress

    PubMed Central

    Yue, Hong-Wei; Jing, Qing-Chuan; Liu, Ping-Ping; Liu, Jing; Li, Wen-Jing; Zhao, Jing

    2015-01-01

    Sphingosylphosphorylcholine (SPC) is a naturally occurring bioactive sphingolipid in blood plasma, metabolizing from the hydrolysis of the membrane sphingolipid. It has been shown to exert multifunctional role in cell physiological regulation either as an intracellular second messenger or as an extracellular agent through G protein coupled receptors (GPCRs). Because of elevated levels of SPC in malicious ascites of patients with cancer, the role of SPC in tumor progression has prompted wide interest. The factor was reported to affect the proliferation and/or migration of many cancer cells, including pancreatic cancer cells, epithelial ovarian carcinoma cells, rat C6 glioma cells, neuroblastoma cells, melanoma cells, and human leukemia cells. This review covers current knowledge of the role of SPC in tumor. PMID:26550104

  14. Identification and characterization of cancer stem cells in canine mammary tumors.

    PubMed

    Rybicka, Agata; Król, Magdalena

    2016-12-19

    Cancer stem cells (CSC) represent a small subpopulation of cells in malignant tumors that possess the unique ability to self-renew, differentiate and resist chemo- and radiotherapy. These cells have been postulated to be the basis for some of the difficulties in treating cancer, and therefore, numerous approaches have been developed to specifically target and eliminate CSC in diverse types of cancer, including breast cancer. Spontaneously occurring mammary tumors in canines share clinical and molecular similarities with the human counterpart, making the dog a potentially powerful model for the study of human breast cancer and clinical trials. Studies focused on canine mammary CSC might therefore enhance our understanding of the biology and possible treatment of the disease in both dogs and humans. In this review, we discuss various approaches currently in use to isolate and characterize canine mammary CSC.

  15. Mammary Gland Involution Provides a Unique Model to Study the TGF-β Cancer Paradox.

    PubMed

    Guo, Qiuchen; Betts, Courtney; Pennock, Nathan; Mitchell, Elizabeth; Schedin, Pepper

    2017-01-13

    Transforming Growth Factor-β (TGF-β) signaling in cancer has been termed the "TGF-β paradox", acting as both a tumor suppresser and promoter. The complexity of TGF-β signaling within the tumor is context dependent, and greatly impacted by cellular crosstalk between TGF-β responsive cells in the microenvironment including adjacent epithelial, endothelial, mesenchymal, and hematopoietic cells. Here we utilize normal, weaning-induced mammary gland involution as a tissue microenvironment model to study the complexity of TGF-β function. This article reviews facets of mammary gland involution that are TGF-β regulated, namely mammary epithelial cell death, immune activation, and extracellular matrix remodeling. We outline how distinct cellular responses and crosstalk between cell types during physiologically normal mammary gland involution contribute to simultaneous tumor suppressive and promotional microenvironments. We also highlight alternatives to direct TGF-β blocking anti-cancer therapies with an emphasis on eliciting concerted microenvironmental-mediated tumor suppression.

  16. Estrogens in the wrong place at the wrong time: Fetal BPA exposure and mammary cancer.

    PubMed

    Paulose, Tessie; Speroni, Lucia; Sonnenschein, Carlos; Soto, Ana M

    2015-07-01

    Iatrogenic gestational exposure to diethylstilbestrol (DES) induced alterations of the genital tract and predisposed individuals to develop clear cell carcinoma of the vagina as well as breast cancer later in life. Gestational exposure of rodents to a related compound, the xenoestrogen bisphenol-A (BPA) increases the propensity to develop mammary cancer during adulthood, long after cessation of exposure. Exposure to BPA during gestation induces morphological alterations in both the stroma and the epithelium of the fetal mammary gland at 18 days of age. We postulate that the primary target of BPA is the fetal stroma, the only mammary tissue expressing estrogen receptors during fetal life. BPA would then alter the reciprocal stroma-epithelial interactions that mediate mammogenesis. In addition to this direct effect on the mammary gland, BPA is postulated to affect the hypothalamus and thus in turn affect the regulation of mammotropic hormones at puberty and beyond.

  17. Mammary Development and Breast Cancer: A Wnt Perspective

    PubMed Central

    Yu, Qing Cissy; Verheyen, Esther M.; Zeng, Yi Arial

    2016-01-01

    The Wnt pathway has emerged as a key signaling cascade participating in mammary organogenesis and breast oncogenesis. In this review, we will summarize the current knowledge of how the pathway regulates stem cells and normal development of the mammary gland, and discuss how its various components contribute to breast carcinoma pathology. PMID:27420097

  18. Tamoxifen induces regression of estradiol-induced mammary cancer in the ACI.COP-Ept2 rat model.

    PubMed

    Ruhlen, Rachel L; Willbrand, Dana M; Besch-Williford, Cynthia L; Ma, Lixin; Shull, James D; Sauter, Edward R

    2009-10-01

    The ACI rat is a unique model of human breast cancer in that mammary cancers are induced by estrogen without carcinogens, irradiation, xenografts or transgenic manipulations. We sought to characterize mammary cancers in a congenic variant of the ACI rat, the ACI.COP-Ept2. All rats with estradiol implants developed mammary cancers in 5-7 months. Rats bearing estradiol-induced mammary cancers were treated with tamoxifen for three weeks. Tamoxifen reduced tumor mass, measured by magnetic resonance imaging, by 89%. Tumors expressed estrogen receptors (ER), progesterone receptor (PR), and Erbb2. ERalpha and PR were overexpressed in tumor compared to adjacent non-tumor mammary gland. Thus, this model is highly relevant to hormone responsive human breast cancers.

  19. New methods in mammary gland development and cancer: proteomics, epigenetics, symmetric division and metastasis

    PubMed Central

    2012-01-01

    The European Network for Breast Development and Cancer (ENBDC) meeting on 'Methods in Mammary Gland Development and Cancer' has become an annual international rendezvous for scientists with interests in the normal and neoplastic breast. The fourth meeting in this series, held in April in Weggis, Switzerland, focused on proteomics, epigenetics, symmetric division, and metastasis. PMID:22809213

  20. Life After Cancer | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  1. Prostate Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  2. Kidney Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  3. Lung Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  4. Ovarian Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  5. Colorectal Cancer Screening | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  6. Breast Cancer Screening | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  7. Cervical Cancer Screening | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  8. Colorectal Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  9. Bladder Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  10. Breast Cancer Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  11. An improved syngeneic orthotopic murine model of human breast cancer progression.

    PubMed

    Rashid, Omar M; Nagahashi, Masayuki; Ramachandran, Suburamaniam; Dumur, Catherine; Schaum, Julia; Yamada, Akimitsu; Terracina, Krista P; Milstien, Sheldon; Spiegel, Sarah; Takabe, Kazuaki

    2014-10-01

    Breast cancer drug development costs nearly $610 million and 37 months in preclinical mouse model trials with minimal success rates. Despite these inefficiencies, there are still no consensus breast cancer preclinical models. Murine mammary adenocarcinoma 4T1-luc2 cells were implanted subcutaneous (SQ) or orthotopically percutaneous (OP) injection in the area of the nipple, or surgically into the chest 2nd mammary fat pad under direct vision (ODV) in Balb/c immunocompetent mice. Tumor progression was followed by in vivo bioluminescence and direct measurements, pathology and survival determined, and tumor gene expression analyzed by genome-wide microarrays. ODV produced less variable-sized tumors and was a reliable method of implantation. ODV implantation into the chest 2nd mammary pad rather than into the abdominal 4th mammary pad, the most common implantation site, better mimicked human breast cancer progression pattern, which correlated with bioluminescent tumor burden and survival. Compared to SQ, ODV produced tumors that differentially expressed genes whose interaction networks are of importance in cancer research. qPCR validation of 10 specific target genes of interest in ongoing clinical trials demonstrated significant differences in expression. ODV implantation into the chest 2nd mammary pad provides the most reliable model that mimics human breast cancer compared from subcutaneous implantation that produces tumors with different genome expression profiles of clinical significance. Increased understanding of the limitations of the different preclinical models in use will help guide new investigations and may improve the efficiency of breast cancer drug development .

  12. Clinically Apparent Internal Mammary Nodal Metastasis in Patients With Advanced Breast Cancer: Incidence and Local Control

    SciTech Connect

    Zhang Yujing; Oh, Julia L.; Whitman, Gary J.

    2010-07-15

    Purpose: To investigate the incidence and local control of internal mammary lymph node metastases (IMN+) in patients with clinical N2 or N3 locally advanced breast cancer. Methods and Materials: We retrospectively reviewed the records of 809 breast cancer patients diagnosed with advanced nodal disease (clinical N2-3) who received radiation treatment at our institution from January 2000 December 2006. Patients were considered IMN+ on the basis of imaging studies. Results: We identified 112 of 809 patients who presented with IMN+ disease (13.8%) detected on ultrasound, computed tomography (CT), positron emission tomography/CT (PET/CT), and/or magnetic resonance imaging (MRI) studies. All 112 patients with IMN+ disease received anthracycline and taxane-based chemotherapy. Neoadjuvant chemotherapy (NCT) resulted in a complete response (CR) on imaging studies of IMN disease in 72.1% of patients. Excluding 16 patients with progressive disease, 96 patients received adjuvant radiation to the breast or the chest wall and the regional lymphatics including the IMN chain with a median dose of 60 Gy if the internal mammary lymph nodes normalized after chemotherapy and 66 Gy if they did not. The median follow-up of surviving patients was 41 months (8-118 months). For the 96 patients able to complete curative therapy, the actuarial 5-year IMN control rate, locoregional control, overall survival, and disease-free survival were 89%, 80%, 76%, and 56%. Conclusion: Over ten percent of patients with advanced nodal disease will have IMN metastases on imaging studies. Multimodality therapy including IMN irradiation achieves excellent rates of control in the IMN region and a DFS of more than 50% after curative treatment.

  13. Arsenic | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  14. Home | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  15. Radon | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  16. Prevention | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  17. Introduction | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  18. Treatment | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  19. Diagnosis | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  20. Sunburn | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  1. Weight | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  2. Mortality | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  3. Survival | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  4. Incidence | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  5. Benzene | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  6. Acknowledgements | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  7. Nitrate | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  8. Cadmium | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  9. The effect of neighboring cells on the stiffness of cancerous and non-cancerous human mammary epithelial cells

    NASA Astrophysics Data System (ADS)

    Guo, Xinyi; Bonin, Keith; Scarpinato, Karin; Guthold, Martin

    2014-10-01

    Using an Atomic Force Microscope (AFM) with a 5.3 μm diameter spherical probe, we determined mechanical properties of individual human mammary epithelial cells. The cells were derived from a pair of cell lines that mimic cell progression through four phases of neoplastic transformation: normal (non-transformed), immortal, tumorigenic, and metastatic. Measurements on cells in all four phases were taken over both the cytoplasmic and nuclear regions. Moreover, the measurements were made for cells in different microenvironments as related to cell-cell contacts: isolated cells; cells residing on the periphery of a contiguous cell monolayer; and cells on the inside of a contiguous cell monolayer. By fitting the AFM force versus indentation curves to a Hertz model, we determined the pseudo-elastic Young’s modulus, E. Combining all data for the cellular subregions (over nucleus and cytoplasm) and the different cell microenvironments, we obtained stiffness values for normal, immortal, tumorigenic, and metastatic cells of 870 Pa, 870 Pa, 490 Pa, and 580 Pa, respectively. That is, cells become softer as they advance to the tumorigenic phase and then stiffen somewhat in the final step to metastatic cells. We also found a distinct contrast in the influence of a cell’s microenvironment on cell stiffness. Normal mammary epithelial cells inside a monolayer are stiffer than peripheral cells, which are stiffer than isolated cells. However, the microenvironment had a slight, opposite effect on tumorigenic and little effect on immortal and metastatic cell stiffness. Thus, the stiffness of cancer cells is less sensitive to the microenvironment than normal cells. Our results show that the mechanical properties of a cell can depend on cancer progression and microenvironment (cell-cell interactions).

  10. MTA family of transcriptional metaregulators in mammary gland morphogenesis and breast cancer.

    PubMed

    Singh, Rajesh R; Kumar, Rakesh

    2007-09-01

    Since breast cancer and its associated metastasis are a global health problem and a major cause of mortality among women, research efforts to understand the development, morphogenesis, and functioning of the mammary gland are a high priority. Myriad signaling pathways, transcription factors, and associated transcriptional coregulators have been identified in both normal functioning and neoplastic transformation of the mammary gland. The discovery of the metastasis tumor antigen 1 (MTA1) gene, its overexpression in cancer and metastasis and its subsequent identification as an integral part of the chromatin remodeling complex heralded extensive research on its physiological role. Subsequent identification of additional gene family members, namely MTA1s, MTA2, and MTA3, and their functions in the cell has resulted in the establishment of the significance of the MTA family. The role of these proteins in modulating hormonal responses in normal mammary glands and in breast cancer has resulted in their identification as important molecular markers and potential therapeutic targets.

  11. Targeting ECM Disrupts Cancer Progression.

    PubMed

    Venning, Freja A; Wullkopf, Lena; Erler, Janine T

    2015-01-01

    Metastatic complications are responsible for more than 90% of cancer-related deaths. The progression from an isolated tumor to disseminated metastatic disease is a multistep process, with each step involving intricate cross talk between the cancer cells and their non-cellular surroundings, the extracellular matrix (ECM). Many ECM proteins are significantly deregulated during the progression of cancer, causing both biochemical and biomechanical changes that together promote the metastatic cascade. In this review, the influence of several ECM proteins on these multiple steps of cancer spread is summarized. In addition, we highlight the promising (pre-)clinical data showing benefits of targeting these ECM macromolecules to prevent cancer progression.

  12. Targeting ECM Disrupts Cancer Progression

    PubMed Central

    Venning, Freja A.; Wullkopf, Lena; Erler, Janine T.

    2015-01-01

    Metastatic complications are responsible for more than 90% of cancer-related deaths. The progression from an isolated tumor to disseminated metastatic disease is a multistep process, with each step involving intricate cross talk between the cancer cells and their non-cellular surroundings, the extracellular matrix (ECM). Many ECM proteins are significantly deregulated during the progression of cancer, causing both biochemical and biomechanical changes that together promote the metastatic cascade. In this review, the influence of several ECM proteins on these multiple steps of cancer spread is summarized. In addition, we highlight the promising (pre-)clinical data showing benefits of targeting these ECM macromolecules to prevent cancer progression. PMID:26539408

  13. [FACTORS OF PROGNOSIS IN PATIENTS WITH EARLY CANCER OF MAMMARY GLAND].

    PubMed

    Shchurov, M F; Voloshyna, N M; Pogorila, T Yu

    2015-12-01

    A survival indices in patients with early mammary gland cancer of a ductal infiltrating histology stage T1-2N0M0, who were treated in accordance to actual standards, differ significantly, what witnesses the necessity for searching of additional prognostic criteria. The investigation objective was to study the impact of independent and interrelated clinical, morphological and biochemical factors of prognosis on the survival indices in patients with mammary gland cancer stage T1-2N0M0 in conditions of local and systemic treatment.

  14. Characterization of mammary cancer stem cells in the MMTV-PyMT mouse model.

    PubMed

    Ma, Jun; Lanza, Denise Grant; Guest, Ian; Uk-Lim, Chang; Glinskii, Anna; Glinsky, Gennadi; Sell, Stewart

    2012-12-01

    Breast cancer stem cells, the root of tumor growth, present challenges to investigate: Primary human breast cancer cells are difficult to establish in culture and inconsistently yield tumors after transplantation into immune-deficient recipient mice. Furthermore, there is limited characterization of mammary cancer stem cells in mice, the ideal model for the study of breast cancer. We herein describe a pre-clinical breast cancer stem cell model, based on the properties of cancer stem cells, derived from transgenic MMTV-PyMT mice. Using a defined set of cell surface markers to identify cancer stem cells by flow cytometry, at least four cell populations were recovered from primary mammary cancers. Only two of the four populations, one epithelial and one mesenchymal, were able to survive and proliferate in vitro. The epithelial population exhibited tumor initiation potential with as few as 10 cells injected into syngeneic immune-competent recipients. Tumors initiated from injected cell lines recapitulated the morphological and physiological components of the primary tumor. To highlight the stemness potential of the putative cancer stem cells, B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) expression was knocked down via shRNA targeting Bmi-1. Without Bmi-1 expression, putative cancer stem cells could no longer initiate tumors, but tumor initiation was rescued with the introduction of a Bmi-1 overexpression vector in the Bmi-1 knockdown cells. In conclusion, our data show that primary mammary cancers from MMTV-PyMT mice contain putative cancer stem cells that survive in culture and can be used to create a model for study of mammary cancer stem cells.

  15. Tracking the mammary architectural features and detecting breast cancer with magnetic resonance diffusion tensor imaging.

    PubMed

    Nissan, Noam; Furman-Haran, Edna; Feinberg-Shapiro, Myra; Grobgeld, Dov; Eyal, Erez; Zehavi, Tania; Degani, Hadassa

    2014-12-15

    Breast cancer is the most common cause of cancer among women worldwide. Early detection of breast cancer has a critical role in improving the quality of life and survival of breast cancer patients. In this paper a new approach for the detection of breast cancer is described, based on tracking the mammary architectural elements using diffusion tensor imaging (DTI). The paper focuses on the scanning protocols and image processing algorithms and software that were designed to fit the diffusion properties of the mammary fibroglandular tissue and its changes during malignant transformation. The final output yields pixel by pixel vector maps that track the architecture of the entire mammary ductal glandular trees and parametric maps of the diffusion tensor coefficients and anisotropy indices. The efficiency of the method to detect breast cancer was tested by scanning women volunteers including 68 patients with breast cancer confirmed by histopathology findings. Regions with cancer cells exhibited a marked reduction in the diffusion coefficients and in the maximal anisotropy index as compared to the normal breast tissue, providing an intrinsic contrast for delineating the boundaries of malignant growth. Overall, the sensitivity of the DTI parameters to detect breast cancer was found to be high, particularly in dense breasts, and comparable to the current standard breast MRI method that requires injection of a contrast agent. Thus, this method offers a completely non-invasive, safe and sensitive tool for breast cancer detection.

  16. Tracking the Mammary Architectural Features and Detecting Breast Cancer with Magnetic Resonance Diffusion Tensor Imaging

    PubMed Central

    Nissan, Noam; Furman-Haran, Edna; Feinberg-Shapiro, Myra; Grobgeld, Dov; Eyal, Erez; Zehavi, Tania; Degani, Hadassa

    2014-01-01

    Breast cancer is the most common cause of cancer among women worldwide. Early detection of breast cancer has a critical role in improving the quality of life and survival of breast cancer patients. In this paper a new approach for the detection of breast cancer is described, based on tracking the mammary architectural elements using diffusion tensor imaging (DTI). The paper focuses on the scanning protocols and image processing algorithms and software that were designed to fit the diffusion properties of the mammary fibroglandular tissue and its changes during malignant transformation. The final output yields pixel by pixel vector maps that track the architecture of the entire mammary ductal glandular trees and parametric maps of the diffusion tensor coefficients and anisotropy indices. The efficiency of the method to detect breast cancer was tested by scanning women volunteers including 68 patients with breast cancer confirmed by histopathology findings. Regions with cancer cells exhibited a marked reduction in the diffusion coefficients and in the maximal anisotropy index as compared to the normal breast tissue, providing an intrinsic contrast for delineating the boundaries of malignant growth. Overall, the sensitivity of the DTI parameters to detect breast cancer was found to be high, particularly in dense breasts, and comparable to the current standard breast MRI method that requires injection of a contrast agent. Thus, this method offers a completely non-invasive, safe and sensitive tool for breast cancer detection. PMID:25549209

  17. Loss of monocyte chemoattractant protein-1 expression delays mammary tumorigenesis and reduces localized inflammation in the C3(1)/SV40Tag triple negative breast cancer model.

    PubMed

    Cranford, Taryn L; Velázquez, Kandy T; Enos, Reilly T; Bader, Jackie E; Carson, Meredith S; Chatzistamou, Ioulia; Nagarkatti, Mitzi; Murphy, E Angela

    2017-02-01

    Monocyte chemoattractant protein 1 (MCP-1) has been implicated as a major modulator in the progression of mammary tumorigenesis, largely due to its ability to recruit macrophages to the tumor microenvironment. Macrophages are key mediators in the connection between inflammation and cancer progression and have been shown to play an important role in tumorigenesis. Thus, MCP-1 may be a potential therapeutic target in inflammatory and difficult-to-treat cancers such as triple negative breast cancer (TNBC). We examined the effect of MCP-1 depletion on mammary tumorigenesis in a model of TNBC. Tumor measurements were conducted weekly (until 22 weeks of age) and at sacrifice (23 weeks of age) in female C3(1)/SV40Tag and C3(1)/SV40Tag MCP-1 deficient mice to determine tumor numbers and tumorvolumes. Histopathological scoring was performed at 12 weeks of age and 23 weeks of age. Gene expression of macrophage markers and inflammatory mediators were measured in the mammary gland and tumor microenvironment at sacrifice. As expected, MCP-1 depletion resulted in decreased tumorigenesis, indicated by reduced primary tumor volume and multiplicity, and a delay in tumor progression represented by histopathological scoring (12 weeks of age). Deficiency in MCP-1 significantly downregulated expression of macrophage markers in the mammary gland (Mertk and CD64) and the tumor microenvironment (CD64), and also reduced expression of inflammatory cytokines in the mammary gland (TNFα and IL-1β) and the tumor microenvironment (IL-6). These data support the hypothesis that MCP-1 expression contributes to increased tumorigenesis in a model of TNBC via recruitment of macrophages and subsequent increase in inflammatory mediators.

  18. Iodine and doxorubicin, a good combination for mammary cancer treatment: antineoplastic adjuvancy, chemoresistance inhibition, and cardioprotection

    PubMed Central

    2013-01-01

    Background Although mammary cancer (MC) is the most common malignant neoplasia in women, the mortality for this cancer has decreased principally because of early detection and the use of neoadjuvant chemotherapy. Of several preparations that cause MC regression, doxorubicin (DOX) is the most active, first-line monotherapeutic. Nevertheless, its use is limited due to the rapid development of chemoresistance and to the cardiotoxicity caused by free radicals. In previous studies we have shown that supplementation with molecular iodine (I2) has a powerful antineoplastic effect in methylnitrosourea (MNU)-induced experimental models of MC. These studies also showed a consistent antioxidant effect of I2 in normal and tumoral tissues. Methods Here, we analyzed the effect of I2 in combination with DOX treatment in female Sprague Dawley rats with MNU-induced MC. In the first experiment (short) animals were treated with the therapeutic DOX dose (16 mg/kg) or with lower doses (8 and 4 mg/Kg), in each case with and without 0.05% I2 in drinking water. Iodine treatment began on day 0, a single dose of DOX was injected (ip) on day 2, and the analysis was carried out on day 7. In the second experiment (long) animals with and without iodine supplement were treated with one or two injections of 4 mg/kg DOX (on days 0 and 14) and were analyzed on day 56. Results At all DOX doses, the short I2 treatment induced adjuvant antineoplastic effects (decreased tumor size and proliferating cell nuclear antigen level) with significant protection against body weight loss and cardiotoxicity (creatine kinase MB, cardiac lipoperoxidation, and heart damage). With long-term I2, mammary tumor tissue became more sensitive to DOX, since a single injection of the lowest dose of DOX (4 mg/Kg) was enough to stop tumor progression and a second DOX4 injection on day 14 caused a significant and rapid decrease in tumor size, decreased the expression of chemoresistance markers (Bcl2 and survivin), and increased

  19. Extracellular vesicles from women with breast cancer promote an epithelial-mesenchymal transition-like process in mammary epithelial cells MCF10A.

    PubMed

    Galindo-Hernandez, Octavio; Gonzales-Vazquez, Cristina; Cortes-Reynosa, Pedro; Reyes-Uribe, Emmanuel; Chavez-Ocaña, Sonia; Reyes-Hernandez, Octavio; Sierra-Martinez, Mónica; Salazar, Eduardo Perez

    2015-12-01

    Extracellular vesicles (EVs) mediate many stages of tumor progression including angiogenesis, escape from immune surveillance, and extracellular matrix degradation. We studied whether EVs from plasma of women with breast cancer are able to induce an epithelial-mesenchymal transition (EMT) process in mammary epithelial cells MCF10A. Our findings demonstrate that EVs from plasma of breast cancer patients induce a downregulation of E-cadherin expression and an increase of vimentin and N-cadherin expression. Moreover, EVs induce migration and invasion, as well as an increase of NFκB-DNA binding activity and MMP-2 and MMP-9 secretions. In summary, our findings demonstrate, for the first time, that EVs from breast cancer patients induce an EMT-like process in human mammary non-tumorigenic epithelial cells MCF10A.

  20. Raman spectra of normal and cancerous mouse mammary gland tissue using near infrared excitation energy

    NASA Astrophysics Data System (ADS)

    Naik, Vaman; Serhatkulu, G. K.; Dai, H.; Shukla, N.; Weber, R.; Thakur, J. S.; Freeman, D. C.; Pandya, A. K.; Auner, G. W.; Naik, R.; Miller, R. F.; Cao, A.; Klein, M. D.; Rabah, R.

    2006-03-01

    Raman spectra of normal mammary gland tissues, malignant mammary gland tumors, and lymph nodes have been recorded using fresh tissue from mice. Tumors were induced in mice by subcutaneously injecting 4T1 BALB/c mammary tumor (a highly malignant) cell line. The Raman spectra were collected using the same tissues that were examined by histopathology for determining the cancerous/normal state of the tissue. Differences in various peak intensities, peak shifts and peak ratios were analyzed to determine the Raman spectral features that differentiate mammary gland tumors from non-tumorous tissue. Tissues that were confirmed by pathology as cancerous (tumors) show several distinctive features in the Raman spectra compared to the spectra of the normal tissues. For example, the cancerous tissues show Raman peaks at 621, 642, 1004, 1032, 1175 and 1208 cm-1 that are assignable to amino acids containing aromatic side-chains such as phenylalanine, tryptophan and tyrosine. Further, the cancerous tissues show a greatly reduced level of phospholipids compared to the normal tissues. The Raman spectral regions that are sensitive to pathologic alteration in the tissue will be discussed.

  1. Undergraduate Training in Mammary Gland Biology and Breast Cancer

    DTIC Science & Technology

    2005-05-01

    the Office of Management and Budget, Paperwork Reduction Proiect (0704-0188), Washington, DC 20503 1. AGENCY USE ONLY 2. REPORT DATE 3 . REPORT TYPE AND... 3 Introduction .................................................................................... 5 Body...receptors that mediate cell-cell interactions ( 3 ). Studies have shown that when unirradiated non-tumorigenic mammary epithelial COMMA-D cells were

  2. Accelerating Progress Against Cancer

    Cancer.gov

    Investment in cancer research is making a difference, but we still must overcome disparities in cancer incidence and mortality, and expand research to detect cancers earlier and develop more effective, less-toxic treatments. NCI supports research studies and programs across the country that are working to further advance cancer, research, and clinical care.

  3. Vitamin D and the mammary gland: a review on its role in normal development and breast cancer.

    PubMed

    Lopes, Nair; Paredes, Joana; Costa, José Luis; Ylstra, Bauke; Schmitt, Fernando

    2012-05-31

    Breast cancer is a heterogeneous disease associated with diverse biological behaviours and clinical outcome. Although some molecular subgroups of breast cancer have a targeted therapy, the most aggressive tumours still lack a molecular target. Despite vitamin D being classically associated with the physiological role of calcium regulation and phosphate transport in bone metabolism, several studies have demonstrated a wide range of functions for this hormone, which are particularly important in the field of cancer. The mechanisms underlying the protective actions of vitamin D in cancer development are only sparsely understood, but evidence shows that vitamin D participates in cell growth regulation, apoptosis and cell differentiation. In addition, it has been implicated in the suppression of cancer cell invasion, angiogenesis and metastasis. Most of vitamin D biological actions are mediated by the vitamin D receptor and the synthesis and catabolism of this hormone are regulated by the enzymes CYP27B1 and CYP24A1. In the present review we highlight research data concerning the function of this hormone in the mammary gland, with a special focus on breast carcinogenesis. Hence, and although the available data are controversial, we consider not only updated information on the epidemiology of vitamin D in breast cancer and its potential value as a therapeutic agent or prophylactic (with an emphasis on molecular mechanisms and effectors of vitamin D action), but include data on its role in other stages of breast cancer progression as well. Accordingly, we review data on the influence of vitamin D in the development of normal breast and the expression of vitamin D-related proteins (VDR, CYP27B1 and CYP24A21) in benign mammary lesions and ductal carcinomas in situ.

  4. Increased levels of interleukins 8 and 10 as findings of canine inflammatory mammary cancer.

    PubMed

    de Andrés, Paloma Jimena; Illera, Juan Carlos; Cáceres, Sara; Díez, Lucía; Pérez-Alenza, Maria Dolores; Peña, Laura

    2013-04-15

    Inflammatory mammary cancer (IMC) is a distinct form of mammary cancer that affects dogs and women [in humans, IMC is known as inflammatory breast cancer (IBC)], and is characterized by a sudden onset and an aggressive clinical course. Spontaneous canine IMC shares epidemiologic, histopathological and clinical characteristics with the disease in humans and has been proposed as the best spontaneous animal model for studying IBC, although several aspects remain unstudied. Interleukins (ILs) play an important role in cancer as potential modulators of angiogenesis, leukocyte infiltration and tumor growth. The aims of the present study were to assess serum and tumor levels of several ILs (IL-1α, IL-1β, IL-6, IL-8 and IL-10) by enzyme-immunoassay in dogs bearing benign and malignant mammary tumors, including dogs with IMC, for a better understanding of this disease. Forty-eight dogs were prospectively included. Animals consisted of 7 healthy Beagles used as donors for normal mammary glands (NMG) and serum controls (SCs), 10 dogs with hyperplasias and benign mammary tumors (HBMT), 24 with non-inflammatory malignant mammary tumors (non-IMC MMT) and 7 dogs with clinical and pathological IMC. IL-8 (serum) and IL-10 (serum and tissue homogenate) levels were higher in the dogs with IMC compared with the non-IMC MMT group. ILs were increased with tumor malignancy as follows: in tumor homogenates IL-6 levels were higher in malignant tumors (IMC and non-IMC MMT) versus HBMT and versus NMG and tumor IL-8 was increased in malignant tumors versus NMG; in serum, IL-1α and IL-8 levels were higher in the malignant groups respect to HBMT and SCs; interestingly, IL-10 was elevated only in the serum of IMC animals. To the best of our knowledge, this is the first report that analyzes ILs in IMC and IL-10 in canine mammary tumors. Our results indicate a role for IL-6, IL-8 and IL-10 in canine mammary malignancy and specific differences in ILs content in IMC versus non-IMC MMT that could

  5. miR-135b coordinates progression of ErbB2-driven mammary carcinomas through suppression of MID1 and MTCH2.

    PubMed

    Arigoni, Maddalena; Barutello, Giuseppina; Riccardo, Federica; Ercole, Elisabetta; Cantarella, Daniela; Orso, Francesca; Conti, Laura; Lanzardo, Stefania; Taverna, Daniela; Merighi, Irene; Calogero, Raffaele A; Cavallo, Federica; Quaglino, Elena

    2013-06-01

    In an attempt to reveal deregulated miRNAs associated with the progression of carcinomas developed in BALB-neuT transgenic mice, we found increased expression of miR-135b during malignancy. Relevantly, we observed that miR-135b is up-regulated in basal or normal-like human breast cancers, and it correlates with patient survival and early metastatization. Therefore, we investigated its biological functions by modulating its expression (up- or down-regulation) in mammary tumor cells. Although no effect was observed on proliferation in cell culture and in orthotopically injected mice, miR-135b was able to control cancer cell stemness in a mammosphere assay, anchorage-independent growth in vitro, and lung cancer cell dissemination in mice after tail vein injections. Focusing on the miR-135b molecular mechanism, we observed that miR-135b controls malignancy via its direct targets, midline 1 (MID1) and mitochondrial carrier homolog 2 (MTCH2), as proved by biochemical and functional rescuing/phenocopying experiments. Consistently, an anti-correlation between miR-135b and MID1 or MTCH2 was found in human primary tumor samples. In conclusion, our research led us to the identification of miR-135b and its targets, MID1 and MTCH2, as relevant coordinators of mammary gland tumor progression.

  6. Genistein-mediated inhibition of mammary stromal adipocyte differentiation limits expansion of mammary stem/progenitor cells by paracrine signaling

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mammary adiposity may contribute to breast cancer development and progression by releasing cytokines and other inflammatory mediators that promote mammary epithelial proliferation. We evaluated the effects of soy isoflavone genistein (GEN) on the adipogenic differentiation of a SV40-immortalized mou...

  7. GPR56 Plays Varying Roles in Endogenous Cancer Progression

    PubMed Central

    Xu, Lei; Begum, Shahinoor; Barry, Marc; Crowley, Denise; Yang, Liquan; Bronson, Roderick T.; Hynes, Richard O.

    2011-01-01

    GPR56, a non-classical adhesion receptor, was previously reported to suppress tumor growth and metastasis in xenograft models using human melanoma cell lines. To understand whether GPR56 plays similar roles in the development of endogenous tumors, we analyzed cancer progression in Gpr56−/− mice using a variety of transgenic cancer models. Our results showed that GPR56 suppressed prostate cancer progression in the TRAMP model on a mixed genetic background, similar to its roles in progression of melanoma xenografts. However, its roles in other cancer types appeared to be complex. It had marginal effects on tumor onset of mammary tumors in the MMTV-PyMT model, but had no effects on subsequent tumor progression in either the MMTV-PyMT mice or the melanoma model, Ink4a/Arf−/− tyr-Hras. These results indicate diverse roles of GPR56 in cancer progression and provide the first genetic evidence for the involvement of an adhesion GPCR in endogenous cancer development. PMID:20333450

  8. Novel Cytochrome P45OlBl as a Mammary Cancer Risk Factor.

    DTIC Science & Technology

    1998-07-01

    initiation of the cancer process results from a mutational event that requires replication of DNA which has been modified by the metabolite. The...surveillance processes typically prevent this event by preventing replication [cell cycle arrest], by stimulating repair, and by diverting damaged cells...Gould and the UW Comprehensive Cancer Center Cell Bank. The mammary tissue was processed and organoids isolated in the Gould laboratory, according to

  9. Comparison of the Adipose and Luminal Mammary Gland Compartment as Orthotopic Inoculation Sites in a 4T1-Based Immunocompetent Preclinical Model for Triple-Negative Breast Cancer.

    PubMed

    Steenbrugge, Jonas; Breyne, Koen; Denies, Sofie; Dekimpe, Melissa; Demeyere, Kristel; De Wever, Olivier; Vermeulen, Peter; Van Laere, Steven; Sanders, Niek N; Meyer, Evelyne

    2016-12-01

    Breast tumorigenesis is classically studied in mice by inoculating tumor cells in the fat pad, the adipose compartment of the mammary gland. Alternatively, the mammary ducts, which constitute the luminal mammary gland compartment, also provide a suitable inoculation site to induce breast cancer in murine models. The microenvironments in these compartments influence tumor cell progression, yet this effect has not been investigated in an immunocompetent context. Here, we compared both mammary gland compartments as distinct inoculation sites, taking into account the immunological aspect by inoculating 4T1 tumor cells in immunocompetent mice. Following tumor cell inoculation in the adipose compartment of non-pretreated/naive, hormonally pretreated/naive and non-pretreated/lactating mice, the primary tumors developed similarly. However, a slower onset of primary tumor growth was found after inoculations in the luminal compartment of non-pretreated/lactating mice. Despite this difference in tumor development rate, metastasis to the liver and lungs was equally observed and was accompanied by lymphatic spreading of tumor cells and progressive splenomegaly with both inoculation types. Chitinase 3-like 1 (CHI3L1) and lipocalin 2 (LCN2) served as innovative biomarkers for disease progression showing increased levels in primary tumors and sera of the non-pretreated/lactating inoculation groups. A slower increase in circulating CHI3L1 but not LCN2 levels, was observed after inoculations in the luminal compartment which corroborated the slower tumor development at this inoculation site. Our results highlight the critical impact of different mammary gland compartments on tumor development in syngeneic murine models and support the use of novel tumor progression biomarkers in an immune-competent environment.

  10. Mammary Stem Cell Based Somatic Mouse Models Reveal Breast Cancer Drivers Causing Cell Fate Dysregulation

    PubMed Central

    Zhang, Zheng; Christin, John R.; Wang, Chunhui; Ge, Kai; Oktay, Maja H.; Guo, Wenjun

    2016-01-01

    SUMMARY Cancer genomics have provided an unprecedented opportunity for understanding genetic causes of human cancer. However, distinguishing which mutations are functionally relevant to cancer pathogenesis remains a major challenge. We describe here a mammary stem cell (MaSC) organoid-based approach for rapid generation of somatic GEMMs (genetically engineered mouse models). By using RNAi and CRISPR-mediated genome engineering in MaSC-GEMMs, we have discovered that inactivation of Ptpn22 or Mll3, two genes mutated in human breast cancer, greatly accelerated PI3K-driven mammary tumorigenesis. Using these tumor models, we have also identified genetic alterations promoting tumor metastasis and causing resistance to PI3K-targeted therapy. Both Ptpn22 and Mll3 inactivation resulted in disruption of mammary gland differentiation and an increase in stem cell activity. Mechanistically, Mll3 deletion enhanced stem cell activity through activation of the HIF pathway. Thus, our study established a robust in vivo platform for functional cancer genomics and discovered functional breast cancer mutations. PMID:27653681

  11. Mammary renin-angiotensin system-regulating aminopeptidase activities are modified in rats with breast cancer.

    PubMed

    del Pilar Carrera, Maria; Ramírez-Expósito, Maria Jesus; Mayas, Maria Dolores; García, Maria Jesus; Martínez-Martos, Jose Manuel

    2010-12-01

    Angiotensin II in particular and/or the local renin-angiotensin system in general could have an important role in epithelial tissue growth and modelling; therefore, it is possible that it may be involved in breast cancer. In this sense, previous works of our group showed a predominating role of angiotensin II in tumoral tissue obtained from women with breast cancer. However, although classically angiotensin II has been considered the main effector peptide of the renin-angiotensin system cascade, several of its catabolism products such as angiotensin III and angiotensin IV also possess biological functions. These peptides are formed through the activity of several proteolytic regulatory enzymes of the aminopeptidase type, also called angiotensinases. The aim of this work was to analyse several specific angiotensinase activities involved in the renin-angiotensin system cascade in mammary tissue from control rats and from rats with mammary tumours induced by N-methyl-nitrosourea (NMU), which may reflect the functional status of their target peptides under the specific conditions brought about by the tumoural process. The results show that soluble and membrane-bound specific aspartyl aminopeptidase activities and membrane-bound glutamyl aminopeptidase activity increased in mammary tissue from NMU-treated animals and soluble aminopeptidase N and aminopeptidase B activities significantly decreased in mammary tissue from NMU-treated rats. These changes support the existence of a local mammary renin-angiotensin system and that this system and its putative functions in breast tissue could be altered by the tumour process, in which we suggest a predominant role of angiotensin III. All described data about the renin-angiotensin system in mammary tissue support the idea that it must be involved in normal breast tissue functions, and its disruption could be involved in one or more steps of the carcinogenesis process.

  12. MicroRNA-regulated gene networks during mammary cell differentiation are associated with breast cancer.

    PubMed

    Aydoğdu, Eylem; Katchy, Anne; Tsouko, Efrosini; Lin, Chin-Yo; Haldosén, Lars-Arne; Helguero, Luisa; Williams, Cecilia

    2012-08-01

    MicroRNAs (miRNAs) play pivotal roles in stem cell biology, differentiation and oncogenesis and are of high interest as potential breast cancer therapeutics. However, their expression and function during normal mammary differentiation and in breast cancer remain to be elucidated. In order to identify which miRNAs are involved in mammary differentiation, we thoroughly investigated miRNA expression during functional differentiation of undifferentiated, stem cell-like, murine mammary cells using two different large-scale approaches followed by qPCR. Significant changes in expression of 21 miRNAs were observed in repeated rounds of mammary cell differentiation. The majority, including the miR-200 family and known tumor suppressor miRNAs, was upregulated during differentiation. Only four miRNAs, including oncomiR miR-17, were downregulated. Pathway analysis indicated complex interactions between regulated miRNA clusters and major pathways involved in differentiation, proliferation and stem cell maintenance. Comparisons with human breast cancer tumors showed the gene profile from the undifferentiated, stem-like stage clustered with that of poor-prognosis breast cancer. A common nominator in these groups was the E2F pathway, which was overrepresented among genes targeted by the differentiation-induced miRNAs. A subset of miRNAs could further discriminate between human non-cancer and breast cancer cell lines, and miR-200a/miR-200b, miR-146b and miR-148a were specifically downregulated in triple-negative breast cancer cells. We show that miR-200a/miR-200b can inhibit epithelial-mesenchymal transition (EMT)-characteristic morphological changes in undifferentiated, non-tumorigenic mammary cells. Our studies propose EphA2 as a novel and important target gene for miR-200a. In conclusion, we present evidentiary data on how miRNAs are involved in mammary cell differentiation and indicate their related roles in breast cancer.

  13. Sesamin synergistically potentiates the anticancer effects of γ-tocotrienol in mammary cancer cell lines.

    PubMed

    Akl, Mohamed R; Ayoub, Nehad M; Abuasal, Bilal S; Kaddoumi, Amal; Sylvester, Paul W

    2013-01-01

    γ-Tocotrienol and sesamin are phytochemicals that display potent anticancer activity. Since sesamin inhibits the metabolic degradation of tocotrienols, studies were conducted to determine if combined treatment with sesamin potentiates the antiproliferative effects of γ-tocotrienol on neoplastic mouse (+SA) and human (MCF-7 and MDA-MB-231) mammary cancer cells. Results showed that treatment with γ-tocotrienol or sesamin alone induced a significant dose-responsive growth inhibition, whereas combination treatment with these agents synergistically inhibited the growth of +SA, MCF-7 and MDA-MB-231 mammary cancer cells, while similar treatment doses were found to have little or no effect on normal (mouse CL-S1 and human MCF-10A) mammary epithelial cell growth or viability. However, sesamin synergistic enhancement of γ-tocotrienol-induced anticancer effects was not found to be mediated from a reduction in γ-tocotrienol metabolism. Rather, combined treatment with subeffective doses of γ-tocotrienol and sesamin was found to induce G1 cell cycle arrest, and a corresponding decrease in cyclin D1, CDK2, CDK4, CDK6, phospho-Rb, and E2F1 levels, and increase in p27 and p16 levels. Additional studies showed that the antiproliferative effect of combination treatment did not initiate apoptosis or result in a decrease in mammary cancer cell viability. Taken together, these findings indicate that the synergistic antiproliferative action of combined γ-tocotrienol and sesamin treatment in mouse and human mammary cancer cells is cytostatic, not cytotoxic, and results from G1 cell cycle arrest.

  14. microRNAs and EMT in mammary cells and breast cancer.

    PubMed

    Wright, Josephine A; Richer, Jennifer K; Goodall, Gregory J

    2010-06-01

    MicroRNAs are master regulators of gene expression in many biological and pathological processes, including mammary gland development and breast cancer. The differentiation program termed the epithelial to mesenchymal transition (EMT) involves changes in a number of microRNAs. Some of these microRNAs have been shown to control cellular plasticity through the suppression of EMT-inducers or to influence cellular phenotype through the suppression of genes involved in defining the epithelial and mesenchymal cell states. This has led to the suggestion that microRNAs maybe a novel therapeutic target for the treatment of breast cancer. In this review, we will discuss microRNAs that are involved in EMT in mammary cells and breast cancer.

  15. Progress in breast cancer: overview.

    PubMed

    Arteaga, Carlos L

    2013-12-01

    This edition of CCR Focus titled Research in Breast Cancer: Frontiers in Genomics, Biology, and Clinical Investigation reviews six topics that cover areas of translational research of high impact in breast cancer. These topics represent areas of breast cancer research where significant progress has occurred but also where very important challenges remain. The papers in this CCR Focus section are contributed by experts in the respective areas of investigation. Herein, key aspects of these contributions and the research directions they propose are reviewed.

  16. Attenuation of TGF-β signaling supports tumor progression of a mesenchymal-like mammary tumor cell line in a syngeneic murine model

    PubMed Central

    Biswas, Tanuka; Gu, Xiang; Yang, Junhua; Ellies, Lesley G; Sun, Lu-Zhe

    2014-01-01

    Previous studies have suggested that TGF-β functions as a tumor promoter in metastatic, mesenchymal-like breast cancer cells and that TGF-β inhibitors can effectively abrogate tumor progression in several of these models. Here we report a novel observation with the use of genetic and pharmacological approaches, and murine mammary cell injection models in both syngeneic and immune compromised mice. We found that TGF-β receptor II (TβRII) knockdown in the MMTV-PyMT derived Py8119, a mesenchymal-like murine mammary tumor cell line, resulted in increased orthotopic tumor growth potential in a syngeneic background and a similar trend in an immune compromised background. Systemic treatment with a small-molecule TGF-β receptor I kinase inhibitor induced a trend towards increased metastatic colonization of distant organs following intra cardiac inoculation of Py8119 cells, with little effect on the colonization of luminal-like Py230 cells, also derived from MMTV-PyMT tumors. Taken together, our data suggest that the attenuation of TGF-β signaling in mesenchymal-like mammary tumors does not necessarily inhibit their malignant potential, and anti-TGF-β therapeutic intervention requires greater precision in identifying molecular markers in tumors with an indication of functional TGF-β signaling. PMID:24368187

  17. Human breast cancer cells are redirected to mammary epithelial cells upon interaction with the regenerating mammary gland microenvironment in-vivo.

    PubMed

    Bussard, Karen M; Smith, Gilbert H

    2012-01-01

    Breast cancer is the second leading cause of cancer deaths in the United States. At present, the etiology of breast cancer is unknown; however the possibility of a distinct cell of origin, i.e. a cancer stem cell, is a heavily investigated area of research. Influencing signals from the tissue niche are known to affect stem cells. Literature has shown that cancer cells lose their tumorigenic potential and display 'normal' behavior when placed into 'normal' ontogenic environments. Therefore, it may be the case that the tissue microenvironment is able to generate signals to redirect cancer cell fate. Previously, we showed that pluripotent human embryonal carcinoma cells could be redirected by the regenerating mammary gland microenvironment to contribute epithelial progeny for 'normal' gland development in-vivo. Here, we show that that human metastatic, non-metastatic, and metastasis-suppressed breast cancer cells proliferate and contribute to normal mammary gland development in-vivo without tumor formation. Immunochemistry for human-specific mitochondria, keratin 8 and 14, as well as human-specific milk proteins (alpha-lactalbumin, impregnated transplant hosts) confirmed the presence of human cell progeny. Features consistent with normal mammary gland development as seen in intact hosts (duct, lumen formation, development of secretory acini) were recapitulated in both primary and secondary outgrowths from chimeric implants. These results suggest the dominance of the tissue microenvironment over cancer cell fate. This work demonstrates that cultured human breast cancer cells (metastatic and non-metastatic) respond developmentally to signals generated by the mouse mammary gland microenvironment during gland regeneration in-vivo.

  18. Mammary Gland Involution Provides a Unique Model to Study the TGF-β Cancer Paradox

    PubMed Central

    Guo, Qiuchen; Betts, Courtney; Pennock, Nathan; Mitchell, Elizabeth; Schedin, Pepper

    2017-01-01

    Transforming Growth Factor-β (TGF-β) signaling in cancer has been termed the “TGF-β paradox”, acting as both a tumor suppresser and promoter. The complexity of TGF-β signaling within the tumor is context dependent, and greatly impacted by cellular crosstalk between TGF-β responsive cells in the microenvironment including adjacent epithelial, endothelial, mesenchymal, and hematopoietic cells. Here we utilize normal, weaning-induced mammary gland involution as a tissue microenvironment model to study the complexity of TGF-β function. This article reviews facets of mammary gland involution that are TGF-β regulated, namely mammary epithelial cell death, immune activation, and extracellular matrix remodeling. We outline how distinct cellular responses and crosstalk between cell types during physiologically normal mammary gland involution contribute to simultaneous tumor suppressive and promotional microenvironments. We also highlight alternatives to direct TGF-β blocking anti-cancer therapies with an emphasis on eliciting concerted microenvironmental-mediated tumor suppression. PMID:28098775

  19. A hypoxic signature marks tumors formed by disseminated tumor cells in the BALB-neuT mammary cancer model

    PubMed Central

    Msaki, Aichi; Pastò, Anna; Curtarello, Matteo; Arigoni, Maddalena; Barutello, Giuseppina; Calogero, Raffaele Adolfo; Macagno, Marco; Cavallo, Federica

    2016-01-01

    Metastasis is the final stage of cancer progression. Some evidence indicates that tumor cell dissemination occurs early in the natural history of cancer progression. Disseminated tumor cells (DTC) have been described in the bone marrow (BM) of cancer patients as well as in experimental models, where they correlate with later development of metastasis. However, little is known about the tumorigenic features of DTC obtained at different time points along tumor progression. Here, we found that early DTC isolated from BM of 15-17 week-old Her2/neu transgenic (BALB-neuT) mice were not tumorigenic in immunodeficient mice. In contrast, DTC-derived tumors were easily detectable when late DTC obtained from 19-22 week-old BALB-neuT mice were injected. Angiogenesis, which contributes to regulate tumor dormancy, appeared dispensable to reactivate late DTC, although it accelerated growth of secondary DTC tumors. Compared with parental mammary tumors, gene expression profiling disclosed a distinctive transcriptional signature of late DTC tumors which was enriched for hypoxia-related transcripts and was maintained in ex-vivo cell culture. Altogether, these findings highlight a different tumorigenic potential of early and late DTC in the BALB-neuT model and describe a HIF-1α-related transcriptional signature in DTC tumors, which may render DTC angiogenesis-competent, when placed in a favourable environment. PMID:27105499

  20. ErbB/EGF Signaling and EMT in Mammary Development and Breast Cancer

    PubMed Central

    Hardy, Katharine M.; Booth, Brian W.; Hendrix, Mary J. C.; Salomon, David S.

    2010-01-01

    Activation of the ErbB family of receptor tyrosine kinases via cognate Epidermal Growth Factor (EGF)-like peptide ligands constitutes a major group of related signaling pathways that control proliferation, survival, angiogenesis and metastasis of breast cancer. In this respect, clinical trials with various ErbB receptor blocking antibodies and specific tyrosine kinase inhibitors have proven to be partially efficacious in the treatment of this heterogeneous disease. Induction of an embryonic program of epithelial-to-mesenchymal transition (EMT) in breast cancer, whereupon epithelial tumor cells convert to a more mesenchymal-like phenotype, facilitates the migration, intravasation, and extravasation of tumor cells during metastasis. Breast cancers which exhibit properties of EMT are highly aggressive and resistant to therapy. Activation of ErbB signaling can regulate EMT-associated invasion and migration in normal and malignant mammary epithelial cells, as well as modulating discrete stages of mammary gland development. The purpose of this review is to summarize current information regarding the role of ErbB signaling in aspects of EMT that influence epithelial cell plasticity during mammary gland development and tumorigenesis. How this information may contribute to the improvement of therapeutic approaches in breast cancer will also be addressed. PMID:20369376

  1. ErbB/EGF signaling and EMT in mammary development and breast cancer.

    PubMed

    Hardy, Katharine M; Booth, Brian W; Hendrix, Mary J C; Salomon, David S; Strizzi, Luigi

    2010-06-01

    Activation of the ErbB family of receptor tyrosine kinases via cognate Epidermal Growth Factor (EGF)-like peptide ligands constitutes a major group of related signaling pathways that control proliferation, survival, angiogenesis and metastasis of breast cancer. In this respect, clinical trials with various ErbB receptor blocking antibodies and specific tyrosine kinase inhibitors have proven to be partially efficacious in the treatment of this heterogeneous disease. Induction of an embryonic program of epithelial-to-mesenchymal transition (EMT) in breast cancer, whereupon epithelial tumor cells convert to a more mesenchymal-like phenotype, facilitates the migration, intravasation, and extravasation of tumor cells during metastasis. Breast cancers which exhibit properties of EMT are highly aggressive and resistant to therapy. Activation of ErbB signaling can regulate EMT-associated invasion and migration in normal and malignant mammary epithelial cells, as well as modulating discrete stages of mammary gland development. The purpose of this review is to summarize current information regarding the role of ErbB signaling in aspects of EMT that influence epithelial cell plasticity during mammary gland development and tumorigenesis. How this information may contribute to the improvement of therapeutic approaches in breast cancer will also be addressed.

  2. Stage-specific embryonic antigen: determining expression in canine glioblastoma, melanoma, and mammary cancer cells.

    PubMed

    Lin, Weiming; Modiano, Jaime F; Ito, Daisuke

    2017-03-30

    The expression of stage-specific embryonic antigens (SSEAs) was determined in several types of canine cancer cells. Flow cytometry showed SSEA-1 expression in glioblastoma, melanoma, and mammary cancer cells, although none expressed SSEA-3 or SSEA-4. Expression of SSEA-1 was not detected in lymphoma, osteosarcoma, or hemangiosarcoma cell lines. Relatively stable SSEA-1 expression was observed between 24 and 72 h of culture. After 8 days in culture, sorted SSEA-1(-) and SSEA-1(+) cells re-established SSEA-1 expression to levels comparable to those observed in unsorted cells. Our results document, for the first time, the expression of SSEA-1 in several canine cancer cell lines.

  3. Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer.

    PubMed

    Rangel, Maria Cristina; Bertolette, Daniel; Castro, Nadia P; Klauzinska, Malgorzata; Cuttitta, Frank; Salomon, David S

    2016-04-01

    Cancer has been considered as temporal and spatial aberrations of normal development in tissues. Similarities between mammary embryonic development and cell transformation suggest that the underlying processes required for mammary gland development are also those perturbed during various stages of mammary tumorigenesis and breast cancer (BC) development. The master regulators of embryonic development Cripto-1, Notch/CSL, and Wnt/β-catenin play key roles in modulating mammary gland morphogenesis and cell fate specification in the embryo through fetal mammary stem cells (fMaSC) and in the adult organism particularly within the adult mammary stem cells (aMaSC), which determine mammary progenitor cell lineages that generate the basal/myoepithelial and luminal compartments of the adult mammary gland. Together with recognized transcription factors and embryonic stem cell markers, these embryonic regulatory molecules can be inappropriately augmented during tumorigenesis to support the tumor-initiating cell (TIC)/cancer stem cell (CSC) compartment, and the effects of their deregulation may contribute for the etiology of BC, in particular the most aggressive subtype of BC, triple-negative breast cancer (TNBC). This in depth review will present evidence of the involvement of Cripto-1, Notch/CSL, and Wnt/β-catenin in the normal mammary gland morphogenesis and tumorigenesis, from fMaSC/aMaSC regulation to TIC generation and maintenance in TNBC. Specific therapies for treating TNBC by targeting these embryonic pathways in TICs will be further discussed, providing new opportunities to destroy not only the bulk tumor, but also TICs that initiate and promote the metastatic spread and recurrence of this aggressive subtype of BC.

  4. Connected Health and Progress against Cancer

    Cancer.gov

    An NCI Cancer Currents blog post about a new report from President’s Cancer Panel outlining how connective technologies can promote cancer prevention, enhance patients’ treatment experience, and accelerate progress in cancer research.

  5. Antiproliferative effect of berberine on canine mammary gland cancer cell culture.

    PubMed

    Sefidabi, Reyhaneh; Mortazavi, Pejman; Hosseini, Saeed

    2017-01-01

    Canine mammary gland tumors are the most frequent cause of cancer in female dogs. Numerous studies using cancer cell lines and clinical trials have indicated that various natural products and antioxidants reduce or possibly prevent the development of cancer. Berberine (BBR), the most important alkaloid in the Berberidaceae, which exerts a wide range of pharmacological and biochemical effects, has drawn much attention due to its particularly high antitumor activity in vitro and in animal studies. The aim of the present study was to investigate the antiproliferative effect of BBR against a canine mammary gland carcinoma cell line (CF41.Mg) in vitro. CF41.Mg cells were cultured in RPMI-1640 medium containing 10% heat inactived fetal bovine serum (FBS) and 100 mg/ml peniciline-streptomycin. Subsequently the cells were treated with different concentrations of BBR chloride (10, 25, 50, 100 and 200 µM) at a density of 12,000 cells/well in 96-well plates. Following treatment, the MTT assay was used to detect cell viability after 24-, 48- and 72-h incubations at 37°C with 5% CO2. The results indicated that BBR inhibited proliferation of canine mammary gland carcinoma cells, as treatment with 100 µM BBR for 24 h resulted in a significant decrease in cell viability (P<0.005). As the present study demonstrated that BBR (10-200 µM) induced cancer cell death, it is proposed that BBR may serve as a candidate agent against canine mammary tumor cells via its antiproliferative activity.

  6. The myoepithelial cell: its role in normal mammary glands and breast cancer.

    PubMed

    Sopel, M

    2010-02-01

    Mammary gland epithelium is composed of an inner layer of secretory cells (luminal) and an outer layer of myoepithelial cells (MEC) bordering the basal lamina which separates the epithelial layer from the extracellular matrix. Mature MECs morphologically resemble smooth muscle cells; however, they exhibit features typical for epithelial cells, such as the presence of specific cytokeratin filaments. During lactation, secretory cells synthesize milk components, which are collected in alveoli and duct lumen, and transported to the nipple as a result of MEC contraction. Although the induction of MEC contraction results from oxytocin action, also other, still unknown auto/paracrine mechanisms participate in the regulation of this process. As well as milk ejection, MECs are involved in mammary gland morphogenesis in all developmental stages, modulating proliferation and differentiation of luminal cells. They take part in the formation of extracellular matrix, synthesizing its components and secreting proteinases and their inhibitors. In addition, MECs are regarded as natural cancer suppressors, stabilizing the normal structure of the mammary gland, they secrete suppressor proteins (e.g. maspin) limiting cancer growth, invasiveness, and neoangiogenesis. The majority of malignant breast cancers are derived from luminal cells, whereas neoplasms of MEC origin are the most seldom and usually benign form of breast tumours. MECs are markedly resistant to malignant transformation and they are able to suppress the transformation of neighboring luminal cells. Therefore, a deeper insight into the role of MECs in the physiology and pathology of mammary glands would allow a better understanding of cancerogenesis mechanisms and possible application of specific MEC markers in the diagnosis and therapy of breast cancer.

  7. Met Receptor Acts Uniquely for Survival and Morphogenesis of EGFR-Dependent Normal Mammary Epithelial and Cancer Cells

    PubMed Central

    Bersani, Francesca; Quaglino, Elena; Martignani, Eugenio; Baratta, Mario

    2012-01-01

    Mammary gland development and breast cancer growth require multiple factors both of endocrine and paracrine origin. We analyzed the roles of Epidermal Growth Factor Receptor (EGFR) and Hepatocyte Growth Factor Receptor (Met) in mammary epithelial cells and mammary tumor cells derived from a mutated-ErbB2 transgenic mice. By using highly specific tyrosine kinase inhibitors we found that MCF-10A and NMuMG mammary epithelial cell lines are totally dependent on EGFR activation for their growth and survival. Proliferation and 3D-morphogenesis assays showed that HGF had no role in maintaining mammary cell viability, but was the only cytokine able to rescue EGFR-inhibited mammary cells. Insulin-Like Growth Factor-I (IGF-I), basic-Fibroblast Growth Factor (b-FGF) and Neuregulin, which are well known mammary morphogenic factors, did not rescue proliferation or morphogenesis in these cell lines, following EGFR inhibition. Similarly, ErbB2-driven tumor cells are EGFR-dependent and also display HGF-mediated rescue. Western-blot analysis of the signaling pathways involved in rescue after EGFR inhibition indicated that concomitant ERK1/2 and AKT activation was exclusively driven by Met, but not by IGF-I or b-FGF. These results describe a unique role for EGFR and Met in mammary epithelial cells by showing that similar pathways can be used by tumorigenic cells to sustain growth and resist to EGFR-directed anti-tumorigenic drugs. PMID:23028720

  8. Mammary gland involution as an immunotherapeutic target for postpartum breast cancer.

    PubMed

    Fornetti, Jaime; Martinson, Holly A; Betts, Courtney B; Lyons, Traci R; Jindal, Sonali; Guo, Qiuchen; Coussens, Lisa M; Borges, Virginia F; Schedin, Pepper

    2014-07-01

    Postpartum mammary gland involution has been identified as tumor-promotional and is proposed to contribute to the increased rates of metastasis and poor survival observed in postpartum breast cancer patients. In rodent models, the involuting mammary gland microenvironment is sufficient to induce enhanced tumor cell growth, local invasion, and metastasis. Postpartum involution shares many attributes with wound healing, including upregulation of genes involved in immune responsiveness and infiltration of tissue by immune cells. In rodent models, treatment with non-steroidal anti-inflammatory drugs (NSAIDs) ameliorates the tumor-promotional effects of involution, consistent with the immune milieu of the involuting gland contributing to tumor promotion. Currently, immunotherapy is being investigated as a means of breast cancer treatment with the purpose of identifying ways to enhance anti-tumor immune responses. Here we review evidence for postpartum mammary gland involution being a uniquely defined 'hot-spot' of pro-tumorigenic immune cell infiltration, and propose that immunotherapy should be explored for prevention and treatment of breast cancers that arise in this environment.

  9. The impact of adhesion peptides within hydrogels on the phenotype and signaling of normal and cancerous mammary epithelial cells

    PubMed Central

    Weiss, Michael S.; Bernabé, Beatriz Peñalver; Shikanov, Ariella; Bluver, Dennis A.; Mui, Michael D.; Shin, Seungjin; Broadbelt, Linda J.; Shea, Lonnie D.

    2012-01-01

    The microenviroment contributes to directing mammary epithelial cell (MEC) development and the progression of breast cancer. Three-dimensional culture models have been used to support formation of structures that display varying degrees of disorganization that parallel the degree of cancer. Synthetic hydrogels were employed to investigate the mechanisms by which specific adhesion signals in the microenvironment directed development. Polyethylene glycol-based hydrogels supported 3D growth of MECs and directed formation of a range of phenotypes that were functions of genotype, and identity and concentration of adhesion peptides RGD and YIGSR. Non-cancerous and cancerous MECs responded differentially to the same adhesion cues and produced variable structural organizations. An analysis of dynamic signaling pathways revealed differential activities of transcription factors within the MAPK and JAK/STAT pathways in response to genotype and adhesion. These results directly implicate adhesion in cancer development and demonstrate that AP1, CREB, STAT1, and STAT3 all contribute to the genotype dependence of cellular response to adhesion peptides. The tools presented in this work could be applied to other systems and connect extracellular cues with intracellular signaling to molecularly dissect tissue development and further biomaterials development. PMID:22341213

  10. An Improved Syngeneic Orthotopic Murine Model of Human Breast Cancer Progression

    PubMed Central

    Rashid, Omar M.; Nagahashi, Masayuki; Ramachandran, Suburamaniam; Dumur, Catherine; Schaum, Julia; Yamada, Akimitsu; Terracina, Krista P.; Milstien, Sheldon; Spiegel, Sarah; Takabe, Kazuaki

    2014-01-01

    Purpose Breast cancer drug development costs nearly $610 million and 37 months in preclinical mouse model trials with minimal success rates. Despite these inefficiencies, there are still no consensus breast cancer preclinical models. Methods Murine mammary adenocarcinoma 4T1-luc2 cells were implanted subcutaneous (SQ) or orthotopically percutaneous injection in the area of the nipple (OP), or surgically into the chest 2nd mammary fat pad under direct vision (ODV) in Balb/c immunocompetent mice. Tumor progression was followed by in vivo bioluminescence and direct measurements, pathology and survival determined, and tumor gene expression analyzed by genome-wide microarrays. Results ODV produced less variable sized tumors and was a reliable method of implantation. ODV implantation into the chest 2nd mammary pad rather than into the abdominal 4th mammary pad, the most common implantation site, better mimicked human breast cancer progression pattern, which correlated with bioluminescent tumor burden and survival. Compared to SQ, ODV produced tumors that differentially expressed genes whose interaction networks are of importance in cancer research. qPCR validation of 10 specific target genes of interest in ongoing clinical trials demonstrated significant differences in expression. Conclusions ODV implantation into the chest 2nd mammary pad provides the most reliable model that mimics human breast cancer compared from subcutaneous implantation that produces tumors with different genome expression profiles of clinical significance. Increased understanding of the limitations of the different preclinical models in use will help guide new investigations and may improve the efficiency of breast cancer drug development. PMID:25200444

  11. Transcriptional Regulation of p21/CIP1 Cell Cycle Inhibitor by PDEF Controls Cell Proliferation and Mammary Tumor Progression*

    PubMed Central

    Schaefer, Jeremy S.; Sabherwal, Yamini; Shi, Heidi Y.; Sriraman, Venkataraman; Richards, JoAnne; Minella, Alex; Turner, David P.; Watson, Dennis K.; Zhang, Ming

    2010-01-01

    The Ets family of transcription factors control a myriad of cellular processes and contribute to the underlying genetic loss of cellular homeostasis resulting in cancer. PDEF (prostate-derived Ets factor) has been under investigation for its role in tumor development and progression. However, the role of PDEF in cancer development has been controversial. Some reports link PDEF to tumor promoter, and others show tumor-suppressing functions in various systems under different conditions. So far, there has been no conclusive evidence from in vivo experiments to prove the role of PDEF. We have used both in vitro and in vivo systems to provide a conclusive role of PDEF in the progression process. PDEF-expressing cells block the cell growth rate, and this retardation was reversible when PDEF expression was silenced with PDEF-specific small interfering RNA. When these PDEF-expressing cells were orthotopically implanted into the mouse mammary gland, tumor incidence and growth rate were significantly retarded. Cell cycle analysis revealed that PDEF expression partially blocked cell cycle progression at G1/S without an effect on apoptosis. PDEF overexpression resulted in an increase in p21/CIP1 at both the mRNA and protein levels, resulting in decreased Cdk2 activity. Promoter deletion analysis, electrophoresis mobility shift assays, and chromatin immunoprecipitation studies identified the functional Ets DNA binding site at −2118 bp of the p21/CIP1 gene promoter. This site is capable of binding and responding to PDEF. Furthermore, we silenced p21/CIP1 expression in PDEF-overexpressing cells by small interfering RNA. p21-silenced PDEF cells exhibited significantly increased cell growth in vitro and in vivo, demonstrating the p21 regulation by PDEF as a key player. These experiments identified PDEF as a new transcription factor that directly regulates p21/CIP1 expression under non-stressed conditions. This study conclusively proves that PDEF is a breast tumor suppressor for

  12. A new immunization and treatment strategy for mouse mammary tumor virus (MMTV) associated cancers

    PubMed Central

    Braitbard, Ori; Roniger, Maayan; Bar-Sinai, Allan; Rajchman, Dana; Gross, Tamar; Abramovitch, Hillel; Ferla, Marco La; Franceschi, Sara; Lessi, Francesca; Naccarato, Antonio Giuseppe; Mazzanti, Chiara M.; Bevilacqua, Generoso; Hochman, Jacob

    2016-01-01

    Mouse Mammary Tumor Virus (MMTV) causes mammary carcinoma or lymphoma in mice. An increasing body of evidence in recent years supports its involvement also in human sporadic breast cancer. It is thus of importance to develop new strategies to impair the development, growth and metastasis of MMTV-associated cancers. The signal peptide of the envelope precursor protein of this virus: MMTV-p14 (p14) is an excellent target for such strategies, due to unique characteristics distinct from its regular endoplasmic reticulum targeting function. These include cell surface expression in: murine cancer cells that harbor the virus, human breast cancer (MCF-7) cells that ectopically express p14, as well as cultured human cells derived from an invasive ductal breast carcinoma positive for MMTV sequences. These findings support its use in signal peptide-based immune targeting. Indeed, priming and boosting mice with p14 elicits a specific anti-signal peptide immune response sufficient for protective vaccination against MMTV-associated tumors. Furthermore, passive immunization using a combination of anti-p14 monoclonal antibodies or the transfer of T-cells from immunized mice (Adoptive Cell Transfer) is also therapeutically effective. With reports demonstrating involvement of MMTV in human breast cancer, we propose the immune-mediated targeting of p14 as a strategy for prevention, treatment and diagnosis of MMTV-associated cancers. PMID:26934560

  13. Hypoxia Up-Regulates Galectin-3 in Mammary Tumor Progression and Metastasis.

    PubMed

    de Oliveira, Joana T; Ribeiro, Cláudia; Barros, Rita; Gomes, Catarina; de Matos, Augusto J; Reis, Celso A; Rutteman, Gerard R; Gärtner, Fátima

    2015-01-01

    The tumor microenvironment encompasses several stressful conditions for cancer cells such as hypoxia, oxidative stress and pH alterations. Galectin-3, a well-studied member of the beta-galactoside-binding animal family of lectins has been implicated in multiple steps of metastasis as cell-cell and cell-ECM adhesion, promotion of angiogenesis, cell proliferation and resistance to apoptosis. However, both its aberrantly up- and down-regulated expression was observed in several types of cancer. Thus, the mechanisms that regulate galectin-3 expression in neoplastic settings are not clear. In order to demonstrate the putative role of hypoxia in regulating galectin-3 expression in canine mammary tumors (CMT), in vitro and in vivo studies were performed. In malignant CMT cells, hypoxia was observed to induce expression of galectin-3, a phenomenon that was almost completely prevented by catalase treatment of CMT-U27 cells. Increased galectin-3 expression was confirmed at the mRNA level. Under hypoxic conditions the expression of galectin-3 shifts from a predominant nuclear location to cytoplasmic and membrane expressions. In in vivo studies, galectin-3 was overexpressed in hypoxic areas of primary tumors and well-established metastases. Tumor hypoxia thus up-regulates the expression of galectin-3, which may in turn increase tumor aggressiveness.

  14. Roles of the transcription factors snail and slug during mammary morphogenesis and breast carcinoma progression

    PubMed Central

    Côme, Christophe; Arnoux, Valérie; Bibeau, Frédéric; Savagner, Pierre

    2004-01-01

    The zinc-finger transcription factors snail and slug are involved in different processes controlling cell differentiation and apoptosis. They appear to be involved in tumor progression. Their putative involvement in mammary gland development has not been specifically examined so far. Slug is expressed at a significant level in normal breast and indirect evidence suggests it could be implicated in tubulogenesis. As an anti-apoptotic agent, it could also protect epithelial cells from death during ductal lumen formation and during breast involution. In breast carcinomas, Snail transcription factors have been linked to tumor progression and invasiveness. Possible mechanisms include repression of E-cadherin gene by snail or slug. However, it is not clear how this transcriptional activity is implicated in vivo. Other possible mechanisms involve maintenance of plastic phenotype by slug that could participate in local invasion of ductal carcinomas and interference with apoptotic pathways that could contribute to global tumor growth and radioresistance. These processes probably also involve interactions with estrogen, EGF or c-kit pathways. PMID:15300012

  15. c-Jun N-terminal kinase 2 prevents luminal cell commitment in normal mammary glands and tumors by inhibiting p53/Notch1 and breast cancer gene 1 expression

    PubMed Central

    Pfefferle, Adam D.; Perou, Charles M.; Van Den Berg, Carla Lynn

    2015-01-01

    Breast cancer is a heterogeneous disease with several subtypes carrying unique prognoses. Patients with differentiated luminal tumors experience better outcomes, while effective treatments are unavailable for poorly differentiated tumors, including the basal-like subtype. Mechanisms governing mammary tumor subtype generation could prove critical to developing better treatments. C-Jun N-terminal kinase 2 (JNK2) is important in mammary tumorigenesis and tumor progression. Using a variety of mouse models, human breast cancer cell lines and tumor expression data, studies herein support that JNK2 inhibits cell differentiation in normal and cancer-derived mammary cells. JNK2 prevents precocious pubertal mammary development and inhibits Notch-dependent expansion of luminal cell populations. Likewise, JNK2 suppresses luminal populations in a p53-competent Polyoma Middle T-antigen tumor model where jnk2 knockout causes p53-dependent upregulation of Notch1 transcription. In a p53 knockout model, JNK2 restricts luminal populations independently of Notch1, by suppressing Brca1 expression and promoting epithelial to mesenchymal transition. JNK2 also inhibits estrogen receptor (ER) expression and confers resistance to fulvestrant, an ER inhibitor, while stimulating tumor progression. These data suggest that therapies inhibiting JNK2 in breast cancer may promote tumor differentiation, improve endocrine therapy response, and inhibit metastasis. PMID:25970777

  16. c-Jun N-terminal kinase 2 prevents luminal cell commitment in normal mammary glands and tumors by inhibiting p53/Notch1 and breast cancer gene 1 expression.

    PubMed

    Cantrell, Michael A; Ebelt, Nancy D; Pfefferle, Adam D; Perou, Charles M; Van Den Berg, Carla Lynn

    2015-05-20

    Breast cancer is a heterogeneous disease with several subtypes carrying unique prognoses. Patients with differentiated luminal tumors experience better outcomes, while effective treatments are unavailable for poorly differentiated tumors, including the basal-like subtype. Mechanisms governing mammary tumor subtype generation could prove critical to developing better treatments. C-Jun N-terminal kinase 2 (JNK2) is important in mammary tumorigenesis and tumor progression. Using a variety of mouse models, human breast cancer cell lines and tumor expression data, studies herein support that JNK2 inhibits cell differentiation in normal and cancer-derived mammary cells. JNK2 prevents precocious pubertal mammary development and inhibits Notch-dependent expansion of luminal cell populations. Likewise, JNK2 suppresses luminal populations in a p53-competent Polyoma Middle T-antigen tumor model where jnk2 knockout causes p53-dependent upregulation of Notch1 transcription. In a p53 knockout model, JNK2 restricts luminal populations independently of Notch1, by suppressing Brca1 expression and promoting epithelial to mesenchymal transition. JNK2 also inhibits estrogen receptor (ER) expression and confers resistance to fulvestrant, an ER inhibitor, while stimulating tumor progression. These data suggest that therapies inhibiting JNK2 in breast cancer may promote tumor differentiation, improve endocrine therapy response, and inhibit metastasis.

  17. Fingerprinting Breast Cancer vs. Normal Mammary Cells by Mass Spectrometric Analysis of Volatiles

    PubMed Central

    He, Jingjing; Sinues, Pablo Martinez-Lozano; Hollmén, Maija; Li, Xue; Detmar, Michael; Zenobi, Renato

    2014-01-01

    There is increasing interest in the development of noninvasive diagnostic methods for early cancer detection, to improve the survival rate and quality of life of cancer patients. Identification of volatile metabolic compounds may provide an approach for noninvasive early diagnosis of malignant diseases. Here we analyzed the volatile metabolic signature of human breast cancer cell lines versus normal human mammary cells. Volatile compounds in the headspace of conditioned culture medium were directly fingerprinted by secondary electrospray ionization-mass spectrometry. The mass spectra were subsequently treated statistically to identify discriminating features between normal vs. cancerous cell types. We were able to classify different samples by using feature selection followed by principal component analysis (PCA). Additionally, high-resolution mass spectrometry allowed us to propose their chemical structures for some of the most discriminating molecules. We conclude that cancerous cells can release a characteristic odor whose constituents may be used as disease markers. PMID:24903350

  18. Fingerprinting Breast Cancer vs. Normal Mammary Cells by Mass Spectrometric Analysis of Volatiles

    NASA Astrophysics Data System (ADS)

    He, Jingjing; Sinues, Pablo Martinez-Lozano; Hollmén, Maija; Li, Xue; Detmar, Michael; Zenobi, Renato

    2014-06-01

    There is increasing interest in the development of noninvasive diagnostic methods for early cancer detection, to improve the survival rate and quality of life of cancer patients. Identification of volatile metabolic compounds may provide an approach for noninvasive early diagnosis of malignant diseases. Here we analyzed the volatile metabolic signature of human breast cancer cell lines versus normal human mammary cells. Volatile compounds in the headspace of conditioned culture medium were directly fingerprinted by secondary electrospray ionization-mass spectrometry. The mass spectra were subsequently treated statistically to identify discriminating features between normal vs. cancerous cell types. We were able to classify different samples by using feature selection followed by principal component analysis (PCA). Additionally, high-resolution mass spectrometry allowed us to propose their chemical structures for some of the most discriminating molecules. We conclude that cancerous cells can release a characteristic odor whose constituents may be used as disease markers.

  19. THE IMPORTANCE OF CLINICAL AND INSTRUMENTAL DIAGNOSTIC IN THE MAMMARY GLAND CANCER.

    PubMed

    Anton, E; Botnariuc, Natalia; Ancuta, E; Doroftei, B; Ciobica, A; Anton, Carmen

    2015-01-01

    Breast cancer is the most common oncology disease in women and is one of the major public health issues. Worldwide, is the second leading cause of cancer death in women and cancer research is a priority in all the laboratories of the world, in terms of uncovering the appearance causes of the malignant process, understanding the mechanisms of development, but most of all, the discovery of early diagnostic methods and effective treatment. Ignorance, fear of diagnosis, lack of health education and of efficient programmes for prevention and screening could cause diagnosis of the disease to be detected in the majority of cases in advanced stages, when treatment remains only palliative and very costly, in this cases the patient's suffering being immense. In this way, regarding the clinical diagnosis in stage I mammary gland cancer, in the 496 stage I MGC patients, during the primary clinical investigation the diagnosis of stage I MGC was established only in 165 (33.3%) patients, and in 232 (46,8%) patients the diagnosis of suspicion MGC was obtained. Also, in terms of instrumental diagnosis, such as mammography, ultrasonography in mammary gland cancer stage I, it seems that in accordance with literature data the pathological process features assessment in the mammary gland is problematic especially in young age. Thus, it seems that MGC represents a polymorphic and pathogenic disease and it cannot be admitted that all subgroups of patients will obtain identical results from one tactic of treatment determined for all the patients with MGC. In this way, the concept of MGC both clinical and patho morphological, combines different cell clones depending on its microstructure and biology. As a result, the evolution of the disease, the prognosis and the effectiveness of the treatment may vary in different patients at the same stage, depending on the degree of malignancy of the tumor, its histopathological structure, the degree of expression of molecular markers identification

  20. Canine Mammary Cancer Stem Cells are Radio- and Chemo- Resistant and Exhibit an Epithelial-Mesenchymal Transition Phenotype.

    PubMed

    Pang, Lisa Y; Cervantes-Arias, Alejandro; Else, Rod W; Argyle, David J

    2011-03-30

    Canine mammary carcinoma is the most common cancer among female dogs and is often fatal due to the development of distant metastases. In humans, solid tumors are made up of heterogeneous cell populations, which perform different roles in the tumor economy. A small subset of tumor cells can hold or acquire stem cell characteristics, enabling them to drive tumor growth, recurrence and metastasis. In veterinary medicine, the molecular drivers of canine mammary carcinoma are as yet undefined. Here we report that putative cancer stem cells (CSCs) can be isolated form a canine mammary carcinoma cell line, REM134. We show that these cells have an increased ability to form tumorspheres, a characteristic of stem cells, and that they express embryonic stem cell markers associated with pluripotency. Moreover, canine CSCs are relatively resistant to the cytotoxic effects of common chemotherapeutic drugs and ionizing radiation, indicating that failure of clinical therapy to eradicate canine mammary cancer may be due to the survival of CSCs. The epithelial to mesenchymal transition (EMT) has been associated with cancer invasion, metastasis, and the acquisition of stem cell characteristics. Our results show that canine CSCs predominantly express mesenchymal markers and are more invasive than parental cells, indicating that these cells have a mesenchymal phenotype. Furthermore, we show that canine mammary cancer cells can be induced to undergo EMT by TGFβ and that these cells have an increased ability to form tumorspheres. Our findings indicate that EMT induction can enrich for cells with CSC properties, and provide further insight into canine CSC biology.

  1. Dietary effects of mead acid on N-methyl-N-nitrosourea-induced mammary cancers in female Sprague-Dawley rats.

    PubMed

    Kinoshita, Yuichi; Yoshizawa, Katsuhiko; Hamazaki, Kei; Emoto, Yuko; Yuri, Takashi; Yuki, Michiko; Kawashima, Hiroshi; Shikata, Nobuaki; Tsubura, Airo

    2016-01-01

    The effect of mead acid (MA; 5,8,11-eicosatrienoic acid) on the suppression of the development and growth of N-methyl-N-nitrosourea (MNU)-induced mammary cancer in female Sprague-Dawley rats was examined. The MA diet (2.4% MA) or control (CTR) diet (0% MA) was started at 6 weeks of age, MNU was injected intraperitoneally at 7 weeks of age, and the rats were maintained on the respective diets for the whole experimental period (until 19 weeks of age). All induced mammary tumors were luminal A subtype carcinomas (estrogen and progesterone receptor positive and HER2/neu negative). The MA diet significantly suppressed the initiation and promotion phases of mammary carcinogenesis; MA suppressed the development (incidence, 61.5 vs. 100%; multiplicity, 2.1 vs. 4.5) and the growth (final tumor weight, 427.1 vs. 1,796.3 mg) of mammary cancers by suppressing cell proliferation, but not by accelerating cell death. There were evident changes in the major fatty acid composition of n-3, n-6, and n-9 fatty acids in the serum of the MA diet group; there was a significant increase in MA and significant decreases in oleic acid (OA), linoleic acid, arachidonic acid and docosahexaenoic acid. In non-tumorous mammary tissue, there was a significant increase in MA and a significant decrease in OA in the MA diet group. The n-6/n-3 ratios in serum and mammary tissue of the MA diet group were significantly decreased. The MA diet suppressed MNU-induced luminal A mammary cancer by lowering cancer cell proliferation. Therefore, MA may be a chemopreventive and chemotherapeutic agent. In addition to hormone therapy, MA supplementation may be a beneficial chemotherapeutic agent for the luminal A subtype of breast cancer.

  2. Genetic Mapping in Mice Identifies DMBT1 as a Candidate Modifier of Mammary Tumors and Breast Cancer Risk

    PubMed Central

    Blackburn, Anneke C.; Hill, Linda Z.; Roberts, Amy L.; Wang, Jun; Aud, Dee; Jung, Jimmy; Nikolcheva, Tania; Allard, John; Peltz, Gary; Otis, Christopher N.; Cao, Qing J.; Ricketts, Reva St. J.; Naber, Stephen P.; Mollenhauer, Jan; Poustka, Annemarie; Malamud, Daniel; Jerry, D. Joseph

    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 ∼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 of the susceptible BALB/c mice. Immunohistochemical staining demonstrated that DMBT1 protein expression was also significantly reduced in normal breast tissue from women with breast cancer (staining score, 1.8; n = 46) compared with cancer-free controls (staining score, 3.9; n = 53; P < 0.0001). These experiments demonstrate the use of Trp53+/− mice as a sensitized background to screen for low-penetrance modifiers of cancer. The results identify a novel mammary tumor susceptibility locus in mice and support a role for DMBT1 in suppression of mammary tumors in both mice and women. PMID:17525270

  3. Radiogenic neoplasia in thyroid and mammary clonogens. Final progress report, 1 January 1987--31 December 1997

    SciTech Connect

    Clifton, K.H.

    1998-07-10

    The induction of cancer by ionizing radiation is a matter of great practical importance to the nuclear industry, to national defense, to radiological medicine and to the general public. It is increasingly apparent that carcinogenesis is a leading dose-limiting effect of radiation exposure. The thyroid and mammary glands are among the most sensitive human tissues to radiogenic initiation of cancer, and there is a profoundly higher risk of neoplastic initiation in these glands among individuals irradiated before or during puberty than among those exposed in later life. The authors developed unique quantitative experimental models to investigate and characterize the cells of origin of thyroid and mammary cancers and the effects of radiation on them (C185). To study these progenitor cells in vivo it is necessary to have a system by which their concentrations, total numbers and responses to radiation and other factors can be measured. It is a truism that not all cells in a tissue are equally sensitive to neoplastic initiation. They reasoned that the progenitor cells are most likely members of that subpopulation that is necessary to maintenance of normal tissue cell numbers and to repair and replacement after tissue damage. They further reasoned that such cells would likely be responsive to specific mitogenic stimulation by hormones. On the basis of these considerations, they developed quantitative rat thyroid and mammary epithelial cell transplantation systems.

  4. Trans-Resveratrol Alters Mammary Promoter Hypermethylation in Women at Increased Risk for Breast Cancer

    PubMed Central

    Zhu, Weizhu; Qin, Wenyi; Zhang, Ke; Rottinghaus, George E.; Chen, Yin-Chieh; Kliethermes, Beth; Sauter, Edward R.

    2012-01-01

    Trans-resveratrol, present in high concentration in the skin of red grapes and red wine, has a dose-dependent antiproliferative effect in vitro, prevents the formation of mammary tumors, and has been touted as a chemopreventive agent. Based upon in vitro studies demonstrating that trans-resveratrol downregulates the expression of 1) DNA methyltransferases and 2) the cancer promoting prostaglandin (PG)E2, we determined if trans-resveratrol had a dose-related effect on DNA methylation and prostaglandin expression in humans. Thirty-nine adult women at increased breast cancer risk were randomized in double-blind fashion to placebo, 5 or 50 mg trans-resveratrol twice daily for 12 wk. Methylation assessment of 4 cancer-related genes (p16, RASSF-1α, APC, CCND2) was performed on mammary ductoscopy specimens. The predominant resveratrol species in serum was the glucuronide metabolite. Total trans-resveratrol and glucuronide metabolite serum levels increased after consuming both trans-resveratrol doses (P < .001 for both). RASSF-1α methylation decreased with increasing levels of serum trans-resveratrol (P = .047). The change in RASSF-1α methylation was directly related to the change in PGE2 (P = .045). This work provides novel insights into the effects of trans-resveratrol on the breast of women at increased breast cancer risk, including a decrease in methylation of the tumor suppressor gene RASSF-1α. Because of the limited sample size, our findings should be validated in a larger study. PMID:22332908

  5. Cytokine networks that mediate epithelial cell-macrophage crosstalk in the mammary gland: implications for development and cancer.

    PubMed

    Sun, Xuan; Ingman, Wendy V

    2014-07-01

    Dynamic interactions between the hormone responsive mammary gland epithelium and surrounding stromal macrophage populations are critical for normal development and function of the mammary gland. Macrophages are versatile cells capable of diverse roles in mammary gland development and maintenance of homeostasis, and their function is highly dependent on signals within the local cytokine microenvironment. The mammary epithelium secretes a number of cytokines, including colony stimulating factor 1 (CSF1), transforming growth factor beta 1 (TGFB1), and chemokine ligand 2 (CCL2) that affect the abundance, phenotype and function of macrophages. However, aberrations in these interactions have been found to increase the risk of tumour formation, and utilisation of stromal macrophage support by tumours can increase the invasive and metastatic potential of the cancer. Studies utilising genetically modified mouse models have shed light on the significance of epithelial cell-macrophage crosstalk, and the cytokines that mediate this communication, in mammary gland development and tumourigenesis. This article reviews the current status of our understanding of the roles of epithelial cell-derived cytokines in mammary gland development and cancer, with a focus on the crosstalk between epithelial cells and the local macrophage population.

  6. The T-box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer.

    PubMed

    Douglas, Nataki C; Papaioannou, Virginia E

    2013-06-01

    TBX2 and TBX3, closely related members of the T-box family of transcription factor genes, are expressed in mammary tissue in both humans and mice. Ulnar mammary syndrome (UMS), an autosomal dominant disorder caused by mutations in TBX3, underscores the importance of TBX3 in human breast development, while abnormal mammary gland development in Tbx2 or Tbx3 mutant mice provides models for experimental investigation. In addition to their roles in mammary development, aberrant expression of TBX2 and TBX3 is associated with breast cancer. TBX2 is preferentially amplified in BRCA1/2-associated breast cancers and TBX3 overexpression has been associated with advanced stage disease and estrogen-receptor-positive breast tumors. The regulation of Tbx2 and Tbx3 and the downstream targets of these genes in development and disease are not as yet fully elucidated. However, it is clear that the two genes play unique, context-dependent roles both in mammary gland development and in mammary tumorigenesis.

  7. Genetic bases of estrogen-induced tumorigenesis in the rat: mapping of loci controlling susceptibility to mammary cancer in a Brown Norway x ACI intercross.

    PubMed

    Schaffer, Beverly S; Lachel, Cynthia M; Pennington, Karen L; Murrin, Clare R; Strecker, Tracy E; Tochacek, Martin; Gould, Karen A; Meza, Jane L; McComb, Rodney D; Shull, James D

    2006-08-01

    Exposure to estrogens is associated with an increased risk of breast cancer. Our laboratory has shown that the ACI rat is uniquely susceptible to 17beta-estradiol (E2)-induced mammary cancer. We previously mapped two loci, Emca1 and Emca2 (estrogen-induced mammary cancer), that act independently to determine susceptibility to E2-induced mammary cancer in crosses between the susceptible ACI rat strain and the genetically related, but resistant, Copenhagen (COP) rat strain. In this study, we evaluate susceptibility to E2-induced mammary cancer in a cross between the ACI strain and the unrelated Brown Norway (BN) rat strain. Whereas nearly 100% of the ACI rats developed mammary cancer when treated continuously with E2, BN rats did not develop palpable mammary cancer during the 196-day course of E2 treatment. Susceptibility to E2-induced mammary cancer segregated as a dominant or incompletely dominant trait in a cross between BN females and ACI males. In a population of 251 female (BN x ACI)F(2) rats, we observed evidence for a total of five genetic determinants of susceptibility. Two loci, Emca4 and Emca5, were identified when mammary cancer status at sacrifice was evaluated as the phenotype, and three additional loci, Emca6, Emca7, and Emca8, were identified when mammary cancer number was evaluated as the phenotype. A total of three genetic interactions were identified. These data indicate that susceptibility to E2-induced mammary cancer in the BN x ACI cross behaves as a complex trait controlled by at least five loci and multiple gene-gene interactions.

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

    PubMed

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

    2011-04-01

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

  9. Repression of mammary adipogenesis by genistein limits mammosphere formation of human MCF-7 cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mammary adipose tissue may contribute to breast cancer development and progression by altering neighboring epithelial cell behavior and phenotype through paracrine signaling. Dietary exposure to soy foods is associated with lower mammary tumor risk and reduced body weight and adiposity in humans and...

  10. Murine Models of Breast Cancer: Assessment of the Role of c-Src in Mammary Tumorigenesis

    DTIC Science & Technology

    2004-10-01

    luc) as shown along with the HSV -TK-Renilla-luciferase reporter (A to E). The fold activation for NFAT-and AP- 1 -firefly-luciferase and actual...Vo AD Award Number: DAMD17-99- 1 -9151 TITLE: Murine Models of Breast Cancer: Assessment of the Role of c-Src in Mammary Tumorigenesis PRINCIPAL...PAGE OMB No. 074-0188 Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for

  11. Is internal mammary nodes irradiation as a part of breast cancer postoperative radiotherapy necessary?

    PubMed Central

    Zhou, Zhi-Rui; Yang, Zhao-Zhi

    2016-01-01

    Postoperative radiotherapy plays an important role in the multidisciplinary treatment of breast cancer. However, it remains a controversy whether it is necessary to carry out prophylactic internal mammary nodes irradiation (IMNI). This review will focus on this topic. In our opinion, the total risk of relapse should be considered during the decision-making on IMNI; in particular, IMNI is recommended for high-risk patients whose tumor is located at the central/medial area or in patients with positive axillary lymph nodes. PMID:28066623

  12. Mammary stem cells and parity-induced breast cancer protection- new insights.

    PubMed

    Dall, Genevieve; Risbridger, Gail; Britt, Kara

    2016-02-22

    Parity (childbearing) significantly decreases a woman's risk of breast cancer and the protective effect is greater if the woman is younger and has more children. The mechanism/s of parity-induced protection are not known. Although several factors are postulated to play a role, we discuss how a reduction in the number of mammary stem cells (MaSCs) may lead to a reduction in breast cancer risk in parous women. Firstly we review the epidemiology linking childbearing to reduced breast cancer risk and discuss how additional births, a young age at first full term birth, and breastfeeding impact the protection. We then detail the mouse and human studies implicating MaSC in parity induced protection and the in-vivo work being performed in mice to directly investigate the effect of parity on MaSC. Finally we discuss the transplant and lineage tracing experiments assessing MaSC activity according to parity and the need to define if MaSC are indeed more carcinogen sensitive than mature mammary epithelial cells. Continuing and future studies attempting to define the parity induced mechanisms will aid in the development of preventative therapies.

  13. Stage-specific embryonic antigen: determining expression in canine glioblastoma, melanoma, and mammary cancer cells

    PubMed Central

    Ito, Daisuke

    2017-01-01

    The expression of stage-specific embryonic antigens (SSEAs) was determined in several types of canine cancer cells. Flow cytometry showed SSEA-1 expression in glioblastoma, melanoma, and mammary cancer cells, although none expressed SSEA-3 or SSEA-4. Expression of SSEA-1 was not detected in lymphoma, osteosarcoma, or hemangiosarcoma cell lines. Relatively stable SSEA-1 expression was observed between 24 and 72 h of culture. After 8 days in culture, sorted SSEA-1− and SSEA-1+ cells re-established SSEA-1 expression to levels comparable to those observed in unsorted cells. Our results document, for the first time, the expression of SSEA-1 in several canine cancer cell lines. PMID:27456773

  14. From milk to malignancy: the role of mammary stem cells in development, pregnancy and breast cancer.

    PubMed

    Tiede, Benjamin; Kang, Yibin

    2011-02-01

    Adult stem cells of the mammary gland (MaSCs) are a highly dynamic population of cells that are responsible for the generation of the gland during puberty and its expansion during pregnancy. In recent years significant advances have been made in understanding how these cells are regulated during these developmentally important processes both in humans and in mice. Understanding how MaSCs are regulated is becoming a particularly important area of research, given that they may be particularly susceptible targets for transformation in breast cancer. Here, we summarize the identification of MaSCs, how they are regulated and the evidence for their serving as the origins of breast cancer. In particular, we focus on how changes in MaSC populations may explain both the increased risk of developing aggressive ER/PR(-) breast cancer shortly after pregnancy and the long-term decreased risk of developing ER/PR(+) tumors.

  15. Aldehyde dehydrogenase activity in cancer stem cells from canine mammary carcinoma cell lines.

    PubMed

    Michishita, M; Akiyoshi, R; Suemizu, H; Nakagawa, T; Sasaki, N; Takemitsu, H; Arai, T; Takahashi, K

    2012-08-01

    Increasing evidence suggests that diverse solid tumours arise from a small population of cells known as cancer stem cells or tumour-initiating cells. Cancer stem cells in several solid tumours are enriched for aldehyde dehydrogenase (ALDH) activity. High levels of ALDH activity (ALDH(high)) were detected in four cell lines derived from canine mammary carcinomas. ALDH(high) cells were enriched in a CD44(+)CD24(-) population having self-renewal capacity. Xenotransplantation into immunodeficient mice demonstrated that 1×10(4) ALDH(high) cells were sufficient for tumour formation in all injected mice, whereas 1×10(4) ALDH(low) cells failed to initiate any tumours. ALDH(high)-derived tumours contained both ALDH(+) and ALDH(-) cells, indicating that these cells had cancer stem cell-like properties.

  16. Alcohol drinking and mammary cancer: Pathogenesis and potential dietary preventive alternatives.

    PubMed

    Castro, Gerardo Daniel; Castro, José A

    2014-10-10

    Alcohol consumption is associated with an increased risk of breast cancer, increasing linearly even with a moderate consumption and irrespectively of the type of alcoholic beverage. It shows no dependency from other risk factors like menopausal status, oral contraceptives, hormone replacement therapy, or genetic history of breast cancer. The precise mechanism for the effect of drinking alcohol in mammary cancer promotion is still far from being established. Studies by our laboratory suggest that acetaldehyde produced in situ and accumulated in mammary tissue because of poor detoxicating mechanisms might play a role in mutational and promotional events. Additional studies indicated the production of reactive oxygen species accompanied of decreases in vitamin E and GSH contents and of glutathione transferase activity. The resulting oxidative stress might also play a relevant role in several stages of the carcinogenic process. There are reported in literature studies showing that plasmatic levels of estrogens significantly increased after alcohol drinking and that the breast cancer risk is higher in receptor ER-positive individuals. Estrogens are known that they may produce breast cancer by actions on ER and also as chemical carcinogens, as a consequence of their oxidation leading to reactive metabolites. In this review we introduce our working hypothesis integrating the acetaldehyde and the oxidative stress effects with those involving increased estrogen levels. We also analyze potential preventive actions that might be accessible. There remains the fact that alcohol drinking is just one of the avoidable causes of breast cancer and that, at present, the suggested acceptable dose for prevention of this risk is of one drink per day.

  17. Trypanosoma cruzi extracts elicit protective immune response against chemically induced colon and mammary cancers.

    PubMed

    Ubillos, Luis; Freire, Teresa; Berriel, Edgardo; Chiribao, María Laura; Chiale, Carolina; Festari, María Florencia; Medeiros, Andrea; Mazal, Daniel; Rondán, Mariella; Bollati-Fogolín, Mariela; Rabinovich, Gabriel A; Robello, Carlos; Osinaga, Eduardo

    2016-04-01

    Trypanosoma cruzi, the protozoan parasite that causes Chagas' disease, has anticancer effects mediated, at least in part, by parasite-derived products which inhibit growth of tumor cells. We investigated whether immunity to T. cruzi antigens could induce antitumor activity, using two rat models which reproduce human carcinogenesis: colon cancer induced by 1,2-dimethylhydrazine (DMH), and mammary cancer induced by N-nitroso-N-methylurea (NMU). We found that vaccination with T. cruzi epimastigote lysates strongly inhibits tumor development in both animal models. Rats immunized with T. cruzi antigens induce activation of both CD4(+) and CD8(+) T cells and splenocytes from these animals showed higher cytotoxic responses against tumors as compared to rats receiving adjuvant alone. Tumor-associated immune responses included increasing number of CD11b/c(+) His48(-) MHC II(+) cells corresponding to macrophages and/or dendritic cells, which exhibited augmented NADPH-oxidase activity. We also found that T. cruzi lysate vaccination developed antibodies specific for colon and mammary rat cancer cells, which were capable of mediating antibody-dependent cellular cytotoxicity (ADCC) in vitro. Anti-T. cruzi antibodies cross-reacted with human colon and breast cancer cell lines and recognized 41/60 (68%) colon cancer and 38/63 (60%) breast cancer samples in a series of 123 human tumors. Our results suggest that T. cruzi antigens can evoke an integrated antitumor response involving both the cellular and humoral components of the immune response and provide novel insights into the understanding of the intricate relationship between parasite infection and tumor growth.

  18. Alcohol drinking and mammary cancer: Pathogenesis and potential dietary preventive alternatives

    PubMed Central

    Castro, Gerardo Daniel; Castro, José A

    2014-01-01

    Alcohol consumption is associated with an increased risk of breast cancer, increasing linearly even with a moderate consumption and irrespectively of the type of alcoholic beverage. It shows no dependency from other risk factors like menopausal status, oral contraceptives, hormone replacement therapy, or genetic history of breast cancer. The precise mechanism for the effect of drinking alcohol in mammary cancer promotion is still far from being established. Studies by our laboratory suggest that acetaldehyde produced in situ and accumulated in mammary tissue because of poor detoxicating mechanisms might play a role in mutational and promotional events. Additional studies indicated the production of reactive oxygen species accompanied of decreases in vitamin E and GSH contents and of glutathione transferase activity. The resulting oxidative stress might also play a relevant role in several stages of the carcinogenic process. There are reported in literature studies showing that plasmatic levels of estrogens significantly increased after alcohol drinking and that the breast cancer risk is higher in receptor ER-positive individuals. Estrogens are known that they may produce breast cancer by actions on ER and also as chemical carcinogens, as a consequence of their oxidation leading to reactive metabolites. In this review we introduce our working hypothesis integrating the acetaldehyde and the oxidative stress effects with those involving increased estrogen levels. We also analyze potential preventive actions that might be accessible. There remains the fact that alcohol drinking is just one of the avoidable causes of breast cancer and that, at present, the suggested acceptable dose for prevention of this risk is of one drink per day. PMID:25300769

  19. Anticancer Potential of Nutraceutical Formulations in MNU-induced Mammary Cancer in Sprague Dawley Rats

    PubMed Central

    Pitchaiah, Gummalla; Akula, Annapurna; Chandi, Vishala

    2017-01-01

    Background: Nutraceuticals help in combating some of the major health problems of the century including cancer, and ‘nutraceutical formulations’ have led to the new era of medicine and health. Objective: To develop different nutraceutical formulations and to assess the anticancer potential of nutraceutical formulations in N-methyl-N-nitrosourea (MNU)-induced mammary cancer in Sprague Dawley rats. Materials and Methods: Different nutraceutical formulations were prepared using fine powders of amla, apple, garlic, onion, papaya, turmeric, and wheat grass with and without cow urine distillate. Total phenolic content, acute oral toxicity, and microbial load of nutraceutical formulations were assessed. The anticancer potential of nutraceutical formulations was evaluated against MNU-induced mammary cancer in female Sprague Dawley rats. Results: Improvement in total phenolic content was significant (P < 0.001) after self-fortification process. Toxicity studies showed that the nutraceutical formulations were safe to use in animals. Microbial load was within the limits. Significant longer tumor-free days (P < 0.01), lower tumor incidence (P < 0.01), lower tumor multiplicity (P < 0.05) and tumor burden (P < 0.01) were observed for nutraceutical formulation-treated groups. Conclusion: Combination of whole food-based nutraceuticals acted synergistically in the prevention of mammary cancer. Further, the process of fortification is novel and enhanced the anticancer potential of nutraceutical formulations. SUMMARY Nutraceuticals help in combating some of the major health problems of the century including cancer, and ‘nutraceutical formulations’ have led to the new era of medicine and health. In this study, different nutraceutical formulations using fine powders of amla, apple, garlic, onion, papaya, turmeric, and wheat grass with and without cow urine distillate. Total phenolic content, acute oral toxicity, and microbial load of nutraceutical formulations were assessed

  20. Protein kinase Cδ is required for ErbB2-driven mammary gland tumorigenesis and negatively correlates with prognosis in human breast cancer.

    PubMed

    Allen-Petersen, B L; Carter, C J; Ohm, A M; Reyland, M E

    2014-03-06

    Protein kinase C δ (PKCδ) regulates apoptosis in the mammary gland, however, the functional contribution of PKCδ to the development or progression of breast cancer has yet to be determined. Meta-analysis of ErbB2-positive breast cancers shows increased PKCδ expression, and a negative correlation between PKCδ expression and prognosis. Here, we present in-vivo evidence that PKCδ is essential for the development of mammary gland tumors in a ErbB2-overexpressing transgenic mouse model, and in-vitro evidence that PKCδ is required for proliferative signaling downstream of the ErbB2 receptor. Mouse mammary tumor virus (MMTV)-ErbB2 mice lacking PKCδ (δKO) have increased tumor latency compared with MMTV-ErbB2 wild-type (δWT) mice, and the tumors show a dramatic decrease in Ki-67 staining. To explore the relationship between PKCδ and ErbB2-driven proliferation more directly, we used MCF-10A cells engineered to express a synthetic ligand-inducible form of the ErbB2 receptor. Depletion of PKCδ with short hairpin RNA inhibited ligand-induced growth in both two-dimensional (2D) (plastic) and three-dimensional (3D) (Matrigel) culture, and correlated with decreased phosphorylation of the ErbB2 receptor and reduced activation of Src and MAPK/ERK pathways. Similarly, in human breast cancer cell lines in which ErbB2 is overexpressed, depletion of PKCδ suppresses proliferation, Src and ERK activation. PKCδ appears to drive proliferation through the formation of an active ErbB2/PKCδ/Src signaling complex, as depletion of PKCδ disrupts association of Src with the ErbB2 receptor. Taken together, our studies present the first evidence that PKCδ is a critical regulator of ErbB2-mediated tumorigenesis, and suggest further investigation of PKCδ as a target in ErbB2-positive breast cancer.

  1. Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer

    PubMed Central

    2011-01-01

    Background Several studies have demonstrated that sites of chronic inflammation are often associated with the establishment and growth of various malignancies. A common inflammatory condition in humans is autoimmune arthritis (AA). Although AA and cancer are different diseases, many of the underlying processes that contribute to the disorders of the joints and connective tissue that characterize AA also affect cancer progression and metastasis. Systemically, AA can lead to cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge being available, there has been minimal research linking breast cancer, arthritis, and metastasis associated with breast cancer. Notably both diseases are extremely prevalent in older post-menopausal women. Methods To establish the novel link between arthritis induced inflammation and secondary metastasis associated with breast cancer, PyV MT mice that spontaneously develop mammary gland carcinoma were injected with Type II collagen (CII) to induce arthritis at 9 and 18 weeks of age for pre-metastatic and metastatic condition. The sites of secondary metastasis and the associated inflammatory microenvironment were evaluated. Results A significant increase in breast cancer-associated secondary metastasis to the lungs and bones was observed in the arthritic versus the non-arthritic PyV MT mice along with an increase in primary tumor burden. We report significant increases in the levels of interstitial cellular infiltrates and pro-inflammatory cytokines such as interleukin-17 (IL-17), interleukin-6 (IL-6), Pro- Matrix metallopeptidase 9 (Pro-MMP9), insulin like growth factor-II (GF-II) and macrophage colony stimulating factor (M-CSF) in the arthritic lung and bone milieu as well as in the circulation. These pro-inflammatory cytokines along with the inflammatory microenvironment may be the underlying factors facilitating tumor

  2. A mammary adenocarcinoma murine model suitable for the study of cancer immunoediting

    PubMed Central

    2014-01-01

    Background Cancer immunoediting is a dynamic process composed of three phases: elimination (EL), equilibrium (EQ) and escape (ES) that encompasses the potential host-protective and tumor-sculpting functions of the immune system throughout tumor development. Animal models are useful tools for studying diseases such as cancer. The present study was designed to characterize the interaction between mammary adenocarcinoma M-406 and CBi, CBi− and CBi/L inbred mice lines. Results The mammary adenocarcinoma M-406 developed spontaneously in a CBi mouse. CBi/L and CBi− mice were artificially selected for body conformation from CBi. When CBi mice are s.c. challenged with M-406, tumor growths exponentially in 100% of animals, while in CBi− the tumor growths briefly and then begins a rejection process in 100% of the animals. In CBi/L the growth of the tumor shows the three phases: 51.6% in ES, 18.5% in EQ and 29.8% in EL. Conclusions The results obtained support the conclusion that the system M-406 plus the inbred mouse lines CBi, CBi− and CBi/L, is a good murine model to study the process of tumor immunoediting. PMID:24885995

  3. Antiproliferative Effects of Oxytocin and Desmopressin on Canine Mammary Cancer Cells

    PubMed Central

    Benavente, Micaela Andrea; Bianchi, Carolina Paula; Imperiale, Fernanda; Aba, Marcelo Alfredo

    2016-01-01

    Neoplasms of the mammary gland represent the most frequent tumor type in the female dog, and according to the histologic criteria, approximately 50% of them are malignant. In the most aggressive cases of mammary cancer, surgery is not enough to warrant a favorable outcome, and adjuvant therapies are needed to improve the patient’s overall survival. The aim of the present study was to evaluate the effects of two peptides on proliferation of a canine mammary cancer cell line derived from a simple carcinoma. The cell line CMT-U27 was grown in 96-well plates, at two cell densities (4 × 103 and 8 × 103 cells/well). Cultures were treated with oxytocin (OT) or desmopressin at five concentrations (10, 50, 100, 500, and 1000 nM). After 72 h of incubation, cell proliferation was determined by the MTT assay. Results showed that with 4 × 103 cells/well, OT at 50, 500, and 1000 nM was growth inhibitory for the cells, being statistically significant at 1000 nM. On the contrary, no antiproliferative effect was observed with 10 or 100 nM. At 8 × 103 cells/well, OT showed a significant antiproliferative effect only with the highest concentration (1000 nM). Desmopressin at 4 × 103 cells/well decreased cell viability at concentrations of 50, 100, 500, and 1000 nM (statistically significant with the highest concentration), while no effect was observed with 10 nM. With 8 × 103 cells/well, this peptide reduced cell growth at 100, 500, and 1000 nM. In conclusion, we suggest that these peptides may be potential and promising compounds for the treatment of dogs with simple carcinomas of the mammary gland. In vivo studies are required to confirm this hypothesis. PMID:28083539

  4. Secondhand Smoke Exposure | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  5. Basic Research and Progress against Cancer

    Cancer.gov

    An infographic about the importance of basic research for making progress against cancer. The graphic shows the research milestones that led to the development and approval of crizotinib (Xalkori®) to treat certain non-small cell lung cancers.

  6. Basic Research and Progress against Pediatric Cancer

    Cancer.gov

    An infographic about the importance of basic research for making progress against childhood cancers. Shows the milestones that led to development and approval of dinutuximab (Unituxin®) to treat neuroblastoma, a cancer seen mainly in children.

  7. End of Life | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  8. Early Detection | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  9. Adult Tobacco Use | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  10. Data Sources | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  11. Director's Message | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  12. Indoor Tanning | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  13. Data Resources | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  14. Treatment Summary Tables | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  15. Frequently Asked Questions | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  16. Alcohol Consumption | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  17. Tobacco Use Initiation | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  18. Secondhand Smoke | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  19. Smoking Cessation | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  20. Custom Report | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  1. Fat Consumption | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  2. Youth Tobacco Use | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  3. Tobacco Use | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  4. Chemical Exposures | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  5. Prevention Summary Tables | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  6. Red Meat Consumption | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  7. Quitting Smoking | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  8. About the Report | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  9. Summary Tables | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  10. Report Highlights | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  11. Stage at Diagnosis | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  12. NCI Dictionary | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  13. HPV Immunization | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  14. Physical Activity | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  15. Contact Us | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  16. Associated expressions of FGFR-2 and FGFR-3: from mouse mammary gland physiology to human breast cancer.

    PubMed

    Cerliani, Juan P; Vanzulli, Silvia I; Piñero, Cecilia Pérez; Bottino, María C; Sahores, Ana; Nuñez, Myriam; Varchetta, Romina; Martins, Rubén; Zeitlin, Eduardo; Hewitt, Stephen M; Molinolo, Alfredo A; Lanari, Claudia; Lamb, Caroline A

    2012-06-01

    Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors which have been implicated in breast cancer. The aim of this study was to evaluate FGFR-1, -2, -3, and -4 protein expressions in normal murine mammary gland development, and in murine and human breast carcinomas. Using immunohistochemistry and Western blot, we report a hormonal regulation of FGFR during postnatal mammary gland development. Progestin treatment of adult virgin mammary glands resulted in changes in localization of FGFR-3 from the cytoplasm to the nucleus, while treatment with 17-β-estradiol induced changes in the expressions and/or localizations of FGFR-2 and -3. In murine mammary carcinomas showing different degrees of hormone dependence, we found progestin-induced increased expressions, mainly of FGFR-2 and -3. These receptors were constitutively activated in hormone-independent variants. We studied three luminal human breast cancer cell lines growing as xenografts, which particularly expressed FGFR-2 and -3, suggesting a correlation between hormonal status and FGFR expression. Most importantly, in breast cancer samples from 58 patients, we found a strong association (P < 0.01; Spearman correlation) between FGFR-2 and -3 expressions and a weaker correlation of each receptor with estrogen receptor expression. FGFR-4 correlated with c-erbB2 over expression. We conclude that FGFR-2 and -3 may be mechanistically linked and can be potential targets for treatment of estrogen receptor-positive breast cancer patients.

  17. In-silico QTL mapping of postpubertal mammary ductal development in the mouse uncovers potential human breast cancer risk loci

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genetic background plays a dominant role in mammary gland development and breast cancer (BrCa). Despite this, the role of genetics is only partially understood. This study used strain-dependent variation in an inbred mouse mapping panel, to identify quantitative trait loci (QTL) underlying structura...

  18. Overexpression of LMO4 induces mammary hyperplasia, promotes cell invasion, and is a predictor of poor outcome in breast cancer

    PubMed Central

    Sum, Eleanor Y. M.; Segara, Davendra; Duscio, Belinda; Bath, Mary L.; Field, Andrew S.; Sutherland, Robert L.; Lindeman, Geoffrey J.; Visvader, Jane E.

    2005-01-01

    The zinc finger protein LMO4 is overexpressed in a high proportion of breast carcinomas. Here, we report that overexpression of a mouse mammary tumor virus (MMTV)-Lmo4 transgene in the mouse mammary gland elicits hyperplasia and mammary intraepithelial neoplasia or adenosquamous carcinoma in two transgenic strains with a tumor latency of 13–18 months. To investigate cellular processes controlled by LMO4 and those that may be deregulated during oncogenesis, we used RNA interference. Down-regulation of LMO4 expression reduced proliferation of human breast cancer cells and increased differentiation of mouse mammary epithelial cells. Furthermore, small-interfering-RNA-transfected breast cancer cells (MDA-MB-231) had a reduced capacity to migrate and invade an extracellular matrix. Conversely, overexpression of LMO4 in noninvasive, immortalized human MCF10A cells promoted cell motility and invasion. Significantly, in a cohort of 159 primary breast cancers, high nuclear levels of LMO4 were an independent predictor of death from breast cancer. Together, these findings suggest that deregulation of LMO4 in breast epithelium contributes directly to breast neoplasia by altering the rate of cellular proliferation and promoting cell invasion. PMID:15897450

  19. Evaluation of the circulating glycoprotein CA549 in mammary cancer and other malignancies.

    PubMed

    Clocchiatti, L; De Biasi, F; Cartei, G; Sibau, A; Vigevani, E; Signor, M; Giovannoni, M; Ceschia, V; Di Chiara, F; Grandis, S

    1991-10-31

    A prospective study was carried out on a recent marker for breast cancer, CA549, a mucine-like acid glycoprotein present in the fat membranes of human milk. Fifty healthy control subjects and 91 with benign conditions, 103 mammary cancer patients and 256 patients with other types of malignancy were studied. For comparison, CEA and CA15-3 were also investigated. The CA549 cutoff was 11 U/ml. In breast cancer the marker was below the cutoff in 9 cases (92.8%); in malignancies other than breast cancer it was above the cutoff in 5 to 50% of patients. In breast cancer it was raised in 83.3% of cases (CA15-3 showed 82.9% and CEA 50%). In breast cancer after radical surgery, CA549 was normal in patients who were in TNM stage I but above the cutoff in 57.1% of those at more advanced stages. The follow-up study is ongoing among these patients. In all the study conditions, CA549 favorably compared to CA15-3 values, with sensitivity and specificity greater than CEA.

  20. Histone Demethylase JMJD2B Functions as a Co-Factor of Estrogen Receptor in Breast Cancer Proliferation and Mammary Gland Development

    PubMed Central

    Kawazu, Masahito; McQuire, Tracy; Goto, Kouichiro; Son, Dong-Ok; Wakeham, Andrew; Miyagishi, Makoto; Mak, Tak W.; Okada, Hitoshi

    2011-01-01

    Estrogen is a key regulator of normal function of female reproductive system and plays a pivotal role in the development and progression of breast cancer. Here, we demonstrate that JMJD2B (also known as KDM4B) constitutes a key component of the estrogen signaling pathway. JMJD2B is expressed in a high proportion of human breast tumors, and that expression levels significantly correlate with estrogen receptor (ER) positivity. In addition, 17-beta-estradiol (E2) induces JMJD2B expression in an ERα dependent manner. JMJD2B interacts with ERα and components of the SWI/SNF-B chromatin remodeling complex. JMJD2B is recruited to ERα target sites, demethylates H3K9me3 and facilitates transcription of ER responsive genes including MYB, MYC and CCND1. As a consequence, knockdown of JMJD2B severely impairs estrogen-induced cell proliferation and the tumor formation capacity of breast cancer cells. Furthermore, Jmjd2b-deletion in mammary epithelial cells exhibits delayed mammary gland development in female mice. Taken together, these findings suggest an essential role for JMJD2B in the estrogen signaling, and identify JMJD2B as a potential therapeutic target in breast cancer. PMID:21445275

  1. Luminal progenitors restrict their lineage potential during mammary gland development.

    PubMed

    Rodilla, Veronica; Dasti, Alessandro; Huyghe, Mathilde; Lafkas, Daniel; Laurent, Cécile; Reyal, Fabien; Fre, Silvia

    2015-02-01

    The hierarchical relationships between stem cells and progenitors that guide mammary gland morphogenesis are still poorly defined. While multipotent basal stem cells have been found within the myoepithelial compartment, the in vivo lineage potential of luminal progenitors is unclear. Here we used the expression of the Notch1 receptor, previously implicated in mammary gland development and tumorigenesis, to elucidate the hierarchical organization of mammary stem/progenitor cells by lineage tracing. We found that Notch1 expression identifies multipotent stem cells in the embryonic mammary bud, which progressively restrict their lineage potential during mammary ductal morphogenesis to exclusively generate an ERαneg luminal lineage postnatally. Importantly, our results show that Notch1-labelled cells represent the alveolar progenitors that expand during pregnancy and survive multiple successive involutions. This study reveals that postnatal luminal epithelial cells derive from distinct self-sustained lineages that may represent the cells of origin of different breast cancer subtypes.

  2. Luminal Progenitors Restrict Their Lineage Potential during Mammary Gland Development

    PubMed Central

    Rodilla, Veronica; Dasti, Alessandro; Huyghe, Mathilde; Lafkas, Daniel; Laurent, Cécile; Reyal, Fabien; Fre, Silvia

    2015-01-01

    The hierarchical relationships between stem cells and progenitors that guide mammary gland morphogenesis are still poorly defined. While multipotent basal stem cells have been found within the myoepithelial compartment, the in vivo lineage potential of luminal progenitors is unclear. Here we used the expression of the Notch1 receptor, previously implicated in mammary gland development and tumorigenesis, to elucidate the hierarchical organization of mammary stem/progenitor cells by lineage tracing. We found that Notch1 expression identifies multipotent stem cells in the embryonic mammary bud, which progressively restrict their lineage potential during mammary ductal morphogenesis to exclusively generate an ERαneg luminal lineage postnatally. Importantly, our results show that Notch1-labelled cells represent the alveolar progenitors that expand during pregnancy and survive multiple successive involutions. This study reveals that postnatal luminal epithelial cells derive from distinct self-sustained lineages that may represent the cells of origin of different breast cancer subtypes. PMID:25688859

  3. Axillary and internal mammary sentinel lymph node biopsy in breast cancer after neoadjuvant chemotherapy

    PubMed Central

    Cao, Xiao-Shan; Li, Hui-Juan; Cong, Bin-Bin; Sun, Xiao; Qiu, Peng-Fei; Liu, Yan-Bing; Wang, Chun-Jian; Wang, Yong-Sheng

    2016-01-01

    With the improvement of neoadjuvant chemotherapy (NAC), the proportion of pathological complete response (pCR) in the breast and axillary lymph node (ALN) is increasing. The evaluation of pCR does not include the status of internal mammary lymph node (IMLN). This study is to evaluate the roles of both axillary sentinel lymph node biopsy (ASLNB) and internal mammary sentinel lymph node biopsy (IM-SLNB) in breast cancer patients after NAC. There were 74 patients enrolled into this study. IM-SLNB was performed on patients with radioactive internal mammary sentinel lymph node (IM-SLN). Patients (n = 8) with cN0 and ycN0 received ASLNB, and axillary lymph node dissection (ALND) in cases of positive axillary sentinel lymph node (ASLN). Patients (n = 48) with cN+ but ycN0 received ASLNB and ALND. Patients (n = 18) with ycN+ received ALND without ASLNB. The visualization rate of IM-SLN was 56.8% (42/74). The success rate of IM-SLNB was 97.6% (41/42) and the metastasis rate of IM-SLN was 7.3% (3/41). The success rate of ASLNB was 100% (56/56). The false negative rate (FNR) of ASLNB was 17.2% (5/29). The FNR in patients with 1, 2 and ≥ 3ASLNs examined was 27.3% (3/11), 20.0% (2/10) and 0% (0/8) respectively. ASLNB could be performed on ycN0 after NAC, and ALND should be performed on initially ALN-positive patients. IM-SLNB should be considered after NAC, especially for patients with clinically positive axillary nodes before NAC, which might help make clear of the pathological nodal staging of both ALN and IMLN, improve the definition of nodal pCR, and guide the individual adjuvant regional and systemic therapy. PMID:27738336

  4. Axillary and internal mammary sentinel lymph node biopsy in breast cancer after neoadjuvant chemotherapy.

    PubMed

    Cao, Xiao-Shan; Li, Hui-Juan; Cong, Bin-Bin; Sun, Xiao; Qiu, Peng-Fei; Liu, Yan-Bing; Wang, Chun-Jian; Wang, Yong-Sheng

    2016-11-08

    With the improvement of neoadjuvant chemotherapy (NAC), the proportion of pathological complete response (pCR) in the breast and axillary lymph node (ALN) is increasing. The evaluation of pCR does not include the status of internal mammary lymph node (IMLN). This study is to evaluate the roles of both axillary sentinel lymph node biopsy (ASLNB) and internal mammary sentinel lymph node biopsy (IM-SLNB) in breast cancer patients after NAC. There were 74 patients enrolled into this study. IM-SLNB was performed on patients with radioactive internal mammary sentinel lymph node (IM-SLN). Patients (n = 8) with cN0 and ycN0 received ASLNB, and axillary lymph node dissection (ALND) in cases of positive axillary sentinel lymph node (ASLN). Patients (n = 48) with cN+ but ycN0 received ASLNB and ALND. Patients (n = 18) with ycN+ received ALND without ASLNB. The visualization rate of IM-SLN was 56.8% (42/74). The success rate of IM-SLNB was 97.6% (41/42) and the metastasis rate of IM-SLN was 7.3% (3/41). The success rate of ASLNB was 100% (56/56). The false negative rate (FNR) of ASLNB was 17.2% (5/29). The FNR in patients with 1, 2 and ≥ 3ASLNs examined was 27.3% (3/11), 20.0% (2/10) and 0% (0/8) respectively. ASLNB could be performed on ycN0 after NAC, and ALND should be performed on initially ALN-positive patients. IM-SLNB should be considered after NAC, especially for patients with clinically positive axillary nodes before NAC, which might help make clear of the pathological nodal staging of both ALN and IMLN, improve the definition of nodal pCR, and guide the individual adjuvant regional and systemic therapy.

  5. Differential Subcellular Localization Renders HAI-2 a Matriptase Inhibitor in Breast Cancer Cells but Not in Mammary Epithelial Cells

    PubMed Central

    Chang, Hsiang-Hua D.; Xu, Yuan; Lai, Hongyu; Yang, Xiaoyu; Tseng, Chun-Che; Lai, Ying-Jung J.; Pan, Yu; Zhou, Emily; Johnson, Michael D.; Wang, Jehng-Kang; Lin, Chen-Yong

    2015-01-01

    The type 2 transmembrane serine protease matriptase is under tight control primarily by the actions of the integral membrane Kunitz-type serine protease inhibitor HAI-1. Growing evidence indicates that HAI-2 might also be involved in matriptase inhibition in some contexts. Here we showed that matriptase inhibition by HAI-2 depends on the subcellular localizations of HAI-2, and is observed in breast cancer cells but not in mammary epithelial cells. HAI-2 is co-expressed with matriptase in 21 out of 26 human epithelial and carcinoma cells examined. HAI-2 is also a potent matriptase inhibitor in solution, but in spite of this, HAI-2 inhibition of matriptase is not observed in all contexts where HAI-2 is expressed, unlike what is seen for HAI-1. Induction of matriptase zymogen activation in mammary epithelial cells results in the formation of matriptase-HAI-1 complexes, but matriptase-HAI-2 complexes are not observed. In breast cancer cells, however, in addition to the appearance of matriptase-HAI-1 complex, three different matriptase-HAI-2 complexes, are formed following the induction of matriptase activation. Immunofluorescent staining reveals that activated matriptase is focused at the cell-cell junctions upon the induction of matriptase zymogen activation in both mammary epithelial cells and breast cancer cells. HAI-2, in contrast, remains localized in vesicle/granule-like structures during matriptase zymogen activation in human mammary epithelial cells. In breast cancer cells, however, a proportion of the HAI-2 reaches the cell surface where it can gain access to and inhibit active matriptase. Collectively, these data suggest that matriptase inhibition by HAI-2 requires the translocation of HAI-2 to the cell surface, a process which is observed in some breast cancer cells but not in mammary epithelial cells. PMID:25786220

  6. A model of spontaneous mouse mammary tumor for human estrogen receptor- and progesterone receptor-negative breast cancer

    PubMed Central

    ZHENG, LIXIANG; ZHOU, BUGAO; MENG, XIANMING; ZHU, WEIFENG; ZUO, AIREN; WANG, XIAOMIN; JIANG, RUNDE; YU, SHIPING

    2014-01-01

    Breast cancer (BC) is the most frequently malignancy in women. Therefore, establishment of an animal model for the development of preventative measures and effective treatment for tumors is required. A novel heterogeneous spontaneous mammary tumor animal model of Kunming mice was generated. The purpose of this study was to characterize the spontaneous mammary tumor model. Histopathologically, invasive nodular masses of pleomorphic tubular neoplastic epithelial cells invaded fibro-vascular stroma, adjacent dermis and muscle tissue. Metastatic spread through blood vessel into liver and lungs was observed by hematoxylin eosin staining. No estrogen receptor (ER) or progesterone receptor (PR) immunoreactivity was detected in their associated malignant tumors, human epidermal growth factor receptor-2 (HER-2) protein weak expression was found by immunohistochemistry. High expression of vascular endothelial growth factor (VEGF), moderate or high expression of c-Myc and cyclin D1 were observed in tumor sections at different stages (2, 4, 6 and 8 weeks after cancer being found) when compared with that of the normal mammary glands. The result showed that the model is of an invasive ductal carcinoma. Remarkably in the mouse model, ER and PR-negative and HER2 weak positivity are observed. The high or moderate expressions of breast cancer markers (VEGF, c-Myc and cyclin D1) in mammary cancer tissue change at different stages. To our knowledge, this is the first report of a spontaneous mammary model displaying colony-strain, outbred mice. This model will be an attractive tool to understand the biology of anti-hormonal breast cancer in women. PMID:25230850

  7. Differential subcellular localization renders HAI-2 a matriptase inhibitor in breast cancer cells but not in mammary epithelial cells.

    PubMed

    Chang, Hsiang-Hua D; Xu, Yuan; Lai, Hongyu; Yang, Xiaoyu; Tseng, Chun-Che; Lai, Ying-Jung J; Pan, Yu; Zhou, Emily; Johnson, Michael D; Wang, Jehng-Kang; Lin, Chen-Yong

    2015-01-01

    The type 2 transmembrane serine protease matriptase is under tight control primarily by the actions of the integral membrane Kunitz-type serine protease inhibitor HAI-1. Growing evidence indicates that HAI-2 might also be involved in matriptase inhibition in some contexts. Here we showed that matriptase inhibition by HAI-2 depends on the subcellular localizations of HAI-2, and is observed in breast cancer cells but not in mammary epithelial cells. HAI-2 is co-expressed with matriptase in 21 out of 26 human epithelial and carcinoma cells examined. HAI-2 is also a potent matriptase inhibitor in solution, but in spite of this, HAI-2 inhibition of matriptase is not observed in all contexts where HAI-2 is expressed, unlike what is seen for HAI-1. Induction of matriptase zymogen activation in mammary epithelial cells results in the formation of matriptase-HAI-1 complexes, but matriptase-HAI-2 complexes are not observed. In breast cancer cells, however, in addition to the appearance of matriptase-HAI-1 complex, three different matriptase-HAI-2 complexes, are formed following the induction of matriptase activation. Immunofluorescent staining reveals that activated matriptase is focused at the cell-cell junctions upon the induction of matriptase zymogen activation in both mammary epithelial cells and breast cancer cells. HAI-2, in contrast, remains localized in vesicle/granule-like structures during matriptase zymogen activation in human mammary epithelial cells. In breast cancer cells, however, a proportion of the HAI-2 reaches the cell surface where it can gain access to and inhibit active matriptase. Collectively, these data suggest that matriptase inhibition by HAI-2 requires the translocation of HAI-2 to the cell surface, a process which is observed in some breast cancer cells but not in mammary epithelial cells.

  8. Mammary stem cells and breast cancer--role of Notch signalling.

    PubMed

    Farnie, Gillian; Clarke, Robert B

    2007-06-01

    Adult stem cells are found in numerous tissues of the body and play a role in tissue development, replacement and repair. Evidence shows that breast stem cells are multipotent and can self renew, which are key characteristics of stem cells, and a single cell enriched with cell surface markers has the ability to grow a fully functional mammary gland in vivo. Many groups have extrapolated the cancer stem cell hypothesis from the haematopoietic system to solid cancers, where using in vitro culture techniques and in vivo transplant models have established evidence of cancer stem cells in colon, pancreas, prostate, brain and breast cancers. In the report we describe the evidence for breast cancer stem cells; studies consistently show that stem cell like and breast cancer initiating populations can be enriched using cell surface makers CD44+/CD24- and have upregulated genes which include Notch. Notch signalling has been highlighted as a pathway involved in the development of the breast and is frequently dysregulated in invasive breast cancer. We have investigated the role of Notch in a pre-invasive breast lesion, ductal carcinoma in situ (DCIS), and have found that aberrant activation of Notch signalling is an early event in breast cancer. High expression of Notch 1 intracellular domain (NICD) in DCIS also predicted a reduced time to recurrence 5 years after surgery. Using a non-adherent sphere culture technique we have grown DCIS mammospheres from primary DCIS tissue, where self-renewal capacity, measured by the number of mammosphere initiating cells, were increased from normal breast tissue. A gamma-secretase inhibitor, DAPT, which inhibits all four Notch receptors and a Notch 4 neutralising antibody were shown to reduce DCIS mammosphere formation, indicating that Notch signalling and other stem cell self-renewal pathways may represent novel therapeutic targets to prevent recurrence of pre-invasive and invasive breast cancer.

  9. Internal Mammary Sentinel Node Biopsy in Breast Cancer. Is it Indicated?

    PubMed

    Maráz, R; Boross, G; Pap-Szekeres, J; Rajtár, M; Ambrózay, E; Cserni, G

    2014-01-01

    Axillary sentinel node (A-SN) biopsy is a standard procedure in breast cancer surgery. Sampling of intenal mammary sentinel nodes (IM-SN) is not performed routinly, although it is also considered an important prognostic factor of breast cancer. The role of this latter procedure was investigated in cases of IM-SN visualized on lymphoscintigraphy. Between January 2001 and June 2012 1542 patients with clinically node negative operable primary breast cancer had sentinel node biopsy (SNB). Both axillary and IM-SN were sampled (whenever detected), based on lymphoscintigraphy, intraoperative gamma probe detection and blu dye mapping. Lymphoscintigraphy showed IM-SN in 83 cases. IM-SN biopsy (IM-SNB) was succesfull in 77 patients (93%). A total of 86 IM-SNs were removed. IM-SN involvement was identified in 14 cases, representing 18% of patients who underwent IM-SNB. This included macrometastases (MAC) in 5 cases, micrometastases (MIC) in 2 cases, isolated tumor cells (ITC) in 7 cases. No significant differences were found between patients with and without IM-SN involvement in terms of age, tumor location, tumor size, axillary involvement, tumor grade or estrogen receptor status. The IM-SN involvement has lead to new therapeutic indications in 2 cases (2.6%), both of them due to MAC in the IM-SN: in 1 case change in chemotherapy and in 1 case change in radiotherapy, with the addition of iradiation of the internal mammary chain. Based on this series and information from the literature, we conclude that the indication for an IM-SNB procedure is very limited and its routine use should not be recommended.

  10. In vitro delivery of anti-breast cancer agents directly via the mammary papilla (nipple).

    PubMed

    Lee, Lay Ming; Davison, Zoë; Heard, Charles M

    2010-03-15

    The objective of this study was to investigate, in vitro, the plausibility of a novel method for delivering a combination of anti-breast cancer agents to the breast via the mammary papilla (nipple). Mammary papillae were prepared from freshly excised strips of porcine sow breasts by blunt dissection. Permeation studies were performed using all glass Franz diffusion cells in both upright and lateral position, with drugs examined individually and in combination. Donor phase was comprised of equimolar PD98059, LY294002 and tamoxifen; 2.54x10(-4) mol dissolved in 950 microL fish oil (containing approximately 23% (w/v) eicosapentaenoic acid, EPA), 25 microL DMSO and 25 microL 1,8-cineole. Also, 4 or 10% Cabosil M5P (w/v) was added to thicken the formulation. After 6 h, the papillae were recovered, cleaned, centrifuged and extracted thrice with methanol. Pooled extracts were analysed by reversed-phase HPLC. The significance of the papilla orientation was also investigated. When applied singly and laterally, the amount extracted from the porcine breast tissue for PD98059, LY294002 and tamoxifen were 1.83+/-0.30, 10.67+/-1.78 and 0.74+/-0.19x10(-2) micromol g(-1) respectively; applied simultaneously and laterally, 2.03+/-0.14, 4.86+/-0.47 and 0.22+/-0.04x10(-2) micromol g(-1) respectively. With 4% Cabosil formulation, amount extracted for PD98059 and LY294002 were 5.71+/-0.95 and 9.91+/-0.92x10(-2) micromol g(-1) respectively; with 10% formulation, 2.64+/-0.5 and 3.90+/-0.78x10(-2) micromol g(-1) respectively. Tamoxifen was below its limit of detection in both Cabosil M5P formulations. To conclude, localized passive delivery via the mammary papilla is a plausible non-invasive means of delivering anti-breast cancer drugs directly to the breast, in levels that have previously been shown to markedly inhibit the growth of breast cancer cell lines, in vitro. The amounts deliverable may be influenced by differential interactions with the thickening agent and patient orientation.

  11. Time-lapse imaging of primary preneoplastic mammary epithelial cells derived from genetically engineered mouse models of breast cancer.

    PubMed

    Nakles, Rebecca E; Millman, Sarah L; Cabrera, M Carla; Johnson, Peter; Mueller, Susette; Hoppe, Philipp S; Schroeder, Timm; Furth, Priscilla A

    2013-02-08

    Time-lapse imaging can be used to compare behavior of cultured primary preneoplastic mammary epithelial cells derived from different genetically engineered mouse models of breast cancer. For example, time between cell divisions (cell lifetimes), apoptotic cell numbers, evolution of morphological changes, and mechanism of colony formation can be quantified and compared in cells carrying specific genetic lesions. Primary mammary epithelial cell cultures are generated from mammary glands without palpable tumor. Glands are carefully resected with clear separation from adjacent muscle, lymph nodes are removed, and single-cell suspensions of enriched mammary epithelial cells are generated by mincing mammary tissue followed by enzymatic dissociation and filtration. Single-cell suspensions are plated and placed directly under a microscope within an incubator chamber for live-cell imaging. Sixteen 650 μm x 700 μm fields in a 4x4 configuration from each well of a 6-well plate are imaged every 15 min for 5 days. Time-lapse images are examined directly to measure cellular behaviors that can include mechanism and frequency of cell colony formation within the first 24 hr of plating the cells (aggregation versus cell proliferation), incidence of apoptosis, and phasing of morphological changes. Single-cell tracking is used to generate cell fate maps for measurement of individual cell lifetimes and investigation of cell division patterns. Quantitative data are statistically analyzed to assess for significant differences in behavior correlated with specific genetic lesions.

  12. Amplification of tumor inducing putative cancer stem cells (CSCs) by vitamin A/retinol from mammary tumors

    SciTech Connect

    Sharma, Rohit B.; Wang, Qingde; Khillan, Jaspal S.

    2013-07-12

    Highlights: •Vitamin A supports self renewal of putative CSCs from mammary tumors. •These cells exhibit impaired retinol metabolism into retinoic acid. •CSCs from mammary tumors differentiate into mammary specific cell lineages. •The cells express mammary stem cell specific CD29 and CD49f markers. •Putative CSCs form highly metastatic tumors in NOD SCID mouse. -- Abstract: Solid tumors contain a rare population of cancer stem cells (CSCs) that are responsible for relapse and metastasis. The existence of CSC however, remains highly controversial issue. Here we present the evidence for putative CSCs from mammary tumors amplified by vitamin A/retinol signaling. The cells exhibit mammary stem cell specific CD29{sup hi}/CD49f{sup hi}/CD24{sup hi} markers, resistance to radiation and chemo therapeutic agents and form highly metastatic tumors in NOD/SCID mice. The cells exhibit indefinite self renewal as cell lines. Furthermore, the cells exhibit impaired retinol metabolism and do not express enzymes that metabolize retinol into retinoic acid. Vitamin A/retinol also amplified putative CSCs from breast cancer cell lines that form highly aggressive tumors in NOD SCID mice. The studies suggest that high purity putative CSCs can be isolated from solid tumors to establish patient specific cell lines for personalized therapeutics for pre-clinical translational applications. Characterization of CSCs will allow understanding of basic cellular and molecular pathways that are deregulated, mechanisms of tumor metastasis and evasion of therapies that has direct clinical relevance.

  13. Contribution of xanthine oxidoreductase to mammary epithelial and breast cancer cell differentiation in part modulates inhibitor of differentiation-1.

    PubMed

    Fini, Mehdi A; Monks, Jenifer; Farabaugh, Susan M; Wright, Richard M

    2011-09-01

    Loss of xanthine oxidoreductase (XOR) has been linked to aggressive breast cancer in vivo and to breast cancer cell aggressiveness in vitro. In the present study, we hypothesized that the contribution of XOR to the development of the normal mammary gland may underlie its capacity to modulate breast cancer. We contrasted in vitro and in vivo developmental systems by differentiation marker and microarray analyses. Human breast cancer microarray was used for clinical outcome studies. The role of XOR in differentiation and proliferation was examined in human breast cancer cells and in a mouse xenograft model. Our data show that XOR was required for functional differentiation of mammary epithelial cells both in vitro and in vivo. Poor XOR expression was observed in a mouse ErbB2 breast cancer model, and pharmacologic inhibition of XOR increased breast cancer tumor burden in mouse xenograft. mRNA microarray analysis of human breast cancer revealed that low XOR expression was significantly associated with time to tumor relapse. The opposing expression of XOR and inhibitor of differentiation-1 (Id1) during HC11 differentiation and mammary gland development suggested a potential functional relationship. While overexpression of Id1 inhibited HC11 differentiation and XOR expression, XOR itself modulated expression of Id1 in differentiating HC11 cells. Overexpression of XOR both inhibited Id1-induced proliferation and -stimulated differentiation of Heregulin-β1-treated human breast cancer cells. These results show that XOR is an important functional component of differentiation whose diminished expression contributes to breast cancer aggressiveness, and they support XOR as both a breast cancer biomarker and a target for pharmacologic activation in therapeutic management of aggressive breast cancer.

  14. The contribution of growth hormone to mammary neoplasia

    PubMed Central

    Perry, Jo K; Mohankumar, Kumarasamypet M; Emerald, B Starling; Mertani, Hichem C; Lobie, Peter E

    2008-01-01

    While the effects of growth hormone (GH) on longitudinal growth are well established, the observation that GH contributes to neoplastic progression is more recent. Accumulating literature implicates GH-mediated signal transduction in the development and progression of a wide range malignancies including breast cancer. Recently autocrine human GH been demonstrated to be an orthotopically expressed oncogene for the human mammary gland. This review will highlight recent evidence linking GH and mammary carcinoma and discuss GH-antagonism as a potential therapeutic approach for treatment of breast cancer. PMID:18253708

  15. Financial Burden of Cancer Care | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  16. Life After Cancer Summary Tables | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  17. Cancer Survivors and Obesity | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  18. Cancer Survivors and Smoking | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  19. Cancer Survivors and Physical Activity | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  20. COX-2 over-expression correlates with VEGF and tumour angiogenesis in canine mammary cancer.

    PubMed

    Queiroga, Felisbina L; Pires, Isabel; Parente, Margarida; Gregório, Hugo; Lopes, Carlos S

    2011-07-01

    This study was designed to investigate the possible roles of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in canine mammary cancer angiogenesis. Immunohistochemistry was performed on 70 tumours (28 benign and 42 malignant) in order to detect COX-2 and VEGF expression. Microvessel density (MVD) was determined by CD31 immunolabelling to assess tumour angiogenesis. There was a significantly higher expression of COX-2 (P<0.001), VEGF (P<0.001) and MVD (P<0.001) in malignant compared to benign tumours. In the malignant group, the MVD of COX-2 positive tumours was significantly higher than that of COX-2 negative tumours (P=0.026). A similar association was observed for VEGF (P<0.001) positive tumours. The results from this study suggested that over-expression of COX-2 and VEGF may contribute to increased angiogenesis and aggression in malignant tumours.

  1. Tyrosine phosphorylation of maspin in normal mammary epithelia and breast cancer cells.

    PubMed

    Odero-Marah, Valerie A; Khalkhali-Ellis, Zhila; Schneider, Galen B; Seftor, Elisabeth A; Seftor, Richard E B; Koland, John G; Hendrix, Mary J C

    2002-07-26

    Maspin is a 42kDa tumor suppressor protein that belongs to the serine protease inhibitor (serpin) family. It inhibits cell motility and invasion in vitro, and tumor growth and metastasis in nude mice; however, maspin's molecular mechanism of action has remained elusive. Maspin contains several tyrosine residues and we hypothesized that phosphorylation of maspin could play a role in its biological function. Our study reveals that maspin is phosphorylated on tyrosine moiety(ies) in normal mammary epithelial cells endogenously expressing maspin. In addition, transfection of the maspin gene, using either a stable or inducible system into maspin-deficient breast cancer cell lines, yields a protein product that is phosphorylated on tyrosine residue(s). Furthermore, recombinant maspin protein can be tyrosine-phosphorylated by the kinase domain from the epidermal growth factor receptor in vitro. These novel observations suggest that maspin, which deviates from the classical serpin, may be an important signal transduction molecule in its phosphorylated form.

  2. CD44+/CD24- Cancer Stem Cells Are Associated With Higher Grade of Canine Mammary Carcinomas.

    PubMed

    Im, K S; Jang, Y G; Shin, J I; Kim, N H; Lim, H Y; Lee, S M; Kim, J H; Sur, J H

    2015-11-01

    The CD44+/CD24- phenotype identifies cancer stem cell (CSC) properties in canine mammary carcinoma (MC); however, the histopathological features associated with this phenotype remain to be elucidated. Here, we determined whether the CD44+/CD24- phenotype was associated with hormonal receptor (HR; estrogen receptor [ER] and/or progesterone receptor [PR]) status and/or triple (ER, PR, and human epithelial growth factor receptor 2)-negative (TN) subtype; conventional histological evaluation was also performed. We found that, as single markers, both CD44+ and CD24+ were associated with less aggressive histological types, low grade, and a non-TN subtype; both markers were associated with HR positivity. On the other hand, a CD44+/CD24- phenotype was associated with higher grade of carcinoma. Therefore, our results suggest that immunohistochemical phenotyping for CD44/CD24 is useful for the evaluation of tumor behavior as well as CSC-like properties in canine MCs.

  3. MicroRNA and Breast Cancer Progression

    DTIC Science & Technology

    2007-08-01

    AD_________________ Award Number: W81XWH-05-1-0428 TITLE: MicroRNA and Breast Cancer Progression...3. DATES COVERED (From - To) 15 JUL 2005 - 14 JUL 2007 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER MicroRNA and Breast Cancer Progression 5b...We hypothesized that certain miRNA species are differentially expressed in the normal breast epithelium and breast cancer cells. Our concept was that

  4. Establishment and characterization of a new cell line of canine inflammatory mammary cancer: IPC-366.

    PubMed

    Caceres, Sara; Peña, Laura; de Andres, Paloma J; Illera, Maria J; Lopez, Mirtha S; Woodward, Wendy A; Reuben, James M; Illera, Juan C

    2015-01-01

    Canine inflammatory mammary cancer (IMC) shares epidemiologic, histopathological and clinical characteristics with the disease in humans and has been proposed as a natural model for human inflammatory breast cancer (IBC). The aim of this study was to characterize a new cell line from IMC (IPC-366) for the comparative study of both IMC and IBC. Tumors cells from a female dog with clinical IMC were collected. The cells were grown under adherent conditions. The growth, cytological, ultrastructural and immunohistochemical (IHC) characteristics of IPC-366 were evaluated. Ten female Balb/SCID mice were inoculated with IPC-366 cells to assess their tumorigenicity and metastatic potential. Chromosome aberration test and Karyotype revealed the presence of structural aberration, numerical and neutral rearrangements, demonstrating a chromosomal instability. Microscopic examination of tumor revealed an epithelial morphology with marked anysocytosis. Cytological and histological examination of smears and ultrathin sections by electron microscopy revealed that IPC-366 is formed by highly malignant large round or polygonal cells characterized by marked atypia and prominent nucleoli and frequent multinucleated cells. Some cells had cytoplasmic empty spaces covered by cytoplasmic membrane resembling capillary endothelial cells, a phenomenon that has been related to s vasculogenic mimicry. IHC characterization of IPC-366 was basal-like: epithelial cells (AE1/AE3+, CK14+, vimentin+, actin-, p63-, ER-, PR-, HER-2, E-cadherin, overexpressed COX-2 and high Ki-67 proliferation index (87.15 %). At 2 weeks after inoculating the IPC-366 cells, a tumor mass was found in 100 % of mice. At 4 weeks metastases in lung and lymph nodes were found. Xenograph tumors maintained the original IHC characteristics of the female dog tumor. In summary, the cell line IPC-366 is a fast growing malignant triple negative cell line model of inflammatory mammary carcinoma that can be used for the comparative

  5. Establishment and Characterization of a New Cell Line of Canine Inflammatory Mammary Cancer: IPC-366

    PubMed Central

    Caceres, Sara; Peña, Laura; de Andres, Paloma J.; Illera, Maria J.; Lopez, Mirtha S.; Woodward, Wendy A.; Reuben, James M.; Illera, Juan C.

    2015-01-01

    Canine inflammatory mammary cancer (IMC) shares epidemiologic, histopathological and clinical characteristics with the disease in humans and has been proposed as a natural model for human inflammatory breast cancer (IBC). The aim of this study was to characterize a new cell line from IMC (IPC-366) for the comparative study of both IMC and IBC. Tumors cells from a female dog with clinical IMC were collected. The cells were grown under adherent conditions. The growth, cytological, ultrastructural and immunohistochemical (IHC) characteristics of IPC-366 were evaluated. Ten female Balb/SCID mice were inoculated with IPC-366 cells to assess their tumorigenicity and metastatic potential. Chromosome aberration test and Karyotype revealed the presence of structural aberration, numerical and neutral rearrangements, demonstrating a chromosomal instability. Microscopic examination of tumor revealed an epithelial morphology with marked anysocytosis. Cytological and histological examination of smears and ultrathin sections by electron microscopy revealed that IPC-366 is formed by highly malignant large round or polygonal cells characterized by marked atypia and prominent nucleoli and frequent multinucleated cells. Some cells had cytoplasmic empty spaces covered by cytoplasmic membrane resembling capillary endothelial cells, a phenomenon that has been related to s vasculogenic mimicry. IHC characterization of IPC-366 was basal-like: epithelial cells (AE1/AE3+, CK14+, vimentin+, actin-, p63-, ER-, PR-, HER-2, E-cadherin, overexpressed COX-2 and high Ki-67 proliferation index (87.15 %). At 2 weeks after inoculating the IPC-366 cells, a tumor mass was found in 100 % of mice. At 4 weeks metastases in lung and lymph nodes were found. Xenograph tumors maintained the original IHC characteristics of the female dog tumor. In summary, the cell line IPC-366 is a fast growing malignant triple negative cell line model of inflammatory mammary carcinoma that can be used for the comparative

  6. Role of mitochondrial dysfunction in cancer progression

    PubMed Central

    Hsu, Chia-Chi; Tseng, Ling-Ming

    2016-01-01

    Deregulated cellular energetics was one of the cancer hallmarks. Several underlying mechanisms of deregulated cellular energetics are associated with mitochondrial dysfunction caused by mitochondrial DNA mutations, mitochondrial enzyme defects, or altered oncogenes/tumor suppressors. In this review, we summarize the current understanding about the role of mitochondrial dysfunction in cancer progression. Point mutations and copy number changes are the two most common mitochondrial DNA alterations in cancers, and mitochondrial dysfunction induced by chemical depletion of mitochondrial DNA or impairment of mitochondrial respiratory chain in cancer cells promotes cancer progression to a chemoresistance or invasive phenotype. Moreover, defects in mitochondrial enzymes, such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase, are associated with both familial and sporadic forms of cancer. Deregulated mitochondrial deacetylase sirtuin 3 might modulate cancer progression by regulating cellular metabolism and oxidative stress. These mitochondrial defects during oncogenesis and tumor progression activate cytosolic signaling pathways that ultimately alter nuclear gene expression, a process called retrograde signaling. Changes in the intracellular level of reactive oxygen species, Ca2+, or oncometabolites are important in the mitochondrial retrograde signaling for neoplastic transformation and cancer progression. In addition, altered oncogenes/tumor suppressors including hypoxia-inducible factor 1 and tumor suppressor p53 regulate mitochondrial respiration and cellular metabolism by modulating the expression of their target genes. We thus suggest that mitochondrial dysfunction plays a critical role in cancer progression and that targeting mitochondrial alterations and mitochondrial retrograde signaling might be a promising strategy for the development of selective anticancer therapy. PMID:27022139

  7. Involvement of Different networks in mammary gland involution after the pregnancy/lactation cycle: Implications in breast cancer.

    PubMed

    Zaragozá, Rosa; García-Trevijano, Elena R; Lluch, Ana; Ribas, Gloria; Viña, Juan R

    2015-04-01

    Early pregnancy is associated with a reduction in a woman's lifetime risk for breast cancer. However, different studies have demonstrated an increase in breast cancer risk in the years immediately following pregnancy. Early and long-term risk is even higher if the mother age is above 35 years at the time of first parity. The proinflammatory microenvironment within the mammary gland after pregnancy renders an "ideal niche" for oncogenic events. Signaling pathways involved in programmed cell death and tissue remodeling during involution are also activated in breast cancer. Herein, the major signaling pathways involved in mammary gland involution, signal transducer and activator of transcription (STAT3), nuclear factor-kappa B (NF-κB), transforming growth factor beta (TGFβ), and retinoid acid receptors (RARs)/retinoid X receptors (RXRs), are reviewed as part of the complex network of signaling pathways that crosstalk in a contextual-dependent manner. These factors, also involved in breast cancer development, are important regulatory nodes for signaling amplification after weaning. Indeed, during involution, p65/p300 target genes such as MMP9, Capn1, and Capn2 are upregulated. Elevated expression and activities of these proteases in breast cancer have been extensively documented. The role of these proteases during mammary gland involution is further discussed. MMPs, calpains, and cathepsins exert their effect by modification of the extracellular matrix and intracellular proteins. Calpains, activated in the mammary gland during involution, cleave several proteins located in cell membrane, lysosomes, mitochondria, and nuclei favoring cell death. Besides, during this period, Capn1 is most probably involved in the modulation of preadipocyte differentiation through chromatin remodeling. Calpains can be implicated in cell anchoring loss, providing a proper microenvironment for tumor growth. A better understanding of the role of any of these proteases in tumorigenesis may

  8. Internal Mammary Lymph Node Irradiation Contributes to Heart Dose in Breast Cancer

    SciTech Connect

    Chargari, Cyrus; Castadot, Pierre; MacDermed, Dhara; Vandekerkhove, Christophe; Bourgois, Nicolas; Van Houtte, Paul; Magne, Nicolas

    2010-10-01

    We assessed the impact of internal mammary chain radiotherapy (IMC RT) to the radiation dose received by the heart in terms of heart dose-volume histogram (DVH). Thirty-six consecutive breast cancer patients presenting with indications for IMC RT were enrolled in a prospective study. The IMC was treated by a standard conformal RT technique (50 Gy). For each patient, a cardiac DVH was generated by taking into account the sole contribution of IMC RT. Cardiac HDV were compared according to breast cancer laterality and the type of previous surgical procedure, simple mastectomy or breast conservative therapy (BCT). The contribution of IMC RT to the heart dose was significantly greater for patients with left-sided versus right-sided tumors (13.8% and 12.8% for left-sided tumors versus 3.9% and 4.2% for right-sided tumors in the BCT group and the mastectomy group, respectively; p < 0.0001). There was no statistically significant difference in IMC contribution depending on the initial surgical procedure. IMC RT contributes to cardiac dose for both left-sided and right-sided breast cancers, although the relative contribution is greater in patients with left-sided tumors.

  9. Hormonally up-regulated neu-associated kinase: A novel target for breast cancer progression.

    PubMed

    Zambrano, Joelle N; Neely, Benjamin A; Yeh, Elizabeth S

    2017-02-09

    Hormonally up-regulated neu-associated Kinase (Hunk) is a protein kinase that was originally identified in the murine mammary gland and has been shown to be highly expressed in Human Epidermal Growth Factor Receptor 2 positive (HER2(+)/ErbB2(+)) breast cancer cell lines as well as MMTV-neu derived mammary tumor cell lines. However, the physiological role of Hunk has been largely elusive since its identification. Though Hunk is predicted to be a Serine/Threonine (Ser/Thr) protein kinase with homology to the SNF1/AMPK family of protein kinases, there are no known Hunk substrates that have been identified to date. Recent work demonstrates a role for Hunk in HER2(+)/ErbB2(+) breast cancer progression, including drug resistance to HER2/ErbB2 inhibitors, with Hunk potentially acting downstream of HER2/ErbB2 and the PI3K/Akt pathway. These studies have collectively shown that Hunk plays a vital role in promoting mammary tumorigenesis, as Hunk knockdown via shRNA in xenograft tumor models or crossing MMTV-neu or Pten-deficient genetically engineered mouse models into a Hunk knockout (Hunk-/-) background impairs mammary tumor growth in vivo. Because the majority of HER2(+)/ErbB2(+) breast cancer patients acquire drug resistance to HER2/ErbB2 inhibitors, the characterization of novel drug targets like Hunk that have the potential to simultaneously suppress tumorigenesis and potentially enhance efficacy of current therapeutics is an important facet of drug development. Therefore, work aimed at uncovering specific regulatory functions for Hunk that could contribute to this protein kinase's role in both tumorigenesis and drug resistance will be informative. This review focuses on what is currently known about this under-studied protein kinase, and how targeting Hunk may prove to be a potential therapeutic target for the treatment of breast cancer.

  10. The Effects of Folate on the Development of Breast Cancer in a Chemical Rodent Model of Mammary Carcinogenesis

    DTIC Science & Technology

    2002-08-01

    AD Award Number: DAMD17-01- 1 -0428 TITLE: The Effects of Folate on the Development of Breast Cancer in a Chemical Rodent Model of Mammary...DOCUMENTATION PAGE OMB No. 074-0188 Public reporting burden for this collection of information is estimated to average 1 hour per response, including...Arlington, VA 22202-4302, and to the Office of Management and Budget, Paperwork Reduction Project (0704-0188), Washington, DC 20503 1 . AGENCY USE

  11. Inhibition of Breast Cancer Progression by Blocking Heterocellular Contact Between Epithelial Cells and Fibroblasts

    DTIC Science & Technology

    2013-04-01

    which cells in the mammary epithelium continuously interact with cells in the surrounding microenvironment. When the microenvironment receives signals...from cells in the mammary epithelium , it sends back cues that help to maintain normal mammary tissue functions. If these interactions are disturbed...targeting activity, Mol. Cancer Ther., 2004, 3(11), 1365–1373. 5 J. Debnath and J. S. Brugge, Modelling glandular epithelial cancers in three

  12. The potential role of COX-2 in cancer stem cell-mediated canine mammary tumor initiation: an immunohistochemical study.

    PubMed

    Huang, Jian; Zhang, Di; Xie, Fuqiang; Lin, Degui

    2015-01-01

    Increasing evidence suggests that cancer stem cells (CSCs) are responsible for tumor initiation and maintenance. Additionally, it is becoming apparent that cyclooxygenase (COX) signaling is associated with canine mammary tumor development. The goals of the present study were to investigate COX-2 expression patterns and their effect on CSC-mediated tumor initiation in primary canine mammary tissues and tumorsphere models using immunohistochemistry. Patterns of COX-2, CD44, octamer-binding transcription factor (Oct)-3/4, and epidermal growth factor receptor (EGFR) expression were examined in malignant mammary tumor (MMT) samples and analyzed in terms of clinicopathological characteristics. COX-2 and Oct-3/4 expression was higher in MMTs compared to other histological samples with heterogeneous patterns. In MMTs, COX-2 expression correlated with tumor malignancy features. Significant associations between COX-2, CD44, and EGFR were observed in low-differentiated MMTs. Comparative analysis showed that the levels of COX-2, CD44, and Oct-3/4 expression varied significantly among TSs of three histological grades. Enhanced COX-2 staining was consistently observed in TSs. Similar levels of staining intensity were found for CD44 and Oct-3/4, but EGFR expression was weak. Our findings indicate the potential role of COX-2 in CSC-mediated tumor initiation, and suggest that COX-2 inhibition may help treat canine mammary tumors by targeting CSCs.

  13. Annexin II-Dependent Mechanism of Breast Cancer Progression

    DTIC Science & Technology

    2010-11-01

    carcinoma patients [13]. The p roliferative ef fects o f TA M w ere d emonstrated in vivo in mice with mammary cancer . The macrophage colony...associated macrophages . Crit Rev Oncol/Hematol 2008; 66 (1): 1-9. [5] Pollard JW. Macrophages define the invasive microenvironment in breast cancer . J...related inflammation: the macrophage connection. Cancer Lett 2008; 267 (2): 204-15. [9] Lin E Y, Pollard JW . T umor-associated m acrophages p ress

  14. Phospholipid makeup of the breast adipose tissue is impacted by obesity and mammary cancer in the mouse: Results of a pilot study.

    PubMed

    Margolis, Michael; Perez, Osvaldo; Martinez, Mitchell; Santander, Ana M; Mendez, Armando J; Nadji, Mehrdad; Nayer, Ali; Bhattacharya, Sanjoy; Torroella-Kouri, Marta

    2015-01-01

    Obesity, an established risk factor for breast cancer (BC), is associated with systemic inflammation. The breast contains adipose tissue (bAT), yet whether it plays a role in BC progression in obese females is being intensively studied. There is scarce knowledge on the lipid composition of bAT in health and disease. The purpose of this pilot study was: 1) to determine whether obesity and BC are associated with inflammatory changes in bAT 2) to analyze for the first time the lipid profile of bAT in obese and lean mammary tumor-bearing and normal mice. Syngeneic E0771 mammary tumor cells were implanted into the mammary fat pad of lean and diet-induced obese C57BL/6 mice. BATs were analyzed four weeks after tumor cell inoculation by immunohistochemistry and mass spectrometry. Phospholipids were identified and subjected to ratiometric quantification using a TSQ Quantum Access Max triple quadrupole mass spectrometer utilizing precursor ion scan or neutral ion loss scan employing appropriate class specific lipid standards in a two step quantification process. Four main classes of phospholipids were analyzed: phosphatidylcholines phosphatidylserines, phosphatidylethanolamines and phosphatidylinositols. Our results showed that bAT in obese (normal and tumor-bearing) mice contained hypertrophic adipocytes compared with their corresponding samples in lean mice; higher numbers of macrophages and crown-like structures were observed in obese tumor bearers compared to obese normal mice. BAT from normal obese mice revealed higher concentrations of phosphatidylethanolamines. Furthermore, bAT from tumor-bearing mice expressed higher phosphatidylcholines than that from non-tumor bearing mice, suggesting the presence of the tumor is associated with phosphatidylcholines. Conversion of phosphatidylethanolamines to phosphatidylcholines will be investigated in E0771 cells. Additional studies are projected to investigate macrophage activation by these specific classes of phospholipids

  15. Shp2 signaling suppresses senescence in PyMT-induced mammary gland cancer in mice

    PubMed Central

    Lan, Linxiang; Holland, Jane D; Qi, Jingjing; Grosskopf, Stefanie; Vogel, Regina; Györffy, Balázs; Wulf-Goldenberg, Annika; Birchmeier, Walter

    2015-01-01

    In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence-associated β-gal (SA-β-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to the inhibition of self-renewal of tumor cells and blockage of tumor formation and growth. A signaling cascade was identified that acts downstream of Shp2 to counter senescence: Src, focal adhesion kinase, and Map kinase inhibit senescence by activating the expression of S-phase kinase-associated protein 2 (Skp2), Aurora kinase A (Aurka), and the Notch ligand Delta-like 1 (Dll1), which block p27 and p53. Remarkably, the expression of Shp2 and of selected target genes predicts human breast cancer outcome. We conclude that therapies, which rely on senescence induction by inhibiting Shp2 or controlling its target gene products, may be useful in blocking breast cancer. PMID:25736378

  16. Screening and analysis of breast cancer genes regulated by the human mammary microenvironment in a humanized mouse model

    PubMed Central

    Zheng, Mingjie; Wang, Jue; Ling, Lijun; Xue, Dandan; Wang, Shui; Zhao, Yi

    2016-01-01

    Tumor microenvironments play critical regulatory roles in tumor growth. Although mouse cancer models have contributed to the understanding of human tumor biology, the effectiveness of mouse cancer models is limited by the inability of the models to accurately present humanized tumor microenvironments. Previously, a humanized breast cancer model in severe combined immunodeficiency mice was established, in which human breast cancer tissue was implanted subcutaneously, followed by injection of human breast cancer cells. It was demonstrated that breast cancer cells showed improved growth in the human mammary microenvironment compared with a conventional subcutaneous mouse model. In the present study, the novel mouse model and microarray technology was used to analyze changes in the expression of genes in breast cancer cells that are regulated by the human mammary microenvironment. Humanized breast and conventional subcutaneous mouse models were established, and orthotopic tumor cells were obtained from orthotopic tumor masses by primary culture. An expression microarray using Illumina HumanHT-12 v4 Expression BeadChip and database analyses were performed to investigate changes in gene expression between tumors from each microenvironment. A total of 94 genes were differentially expressed between the primary cells cultured from the humanized and conventional mouse models. Significant upregulation of genes that promote cell proliferation and metastasis or inhibit apoptosis, such as SH3-domain binding protein 5 (BTK-associated), sodium/chloride cotransporter 3 and periostin, osteoblast specific factor, and genes that promote angiogenesis, such as KIAA1618, was also noted. Other genes that restrain cell proliferation and accelerate cell apoptosis, including tripartite motif containing TRIM36 and NES1, were downregulated. The present results revealed differences in various aspects of tumor growth and metabolism between the two model groups and indicated the functional

  17. Runx1 is associated with breast cancer progression in MMTV-PyMT transgenic mice and its depletion in vitro inhibits migration and invasion

    PubMed Central

    Browne, Gillian; Taipaleenmäki, Hanna; Bishop, Nicole M.; Madasu, Sharath C.; Shaw, Leslie M.; van Wijnen, Andre J.; Stein, Janet L.; Stein, Gary S.; Lian, Jane B.

    2015-01-01

    Runx1 is a transcription factor essential for definitive hematopoiesis, and genetic abnormalities in Runx1 cause leukemia. Runx1 is functionally promiscuous and acts as either an oncogene or tumor suppressor gene in certain epithelial cancers. Recent evidence suggests that Runx1 is an important factor in breast cancer, however its role remains ambiguous. Here, we addressed whether Runx1 has a specific pathological role during breast cancer progression and show that Runx1 has an oncogenic function. We observed elevated Runx1 expression in a subset of human breast cancers. Furthermore, throughout the course of disease progression in a classical mouse model of breast cancer (i.e., the MMTV-PyMT transgenic model), Runx1 expression increases in the primary site (mammary gland) and is further upregulated in tumors and distal lung metastatic lesions. Ex vivo studies using tumor epithelial cells derived from these mice express significantly higher levels of Runx1 than normal mammary epithelial cells. The tumor cells exhibit increased rates of migration and invasion, indicative of an aggressive cancer phenotype. Inhibition of Runx1 expression using RNA interference significantly abrogates these cancer-relevant phenotypic characteristics. Importantly, our data establish that Runx1 contributes to murine mammary tumor development and malignancy and potentially represents a key disease-promoting and prognostic factor in human breast cancer progression and metastasis. PMID:25802202

  18. Connexin's Connection in Breast Cancer Growth and Progression

    PubMed Central

    2016-01-01

    Gap junctions are cell-to-cell junctions that are located in the basolateral surface of two adjoining cells. A gap junction channel is composed of a family of proteins called connexins. Gap junction channels maintain intercellular communication between two cells through the exchange of ions, small metabolites, and electrical signals. Gap junction channels or connexins are widespread in terms of their expression and function in maintaining the development, differentiation, and homeostasis of vertebrate tissues. Gap junction connexins play a major role in maintaining intercellular communication among different cell types of normal mammary gland for proper development and homeostasis. Connexins have also been implicated in the pathogenesis of breast cancer. Differential expression pattern of connexins and their gap junction dependent or independent functions provide pivotal cross talk of breast tumor cells with the surrounding stromal cell in the microenvironment. Substantial research from the last 20 years has accumulated ample evidences that allow us a better understanding of the roles that connexins play in the tumorigenesis of primary breast tumor and its metastatic progression. This review will summarize the knowledge about the connexins and gap junction activities in breast cancer highlighting the differential expression and functional dynamics of connexins in the pathogenesis of the disease. PMID:27642298

  19. Characterization of cell lines derived from breast cancers and normal mammary tissues for the study of the intrinsic molecular subtypes.

    PubMed

    Prat, Aleix; Karginova, Olga; Parker, Joel S; Fan, Cheng; He, Xiaping; Bixby, Lisa; Harrell, J Chuck; Roman, Erick; Adamo, Barbara; Troester, Melissa; Perou, Charles M

    2013-11-01

    Five molecular subtypes (luminal A, luminal B, HER2-enriched, basal-like, and claudin-low) with clinical implications exist in breast cancer. Here, we evaluated the molecular and phenotypic relationships of (1) a large in vitro panel of human breast cancer cell lines (BCCLs), human mammary fibroblasts (HMFs), and human mammary epithelial cells (HMECs); (2) in vivo breast tumors; (3) normal breast cell subpopulations; (4) human embryonic stem cells (hESCs); and (5) bone marrow-derived mesenchymal stem cells (hMSC). First, by integrating genomic data of 337 breast tumor samples with 93 cell lines we were able to identify all the intrinsic tumor subtypes in the cell lines, except for luminal A. Secondly, we observed that the cell lines recapitulate the differentiation hierarchy detected in the normal mammary gland, with claudin-low BCCLs and HMFs cells showing a stromal phenotype, HMECs showing a mammary stem cell/bipotent progenitor phenotype, basal-like cells showing a luminal progenitor phenotype, and luminal B cell lines showing a mature luminal phenotype. Thirdly, we identified basal-like and highly migratory claudin-low subpopulations of cells within a subset of triple-negative BCCLs (SUM149PT, HCC1143, and HCC38). Interestingly, both subpopulations within SUM149PT were enriched for tumor-initiating cells, but the basal-like subpopulation grew tumors faster than the claudin-low subpopulation. Finally, claudin-low BCCLs resembled the phenotype of hMSCs, whereas hESCs cells showed an epithelial phenotype without basal or luminal differentiation. The results presented here help to improve our understanding of the wide range of breast cancer cell line models through the appropriate pairing of cell lines with relevant in vivo tumor and normal cell counterparts.

  20. Comparative effect of inorganic and organic selenocyanate derivatives in mammary cancer chemoprevention.

    PubMed

    Ip, C; el-Bayoumy, K; Upadhyaya, P; Ganther, H; Vadhanavikit, S; Thompson, H

    1994-02-01

    Recently El-Bayoumy and coworkers have reported that 1,4-phenylene-bis(methylene)selenocyanate (p-XSC) was very effective in inhibiting 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis and adduct formation during the initiation phase (Cancer Res., 52, 2402-2407, 1992). Furthermore, this compound was found to be well tolerated by rats at high doses. The present study was designed to extend these earlier observations by investigating the response to lower levels of p-XSC given either before or after DMBA administration. At a level of 15 p.p.m. Se, p-XSC suppressed total mammary tumor yield by 80% and 52% in the initiation phase and post-initiation phase, respectively. A dose-response effect was evident in the range 5-15 p.p.m. Se. When p-XSC was given at a level of 5 p.p.m. Se during the entire course of the experimental period, total tumor yield was reduced by half. This dose is about 4 x less than the maximum tolerable dose (MTD). Other selenocyanate analogs were also examined in an attempt to obtain information on their respective chemopreventive index, which is calculated as the ratio of MTD to the effective dose which produces approximately a 50% inhibition in total tumor yield (ED50). The reagents studied included potassium selenocyanate, methyl selenocyanate and benzyl selenocyanate, as well as sodium selenite (reference compound). Compared to p-XSC, which has a chemopreventive index of 4.0, the other four compounds have a lower index ranging from 1.3 for sodium selenite and potassium selenocyanate to 2.0 for methyl selenocyanate and 2.5 for benzyl selenocyanate. A high chemopreventive index signifies that a compound is well tolerated at doses required for cancer suppression. The last component of the present study involved the repletion assay of liver glutathione peroxidase in selenium-deficient rats as a biomarker to estimate the metabolizability of the above selenium compounds. The bioavailability data suggest that the selenium from p

  1. p63 sustains self-renewal of mammary cancer stem cells through regulation of Sonic Hedgehog signaling

    PubMed Central

    Memmi, Elisa Maria; Sanarico, Anna Giulia; Giacobbe, Arianna; Peschiaroli, Angelo; Frezza, Valentina; Cicalese, Angelo; Pisati, Federica; Tosoni, Daniela; Zhou, Huiqing; Tonon, Giovanni; Antonov, Alexey; Melino, Gerry; Pelicci, Pier Giuseppe; Bernassola, Francesca

    2015-01-01

    The predominant p63 isoform, ΔNp63, is a master regulator of normal epithelial stem cell (SC) maintenance. However, in vivo evidence of the regulation of cancer stem cell (CSC) properties by p63 is still limited. Here, we exploit the transgenic MMTV-ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) mouse model of carcinogenesis to dissect the role of p63 in the regulation of mammary CSC self-renewal and breast tumorigenesis. ErbB2 tumor cells enriched for SC-like properties display increased levels of ΔNp63 expression compared with normal mammary progenitors. Down-regulation of p63 in ErbB2 mammospheres markedly restricts self-renewal and expansion of CSCs, and this action is fully independent of p53. Furthermore, transplantation of ErbB2 progenitors expressing shRNAs against p63 into the mammary fat pads of syngeneic mice delays tumor growth in vivo. p63 knockdown in ErbB2 progenitors diminishes the expression of genes encoding components of the Sonic Hedgehog (Hh) signaling pathway, a driver of mammary SC self-renewal. Remarkably, p63 regulates the expression of Sonic Hedgehog (Shh), GLI family zinc finger 2 (Gli2), and Patched1 (Ptch1) genes by directly binding to their gene regulatory regions, and eventually contributes to pathway activation. Collectively, these studies highlight the importance of p63 in maintaining the self-renewal potential of mammary CSCs via a positive modulation of the Hh signaling pathway. PMID:25739959

  2. SNORD-host RNA Zfas1 is a regulator of mammary development and a potential marker for breast cancer.

    PubMed

    Askarian-Amiri, Marjan E; Crawford, Joanna; French, Juliet D; Smart, Chanel E; Smith, Martin A; Clark, Michael B; Ru, Kelin; Mercer, Tim R; Thompson, Ella R; Lakhani, Sunil R; Vargas, Ana C; Campbell, Ian G; Brown, Melissa A; Dinger, Marcel E; Mattick, John S

    2011-05-01

    Long noncoding RNAs (lncRNAs) are increasingly recognized to play major regulatory roles in development and disease. To identify novel regulators in breast biology, we identified differentially regulated lncRNAs during mouse mammary development. Among the highest and most differentially expressed was a transcript (Zfas1) antisense to the 5' end of the protein-coding gene Znfx1. In vivo, Zfas1 RNA is localized within the ducts and alveoli of the mammary gland. Zfas1 intronically hosts three previously undescribed C/D box snoRNAs (SNORDs): Snord12, Snord12b, and Snord12c. In contrast to the general assumption that noncoding SNORD-host transcripts function only as vehicles to generate snoRNAs, knockdown of Zfas1 in a mammary epithelial cell line resulted in increased cellular proliferation and differentiation, while not substantially altering the levels of the SNORDs. In support of an independent function, we also found that Zfas1 is extremely stable, with a half-life >16 h. Expression analysis of the SNORDs revealed these were expressed at different levels, likely a result of distinct structures conferring differential stability. While there is relatively low primary sequence conservation between Zfas1 and its syntenic human ortholog ZFAS1, their predicted secondary structures have similar features. Like Zfas1, ZFAS1 is highly expressed in the mammary gland and is down-regulated in breast tumors compared to normal tissue. We propose a functional role for Zfas1/ ZFAS1 in the regulation of alveolar development and epithelial cell differentiation in the mammary gland, which, together with its dysregulation in human breast cancer, suggests ZFAS1 as a putative tumor suppressor gene.

  3. Mammary gland cancer in a colony of beagle dogs: Inheritance, and p53 & erbB-2 expression

    SciTech Connect

    Kelly, G.; Griffith, W.C.; Muggenburg, Tierney, L.A.; Lechner, J.F.; Hahn, F.F.

    1994-11-01

    One American woman in nine will be diagnosed with breast cancer in her lifetime. This somber statistic translates into 182,000 new diagnoses and 46,000 deaths per year. Efforts to decrease breast cancer mortality have focused on early detection and improved treatment. Such efforts would be facilitated by the identification of individuals predisposed to the disease. A family history of the disease can increase a woman`s risk for developing breast cancer by two- to six-fold. Inheritance of this disease is consistent with at least one susceptibility locus on chromosome 17 (17q12-21) with incomplete penetrance. However, other mechanisms of inherited susceptibility also contribute to the high incidence of the disease. The purpose of the present study was to characterize familial pattern of mammary cancer development in the dog colony. In addition, the expression of the p53 tumor supressor gene and c-erbB2 (p185{sup erbB2}) oncogene proteins, which are frequently altered in human breast cancer, were examined in dogs susceptible and resistant to mammary cancer.

  4. Increased expression and copy number amplification of LINE-1 and SINE B1 retrotransposable elements in murine mammary carcinoma progression

    PubMed Central

    Gualtieri, Alberto; Andreola, Federica; Sciamanna, Ilaria; Sinibaldi-Vallebona, Paola; Serafino, Annalucia; Spadafora, Corrado

    2013-01-01

    In higher eukaryotic genomes, Long Interspersed Nuclear Element 1 (LINE-1) retrotransposons and endogenous retroviruses represent large families of repeated elements encoding reverse transcriptase (RT) proteins. Short Interspersed Nuclear Element B1 (SINE B1) retrotrasposons do not encode RT, but use LINE-1-derived RT for their retrotransposition. We previously showed that many cancer types have an abundant endogenous RT activity. Inhibition of that activity, by either RNA interference-dependent silencing of active LINE-1 elements or by RT inhibitory drugs, reduced proliferation and promoted differentiation in cancer cells, indicating that LINE-1-encoded RT is required for tumor progression. Using MMTV-PyVT transgenic mice as a well-defined model of breast cancer progression, we now report that both LINE-1 and SINE B1 retrotransposons are up-regulated at a very early stage of tumorigenesis; LINE-1-encoded RT product and enzymatic activity were detected in tumor tissues as early as stage 1, preceding the widespread appearance of histological alterations and specific cancer markers, and further increased in later progression stages, while neither was present in non-pathological breast tissues. Importantly, both LINE-1 and SINE B1 retrotransposon families undergo copy number amplification during tumor progression. These findings therefore indicate that RT activity is distinctive of breast cancer cells and that, furthermore, LINE-1 and SINE B1 undergo copy number amplification during cancer progression. PMID:24231191

  5. Increased expression and copy number amplification of LINE-1 and SINE B1 retrotransposable elements in murine mammary carcinoma progression.

    PubMed

    Gualtieri, Alberto; Andreola, Federica; Sciamanna, Ilaria; Sinibaldi-Vallebona, Paola; Serafino, Annalucia; Spadafora, Corrado

    2013-11-01

    In higher eukaryotic genomes, Long Interspersed Nuclear Element 1 (LINE-1) retrotransposons and endogenous retroviruses represent large families of repeated elements encoding reverse transcriptase (RT) proteins. Short Interspersed Nuclear Element B1 (SINE B1) retrotrasposons do not encode RT, but use LINE-1-derived RT for their retrotransposition. We previously showed that many cancer types have an abundant endogenous RT activity. Inhibition of that activity, by either RNA interference-dependent silencing of active LINE-1 elements or by RT inhibitory drugs, reduced proliferation and promoted differentiation in cancer cells, indicating that LINE-1-encoded RT is required for tumor progression. Using MMTV-PyVT transgenic mice as a well-defined model of breast cancer progression, we now report that both LINE-1 and SINE B1 retrotransposons are up-regulated at a very early stage of tumorigenesis; LINE-1-encoded RT product and enzymatic activity were detected in tumor tissues as early as stage 1, preceding the widespread appearance of histological alterations and specific cancer markers, and further increased in later progression stages, while neither was present in non-pathological breast tissues. Importantly, both LINE-1 and SINE B1 retrotransposon families undergo copy number amplification during tumor progression. These findings therefore indicate that RT activity is distinctive of breast cancer cells and that, furthermore, LINE-1 and SINE B1 undergo copy number amplification during cancer progression.

  6. Genetic determination of susceptibility to estrogen-induced mammary cancer in the ACI rat: mapping of Emca1 and Emca2 to chromosomes 5 and 18.

    PubMed

    Gould, Karen A; Tochacek, Martin; Schaffer, Beverly S; Reindl, Tanya M; Murrin, Clare R; Lachel, Cynthia M; VanderWoude, Eric A; Pennington, Karen L; Flood, Lisa A; Bynote, Kimberly K; Meza, Jane L; Newton, Michael A; Shull, James D

    2004-12-01

    Hormonal, genetic, and environmental factors play major roles in the complex etiology of breast cancer. When treated continuously with 17beta-estradiol (E2), the ACI rat exhibits a genetically conferred propensity to develop mammary cancer. The susceptibility of the ACI rat to E2-induced mammary cancer appears to segregate as an incompletely dominant trait in crosses to the resistant Copenhagen (COP) strain. In both (ACI x COP)F(2) and (COP x ACI)F(2) populations, we find strong evidence for a major genetic determinant of susceptibility to E2-induced mammary cancer on distal rat chromosome 5. Our data are most consistent with a model in which the ACI allele of this locus, termed Emca1 (estrogen-induced mammary cancer 1), acts in an incompletely dominant manner to increase both tumor incidence and tumor multiplicity as well as to reduce tumor latency in these populations. We also find evidence suggestive of a second locus, Emca2, on chromosome 18 in the (ACI x COP)F(2) population. The ACI allele of Emca2 acts in a dominant manner to increase incidence and decrease latency. Together, Emca1 and Emca2 act independently to modify susceptibility to E2-induced mammary cancer.

  7. Does cancer start in the womb? altered mammary gland development and predisposition to breast cancer due to in utero exposure to endocrine disruptors.

    PubMed

    Soto, Ana M; Brisken, Cathrin; Schaeberle, Cheryl; Sonnenschein, Carlos

    2013-06-01

    We are now witnessing a resurgence of theories of development and carcinogenesis in which the environment is again being accepted as a major player in phenotype determination. Perturbations in the fetal environment predispose an individual to disease that only becomes apparent in adulthood. For example, gestational exposure to diethylstilbestrol resulted in clear cell carcinoma of the vagina and breast cancer. In this review the effects of the endocrine disruptor bisphenol-A (BPA) on mammary development and tumorigenesis in rodents is used as a paradigmatic example of how altered prenatal mammary development may lead to breast cancer in humans who are also widely exposed to it through plastic goods, food and drink packaging, and thermal paper receipts. Changes in the stroma and its extracellular matrix led to altered ductal morphogenesis. Additionally, gestational and lactational exposure to BPA increased the sensitivity of rats and mice to mammotropic hormones during puberty and beyond, thus suggesting a plausible explanation for the increased incidence of breast cancer.

  8. ETV6-NTRK3 fusion oncogene initiates breast cancer from committed mammary progenitors via activation of AP1 complex

    PubMed Central

    Li, Zhe; Tognon, Cristina E.; Godinho, Frank J.; Yasaitis, Laura; Hock, Hanno; Herschkowitz, Jason I.; Lannon, Chris L.; Cho, Eunah; Kim, Seong-Jin; Bronson, Roderick T.; Perou, Charles M.; Sorensen, Poul H.; Orkin, Stuart H.

    2007-01-01

    SUMMARY To better understand the cellular origin of breast cancer, we developed a mouse model that recapitulates expression of the ETV6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation characteristic of human secretory breast carcinoma. Activation of EN expression in mammary tissues by Wap-Cre leads to fully penetrant, multifocal malignant breast cancer with short latency. We provide genetic evidence that in nulliparous Wap-Cre;EN females, committed alveolar bipotent or CD61+ luminal progenitors, are targets of tumorigenesis. Furthermore, EN transforms these otherwise transient progenitors through activation of the AP1 complex. Given increasing relevance of chromosomal translocations in epithelial cancers, such mice serve as a paradigm for the study of their genetic pathogenesis and cellular origins, and generation of novel preclinical models. SIGNIFICANCE For the largest class of human tumors, those of epithelial origin, little is known about their initiating genetic hits or cells of origin. Whether tissue stem cells or more committed progenitors are targets for transformation is uncertain. We developed a system in which epithelial tumorigenesis can be assessed from the initial event to frank malignancy. In this breast cancer model based on chromosomal translocation, we show through genetic marking that committed mammary progenitors, rather than mammary stem cells, are direct targets of transformation. We show that activation of the AP1 complex represents a critical downstream event of the ETV6-NTRK3 translocation. Further focus on this transcriptional complex as a target in human breast cancer is warranted. PMID:18068631

  9. Isoform-specific function of calpains in cell adhesion disruption: studies in postlactational mammary gland and breast cancer.

    PubMed

    Rodríguez-Fernández, Lucía; Ferrer-Vicens, Iván; García, Concha; Oltra, Sara S; Zaragozá, Rosa; Viña, Juan R; García-Trevijano, Elena R

    2016-09-15

    Cleavage of adhesion proteins is the first step for physiological clearance of undesired cells during postlactational regression of the mammary gland, but also for cell migration in pathological states such as breast cancer. The intracellular Ca(2+)-dependent proteases, calpains (CAPNs), are known to cleave adhesion proteins. The isoform-specific function of CAPN1 and CAPN2 was explored and compared in two models of cell adhesion disruption: mice mammary gland during weaning-induced involution and breast cancer cell lines according to tumor subtype classification. In both models, E-cadherin, β-catenin, p-120, and talin-1 were cleaved as assessed by western blot analysis. Both CAPNs were able to cleave adhesion proteins from lactating mammary gland in vitro Nevertheless, CAPN2 was the only isoform found to co-localize with E-cadherin in cell junctions at the peak of lactation. CAPN2/E-cadherin in vivo interaction, analyzed by proximity ligation assay, was dramatically increased during involution. Calpain inhibitor administration prevented the cytosolic accumulation of truncated E-cadherin cleaved by CAPN2. Conversely, in breast cancer cells, CAPN2 was restricted to the nuclear compartment. The isoform-specific expression of CAPNs and CAPN activity was dependent on the breast cancer subtype. However, CAPN1 and CAPN2 knockdown cells showed that cleavage of adhesion proteins and cell migration was mediated by CAPN1, independently of the breast cancer cell line used. Data presented here suggest that the subcellular distribution of CAPN1 and CAPN2 is a major issue in target-substrate recognition; therefore, it determines the isoform-specific role of CAPNs during disruption of cell adhesion in either a physiological or a pathological context.

  10. Tumour-associated macrophages influence canine mammary cancer stem-like cells enhancing their pro-angiogenic properties.

    PubMed

    Rybicka, A; Eyileten, C; Taciak, B; Mucha, J; Majchrzak, K; Hellmen, E; Krol, M

    2016-08-01

    Cancer stem-like cells as cells with ability to self-renewal and potential to differentiate into various types of cells are known to be responsible for tumour initiation, recurrence and drug resistance. Hence a comprehensive research is concentrated on discovering cancer stem-like cells biology and interdependence between them and other cells. The aim of our study was to evaluate the impact of macrophages on cancer stem-like cells in canine mammary carcinomas. As recent studies indicated presence of macrophages in cancer environment stimulates cancer cells into more motile and invasive cells by acquisition of macrophage phenotypes. From two canine mammary tumour cell lines, CMT-U27 and P114 cancer stem-like cells were stained with Sca1, CD44 and EpCAM monoclonal antibodies and isolated. Those cells were next co-cultured with macrophages for 5 days and used for further experiments. Canine Gene Expression Microarray revealed 29 different expressed transcripts in cancer stem-like cells co-cultured with macrophages compared to those in mono-culture. Up-regulation of C-C motif chemokine 2 was considered as the most interesting for further investigation. Additionally, those cells showed overexpression of genes involved in non-canonical Wnt pathway. The results of 3D tubule formation in endothelial cells induced by cancer stem-like cells co-cultured with macrophages compared to cancer stem-like cells from mono-cultures and with addition of Recombinant Canine CCL2/MCP-1 revealed the same stimulating effect. Based on those results we can conclude that macrophages have an impact on cancer stem-like cells increasing secretion of pro-angiogenic factors.

  11. Lymphoscintigraphy Can Select Breast Cancer Patients for Internal Mammary Chain Radiotherapy

    SciTech Connect

    Hindie, Elif; Groheux, David; Hennequin, Christophe; Zanotti-Fregonara, Paolo; Vercellino, Laetitia; Berenger, Nathalie; Toubert, Marie-Elisabeth; Maylin, Claude; Vilcoq, Jacques-Robert; Espie, Marc

    2012-07-15

    Purpose: Given the risk of undesired toxicity, prophylactic internal mammary (IM) chain irradiation should be offered only to patients at high risk of occult involvement. Lymphoscintigraphy for axillary sentinel node biopsy might help in selecting these patients. Methods and Materials: We reviewed published studies with the following selection criteria: {>=}300 breast cancer patients referred for axilla sentinel node biopsy; scintigraphy performed after peritumoral or intratumoral tracer injection; IM biopsy in the case of IM drainage; and axilla staged routinely independent of IM status. Results: Six prospective studies, for a total of 3,876 patients, fulfilled the inclusion criteria. Parasternal drainage was present in 792 patients (20.4%). IM biopsy was performed in 644 patients and was positive in 111 (17.2%). Of the positive IM biopsies, 40% were associated with tumors in the lateral breast quadrants. A major difference in the IM positivity rate was found according to the axilla sentinel node status. In patients with negative axilla, the IM biopsy was positive in 7.8% of cases. In patients with positive axilla, however, the IM biopsy was positive in 41% (p < .00001). Because biopsy of multiple IM hot nodes is difficult, the true risk could be even greater, probably close to 50%. Conclusions: Patients with IM drainage on lymphoscintigraphy and a positive axilla sentinel node have a high risk of occult IM involvement. These women should be considered for IM radiotherapy.

  12. Canine mammary tumors contain cancer stem-like cells and form spheroids with an embryonic stem cell signature.

    PubMed

    Ferletta, Maria; Grawé, Jan; Hellmén, Eva

    2011-01-01

    We have investigated the presence of tentative stem-like cells in the canine mammary tumor cell line CMT-U229. This cell line is established from an atypical benign mixed mammary tumor, which has the property of forming duct-like structures in collagen gels. Stem cells in mammary glands are located in the epithelium; therefore we thought that the CMT-U229 cell line would be suitable for detection of tentative cancer stem-like cells. Side population (SP) analyses by flow cytometry were performed with cells that formed spheroids and with cells that did not. Flow cytometric, single sorted cells were expanded and re-cultured as spheroids. The spheroids were paraffin embedded and characterized by immunohistochemistry. SP analyses showed that spheroid forming cells (retenate) as well as single cells (filtrate) contained SP cells. Sca1 positive cells were single cell sorted and thereafter the SP population increased with repeated SP analyses. The SP cells were positively labeled with the cell surface-markers CD44 and CD49f (integrin alpha6); however the expression of CD24 was low or negative. The spheroids expressed the transcription factor and stem cell marker Sox2, as well as Oct4. Interestingly, only peripheral cells of the spheroids and single cells were positive for Oct4 expression. SP cells are suggested to correspond to stem cells and in this study, we have enriched for tentative tumor stem-like cells derived from a canine mammary tumor. All the used markers indicate that the studied CMT-U229 cell line contains SP cells, which in particular have cancer stem-like cell characteristics.

  13. Co-expression of vascular endothelial growth factor (VEGF) and its receptors (flk-1 and flt-1) in hormone-induced mammary cancer in the Noble rat

    PubMed Central

    Xie, B; Tam, N N C; Tsao, S W; Wong, Y C

    1999-01-01

    Vascular endothelial growth factor (VEGF) is recognized to play a predominant role in breast cancer prognosis. The action of VEGF is mediated by two high-affinity receptors with ligand-stimulated tyrosine kinase activity: VEGFR-1/flt-1 and VEGFR-2/flk-1, which are expressed mainly in vascular endothelial cells. To the best of our knowledge, no previous studies on the expression of these receptors in breast cancer cells has been made. We have established a new animal model for breast cancer, using a combination of 17β-oestradiol and testosterone as ‘carcinogens’. Taking advantage of the animal model, we have demonstrated that mammary cancer cells expressed not only high levels of VEGF but also, surprisingly, its receptors (flt-1 and flk-1) in mammary cancer cells. Intense reactivities to VEGF, flt-1 and flk-1 were observed in mammary cancer cells, especially in invasive mammary carcinoma. Western blot analysis confirmed the increase in flk-1 and flt-1 proteins in induced mammary cancers. Based on these observations, we hypothesize that in mammary cancer, VEGF regulates, in addition to endothelial proliferation and angiogenesis, also growth of cancer cells by an autocrine mechanism mediated through its receptors. To further verify this hypothesis, we investigated the correlation between cellular proliferation and the expression of VEGF, flt-1 and flk-1. Using double-labelling immunocytochemistry, we have shown a correlation between high VEGF activity and Ki-67 expression. The Ki-67 indices in the areas of strong and weak VEGF reactivities were 58.3% and 3.7% respectively. Similarly, there was also a correlation of strong flk-1 and Ki-67 reactivity. The Ki-67 indices for areas of strong and weak flk-1 reactivities were 53.9% and 3.1% respectively. On the other hand, there was a reverse correlation between flt-1 and Ki-67 activities. These results indicate that overexpression of VEGF and flk-1 is correlated with high Ki-67 index. The data, therefore, suggest that

  14. Recent Progress in Pancreatic Cancer

    PubMed Central

    Wolfgang, Christopher L.; Herman, Joseph M.; Laheru, Daniel A.; Klein, Alison P.; Erdek, Michael A.; Fishman, Elliot K.; Hruban, Ralph H.

    2013-01-01

    Pancreatic cancer is currently one of the deadliest of the solid malignancies. However, surgery to resect neoplasms of the pancreas is safer and less invasive than ever, novel drug combinations have been shown to improve survival, advances in radiation therapy have resulted in less toxicity, and enormous strides have been made in our understanding of the fundamental genetics of pancreatic cancer. These advances provide hope but they also increase the complexity of caring for patients. It is clear that multidisciplinary care that provides comprehensive and coordinated evaluation and treatment is the most effective way to manage patients with pancreatic cancer. PMID:23856911

  15. Preventing Breast Cancer: Making Progress

    MedlinePlus

    ... medical literature, the Study of Tamoxifen and Raloxifene (STAR) trial was started in 1998. That study enrolled ... in the BCPT. Studies, such as BCPT and STAR, involve women who have not had breast cancer, ...

  16. Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer.

    PubMed Central

    Siegel, P M; Ryan, E D; Cardiff, R D; Muller, W J

    1999-01-01

    To assess the importance of Neu activation during mammary tumorigenesis, altered receptors harboring in-frame deletions within the extracellular domain were expressed in transgenic mice. Females from several independent lines develop multiple mammary tumors that frequently metastasize to the lung. Tumor progression in these strains was associated with elevated levels of tyrosine-phosphorylated Neu and ErbB-3. Consistent with these observations, a survey of primary human breast tumors revealed frequent co-expression of both erbB-2 and erbB-3 transcripts. The ability of altered Neu receptors to induce mammary tumorigenesis in transgenic mice prompted us to examine whether similar mutations occurred in ErbB-2 during human breast cancer progression. Interestingly, an alternatively spliced form of erbB-2, closely resembling spontaneous activated forms of neu, was detected in human breast tumors. The ErbB-2 receptor encoded by this novel transcript harbors an in-frame deletion of 16 amino acids in the extracellular domain and can transform Rat-1 fibroblasts. Together, these observations argue that co-expression of ErbB-2 and ErbB-3 may play a critical role in the induction of human breast tumors, and raise the possibility that activating mutations in the ErbB-2 receptor may also contribute to this process. PMID:10205169

  17. Detection of Internal Mammary Adenopathy in Patients With Breast Cancer by PET/CT and MRI

    PubMed Central

    Jochelson, Maxine S.; Lebron, Lizza; Jacobs, Stefanie S.; Zheng, Junting; Moskowitz, Chaya S.; Powell, Simon N.; Sacchini, Virgilio; Ulaner, Gary A.; Morris, Elizabeth A.; Dershaw, D. David

    2016-01-01

    OBJECTIVE The purpose of this study was to assess the prevalence of internal mammary node (IMN) adenopathy in patients with breast cancer and compare breast MRI and PET/CT for detection of IMN adenopathy. MATERIALS AND METHODS This retrospective study included 90 women who underwent MRI and PET/CT before neoadjuvant chemotherapy for clinical stage IIA through IIIA disease. MRI and PET/CT examinations were read independently by two readers trained in breast imaging and nuclear medicine. All patients underwent follow-up MRI at the end of chemotherapy, and 10 with hypermetabolic IMNs underwent follow-up PET/CT. Histology was not obtained. Women were considered to have IMN adenopathy when nodes seen on MRI or having standardized uptake value (SUV) greater than mediastinal blood pool decreased in either size or SUV (or both) after treatment. Features including lymphovascular invasion, tumor quadrant(s), and axillary adenopathy were compared between presence and absence of IMN adenopathy using Fisher’s exact test. Prevalence was determined on the basis of the percentage of patients with IMN adenopathy by either modality. The McNemar test compared the prevalence of IMN adenopathy on MRI to its prevalence on PET/CT. RESULTS Prevalence of IMN adenopathy was 16% (14/90) by MRI and 14% (13/90) by PET/CT (p = 0.317). After chemotherapy, IMN adenopathy resolved in 12 of 14 patients (86%). In two patients with poor responses in primary tumors, IMN adenopathy persisted, and both patients developed metastatic disease within 6 months. At 3 years, survival was significantly worse in patients with IMN adenopathy than in those without (85.7% vs 53.3%, respectively; p = 0.009). CONCLUSION In women with advanced breast cancer receiving neoadjuvant chemotherapy, prevalence of IMN adenopathy was 16%, equally detected by breast MRI and PET/CT. Identification of IMN adenopathy may affect treatment and provides prognostic information. PMID:26397342

  18. Mammary cancer and epithelial stem cells: a problem or a solution?

    PubMed

    Smith, Gilbert H

    2002-01-01

    The existing paradigms for stem cells in adult tissues include the integument, the alimentary canal, the lung, the liver, skeletal muscle and bone marrow. The mammary gland, by contrast, is the 'new kid on the block'. What little is known about stem cells in the mammary gland indicates that they possess a prodigious capacity for self-renewal. More importantly, in rodents, they persist with undiminished reproductive vigor throughout the organism's lifetime without regard to age or reproductive history. Do these stem cells represent primary targets for mammary neoplasia? If so, what are the implications for prevention/therapy?

  19. Transcriptome analysis of embryonic mammary cells reveals insights into mammary lineage establishment

    PubMed Central

    2011-01-01

    identification of novel potential regulators of mammary fate and mesenchymal-epithelial cross-talk. Since cancers may represent diseases of mesenchymal-epithelial communications, we anticipate these results will provide foundations for further studies into the fundamental links between developmental, stem cell and breast cancer biology. PMID:21834968

  20. Yin Yang 1 cooperates with activator protein 2 to stimulate ERBB2 gene expression in mammary cancer cells.

    PubMed

    Begon, Dominique Y; Delacroix, Laurence; Vernimmen, Douglas; Jackers, Pascale; Winkler, Rosita

    2005-07-01

    Overexpression of the ERBB2 oncogene is observed in about 30% of breast cancers and is generally correlated with a poor prognosis. Previous results from our and other laboratories indicated that elevated transcriptional activity contributes significantly to the overexpression of ERBB2 mRNA in mammary adenocarcinoma cell lines. Activator protein 2 (AP-2) transcription factors account for this overexpression through two recognition sequences located 215 and 500 bp upstream from the transcription start site. Furthermore, AP-2 transcription factors are highly expressed in cancer cell lines overexpressing ERBB2. In this report, we examined the cooperative effect of Yin Yang 1 (YY1) on AP-2-induced activation of ERBB2 promoter activity. We detected high levels of YY1 transcription factor in mammary cancer cell lines. Notably, we showed that YY1 enhances AP-2alpha transcriptional activation of the ERBB2 promoter through an AP-2 site both in HepG2 and in HCT116 cells, whereas a carboxyl-terminal-truncated form of YY1 cannot. Moreover, we demonstrated the interaction between endogenous AP-2 and YY1 factors in the BT-474 mammary adenocarcinoma cell line. In addition, inhibition of endogenous YY1 protein by an antisense decreased the transcription of an AP-2-responsive ERBB2 reporter plasmid in BT-474 breast cancer cells. Finally, we detected in vivo AP-2 and YY1 occupancy of the ERBB2 proximal promoter in chromatin immunoprecipitation assays. Our data thus provide evidence that YY1 cooperates with AP-2 to stimulate ERBB2 promoter activity through the AP-2 binding sites.

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

    PubMed Central

    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.

    2013-01-01

    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. PMID:24131889

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

    NASA Astrophysics Data System (ADS)

    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.

  3. Cancer nanomedicine: progress, challenges and opportunities.

    PubMed

    Shi, Jinjun; Kantoff, Philip W; Wooster, Richard; Farokhzad, Omid C

    2017-01-01

    The intrinsic limits of conventional cancer therapies prompted the development and application of various nanotechnologies for more effective and safer cancer treatment, herein referred to as cancer nanomedicine. Considerable technological success has been achieved in this field, but the main obstacles to nanomedicine becoming a new paradigm in cancer therapy stem from the complexities and heterogeneity of tumour biology, an incomplete understanding of nano-bio interactions and the challenges regarding chemistry, manufacturing and controls required for clinical translation and commercialization. This Review highlights the progress, challenges and opportunities in cancer nanomedicine and discusses novel engineering approaches that capitalize on our growing understanding of tumour biology and nano-bio interactions to develop more effective nanotherapeutics for cancer patients.

  4. Transgenic Mammary Epithelial Osteopontin (Spp1) Expression Induces Proliferation and Alveologenesis

    PubMed Central

    Hubbard, Neil E.; Chen, Qian J.; Sickafoose, Laura K.; Wood, Meghan B.; Gregg, Jeffrey P.; Abrahamsson, Ninnie M.; Engelberg, Jesse A.; Walls, Judith E.

    2013-01-01

    Osteopontin (OPN) Spp1 is involved in differentiation of the mammary gland. We engineered mice to overexpress OPN in mammary epithelium and describe an altered mammary phenotype. Three transgenic (Tg) founder lines FVB/N Tg(MMTV-Opn)(1-3BOR) were propagated after FVB/NJ pronuclear injections. Mammary glands from Tg-OPN mice compared to littermate controls showed, at 4 weeks of age, exaggerated terminal end buds; at 8 and 12 weeks, more numerous and complex ducts with increased luminal protein; and at 16 weeks, increased lobulogenesis. Lactational Tg-OPN mammary glands showed more rapid lobulogenesis and lactational changes with slower gland involution and regression following weaning. Ex vivo lobulogenesis was noticeably increased from organoids of Tg-OPN mice. Immunohistochemistry revealed cytoplasmic OPN accumulation and increased Ki-67 positive mammary epithelial cells in Tg-OPN mammary glands. OPN appears to convey a proliferative stimulus for mammary epithelial cells and alters development and differentiation. These OPN mammary overexpressing mice provide a means to study the role of OPN in cancer progression. PMID:24069507

  5. Homocysteine Is an Oncometabolite in Breast Cancer, Which Promotes Tumor Progression and Metastasis

    DTIC Science & Technology

    2014-09-01

    tissues and compare the expression levels in normal mouse mammary gland . For this, we used biological triplicates by preparing RNA from tumor tissues...homocysteine to be increased 4.5-fold in MMTV-HRAS mouse breast tumor tissues compared to age-matched wild type mouse mammary tissues. Similarly, the...levels of homocysteine went up 7.3-fold in MMTV-PyMT mouse breast cancer tissues 3 compared to age-matched wild type mouse mammary tissues

  6. Maternal blueberry diet programs Wnt-1-induced mammary tumor progression and gene expression in mouse offspring

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Despite the well-accepted notion of peri-natal origins of adult diseases, the factors and regulatory mechanisms underlying breast cancer development at later adult life remains unclear. Diet is a highly modifiable determinant of breast cancer risk, and the effects of the in utero nutritional environ...

  7. Antineoplastic effect of iodine in mammary cancer: participation of 6-iodolactone (6-IL) and peroxisome proliferator-activated receptors (PPAR)

    PubMed Central

    Aceves, Carmen; García-Solís, Pablo; Arroyo-Helguera, Omar; Vega-Riveroll, Laura; Delgado, Guadalupe; Anguiano, Brenda

    2009-01-01

    Introduction Studies in mammary cancer demonstrated that moderately high concentrations of molecular iodine (I2) have a antiproliferative and apoptotic effect either in vivo as in vitro, however the cellular intermediated involved in these effects has not been elucidated. Methods Virgin Sprague-Dawley rats were treated with methyl-nitrosourea (MNU: single dose ip, 50 mg/Kg bw) and the participation of arachidonic acid (AA) and PPAR receptors in the antineoplasic effect of I2 where analyzed. Results I2-treated rats for four weeks exhibited a significant reduction in the incidence (62.5 vs. 100%) and size (0.87 ± 0.98 vs 1.96 ± 1.5 cm3) of mammary tumors. HPLC analysis showed that tumoral but not normal mammary tissue contained an elevated basal concentration of AA and significantly more AA-iodinated called 6-iodolactone (6-IL) after chronic I2 treatment. Tumors from I2-treated rats showed fewer cells positive to proliferating cell nuclear antigen, lower blood vessel density, as well as decreases in vascular endothelial growth factor, urokinase-type plasminogen activator, and PPAR type alpha (PPARα). These same tumors showed increases in the cell death markers, TUNEL-positive cells (p < 0.05) and the enzyme caspase-3 (trend), as well as significant induction of PPAR type gamma (PPARγ). Conclusion Together, these data demonstrate that the antineoplasic effect of iodine involves 6-IL formation and PPARγ induction. PMID:19500378

  8. Hyaluronan, Inflammation, and Breast Cancer Progression

    PubMed Central

    Schwertfeger, Kathryn L.; Cowman, Mary K.; Telmer, Patrick G.; Turley, Eva A.; McCarthy, James B.

    2015-01-01

    Breast cancer-induced inflammation in the tumor reactive stroma supports invasion and malignant progression and is contributed to by a variety of host cells including macrophages and fibroblasts. Inflammation appears to be initiated by tumor cells and surrounding host fibroblasts that secrete pro-inflammatory cytokines and chemokines and remodel the extracellular matrix (ECM) to create a pro-inflammatory “cancerized” or tumor reactive microenvironment that supports tumor expansion and invasion. The tissue polysaccharide hyaluronan (HA) is an example of an ECM component within the cancerized microenvironment that promotes breast cancer progression. Like many ECM molecules, the function of native high-molecular weight HA is altered by fragmentation, which is promoted by oxygen/nitrogen free radicals and release of hyaluronidases within the tumor microenvironment. HA fragments are pro-inflammatory and activate signaling pathways that promote survival, migration, and invasion within both tumor and host cells through binding to HA receptors such as CD44 and RHAMM/HMMR. In breast cancer, elevated HA in the peri-tumor stroma and increased HA receptor expression are prognostic for poor outcome and are associated with disease recurrence. This review addresses the critical issues regarding tumor-induced inflammation and its role in breast cancer progression focusing specifically on the changes in HA metabolism within tumor reactive stroma as a key factor in malignant progression. PMID:26106384

  9. Silencing Vimentin Expression Decreases Pulmonary Metastases in a Pre-Diabetic Mouse Model of Mammary Tumor Progression

    PubMed Central

    Zelenko, Zara; Gallagher, Emily J.; Tobin-Hess, Aviva; Belardi, Valentina; Rostoker, Ran; Blank, Jeffery; Dina, Yemisi; LeRoith, Derek

    2016-01-01

    Increased breast cancer risk and mortality has been associated with obesity and Type 2 diabetes (T2D). Hyperinsulinemia, a key factor in obesity, pre-diabetes and T2D, has been associated with decreased breast cancer survival. In the current study, a mouse model of pre-diabetes (MKR mouse) was used to investigate the mechanisms through which endogenous hyperinsulinemia promotes mammary tumor metastases. The MKR mice developed larger primary tumors and greater number of pulmonary metastases compared to wild type (WT) mice after injection with c-Myc/Vegf overexpressing MVT-1 cells. Analysis of the primary tumors showed significant increase in Vimentin protein expression in the MKR mice compared to WT. We hypothesized that Vimentin was an important mediator in the effect of hyperinsulinemia on breast cancer metastasis. Lentiviral shRNA knockdown of Vimentin led to a significant decrease in invasion of the MVT-1 cells and abrogated the increase in cell invasion in response to insulin. In the pre-diabetic MKR mouse, Vimentin knockdown led to a decrease in pulmonary metastases. In vitro, we found that insulin increased pAKT, prevented Caspase 3 activation, and increased Vimentin. Inhibiting the PI3K/AKT pathway, using NVP-BKM120, increased active Caspase 3 and decreased Vimentin levels. This study is the first to show that Vimentin plays an important role in tumor metastasis in vivo in the setting of pre-diabetes and endogenous hyperinsulinemia. Vimentin targeting may be an important therapeutic strategy to reduce metastases in patients with obesity, pre-diabetes or T2D. PMID:27568979

  10. Catalog of genetic progression of human cancers: breast cancer.

    PubMed

    Desmedt, Christine; Yates, Lucy; Kulka, Janina

    2016-03-01

    With the rapid development of next-generation sequencing, deeper insights are being gained into the molecular evolution that underlies the development and clinical progression of breast cancer. It is apparent that during evolution, breast cancers acquire thousands of mutations including single base pair substitutions, insertions, deletions, copy number aberrations, and structural rearrangements. As a consequence, at the whole genome level, no two cancers are identical and few cancers even share the same complement of "driver" mutations. Indeed, two samples from the same cancer may also exhibit extensive differences due to constant remodeling of the genome over time. In this review, we summarize recent studies that extend our understanding of the genomic basis of cancer progression. Key biological insights include the following: subclonal diversification begins early in cancer evolution, being detectable even in in situ lesions; geographical stratification of subclonal structure is frequent in primary tumors and can include therapeutically targetable alterations; multiple distant metastases typically arise from a common metastatic ancestor following a "metastatic cascade" model; systemic therapy can unmask preexisting resistant subclones or influence further treatment sensitivity and disease progression. We conclude the review by describing novel approaches such as the analysis of circulating DNA and patient-derived xenografts that promise to further our understanding of the genomic changes occurring during cancer evolution and guide treatment decision making.

  11. KISS1R induces invasiveness of estrogen receptor-negative human mammary epithelial and breast cancer cells.

    PubMed

    Cvetkovic, Donna; Dragan, Magdalena; Leith, Sean J; Mir, Zuhaib M; Leong, Hon S; Pampillo, Macarena; Lewis, John D; Babwah, Andy V; Bhattacharya, Moshmi

    2013-06-01

    Kisspeptins (KPs), peptide products of the KISS1 metastasis-suppressor gene, are endogenous ligands for a G protein-coupled receptor (KISS1R). KISS1 acts as a metastasis suppressor in numerous human cancers. However, recent studies have demonstrated that an increase in KISS1 and KISS1R expression in patient breast tumors correlates with higher tumor grade and metastatic potential. We have shown that KP-10 stimulates invasion of estrogen receptor α (ERα)-negative MDA-MB-231 breast cancer cells via transactivation of the epidermal growth factor receptor (EGFR). Here, we report that either KP-10 treatment of ERα-negative nonmalignant mammary epithelial MCF10A cells or expression of KISS1R in MCF10A cells induced a mesenchymal phenotype and stimulated invasiveness. Similarly, exogenous expression of KISS1R in ERα-negative SKBR3 breast cancer cells was sufficient to trigger invasion and induced extravasation in vivo. In contrast, KP-10 failed to transactivate EGFR or stimulate invasiveness in the ERα-positive MCF7 and T47D breast cancer cells. This suggested that ERα negatively regulates KISS1R-dependent breast cancer cell migration, invasion, and EGFR transactivation. In support of this, we found that these KP-10-induced effects were ablated upon exogenous expression of ERα in the MDA-MB-231 cells, by down-regulating KISS1R expression. Lastly, we have identified IQGAP1, an actin cytoskeletal binding protein as a novel binding partner of KISS1R, and have shown that KISS1R regulates EGFR transactivation in breast cancer cells in an IQGAP1-dependent manner. Overall, our data strongly suggest that the ERα status of mammary cells dictates whether KISS1R may be a novel clinical target for treating breast cancer metastasis.

  12. Pleiotropic functions of fibroblast growth factor signaling in embryonic mammary gland development.

    PubMed

    Kim, Eun-Jung; Jung, Han-Sung; Lu, Pengfei

    2013-06-01

    The mammary gland is an ectodermal appendage and a defining feature of mammals. Consistent with it being a recent evolutionary novelty, many of the molecules essential for the ontogeny and morphogenesis of various vertebrate organs, including those in the fibroblast growth factor (FGF) signaling pathway, are co-opted for induction, maintenance and morphogenesis of the mammary glands. Understanding the mechanism whereby FGF signaling regulates the fundamental cell behavior during normal mammary gland develop may facilitate determination of the consequences of its deregulation during breast cancer progression.

  13. In Vivo Role of Six1 in Mammary Gland Tumorigenesis

    DTIC Science & Technology

    2008-04-01

    overexpression is documented in a number of tumor types, including ovarian cancer, hepatocellular carcinoma, Wilms ’ tumor , rhabdomyosarcomas and...Klein, U., and Tycko, B. 2002. Gene expression in Wilms ’ tumor mimics the earliest committed stage in the metanephric mesenchymal-epithelial...progression of breast cancer. Most significantly, we have determined that Six1 is sufficient to induce tumor formation in the mammary glands of mice

  14. Characterization of mammary adenocarcinomas in male rats after N-methyl-N-nitrosourea exposure--Potential for human male breast cancer model.

    PubMed

    Yoshizawa, Katsuhiko; Yuki, Michiko; Kinoshita, Yuichi; Emoto, Yuko; Yuri, Takashi; Shikata, Nobuaki; Elmore, Susan A; Tsubura, Airo

    2016-05-01

    The frequency of breast cancer in men is extremely rare, reported to be less than 1% and there is currently no available animal model for male mammary tumors. We compared the characteristics of various immunohistochemical markers in N-methyl-N-nitrosourea (MNU)-induced mammary adenocarcinomas in male and female Crj:CD(SD)IGS rats including: estrogen receptor α (ER), progesterone receptor (PgR), androgen receptor (AR), receptor tyrosine-protein kinase erbB-2 (HER2), GATA binding protein 3 (GATA3), and proliferating cell nuclear antigen (PCNA). Female mammary adenocarcinomas were strongly positive in the nuclei of tumor cells for PCNA and ER (100%) with only 60% and 53% expressing PgR and GATA3, respectively. 100% of male adenocarcinomas also exhibited strongly positive expression in the nuclei of tumor cells for PCNA, with 25% expressing AR and only 8% showing positivity for ER. Male carcinomas did not express PgR or GATA3 and none of the tumors, male or female, were positive for HER2. Based on the observed ER and PgR positivity and HER2 negativity within these tumors, MNU-induced mammary adenocarcinomas in female rats appear to be hormonally dependent, similar to human luminal A type breast cancer. In contrast, MNU-induced mammary adenocarcinomas in male rats showed no reactivity for ER, PgR, HER2 or GATA3, suggesting no hormonal dependency. Both male and female adenocarcinomas showed high proliferating activity by PCNA immunohistochemistry. Based on our literature review, human male breast cancers are mainly dependent on ER and/or PgR, therefore the biological pathogenesis of MNU-induced male mammary cancer in rats may differ from that of male breast cancer in humans.

  15. Trastuzumab and docetaxel in a preclinical organotypic breast cancer model using tissue slices from mammary fat pad: Translational relevance

    PubMed Central

    VESCI, LOREDANA; CAROLLO, VALERIA; ROSCILLI, GIUSEPPE; AURISICCHIO, LUIGI; FERRARA, FABIANA FOSCA; SPAGNOLI, LUIGI; DE SANTIS, RITA

    2015-01-01

    With the ever-increasing number of drugs approved to treat cancers, selection of the optimal treatment regimen for an individual patient is challenging. Breast cancer complexity requires novel predictive methods and tools. In the present study, we set up experimental conditions to obtain an 'ex vivo' organotypic culture from xenotransplanted mice aiming at recapitulating the human clinical condition. The effect of trastuzumab (large biological molecule) and docetaxel (small chemical entity) was subsequently investigated on this organotypic model and compared with in vivo and in vitro activity on tumor cells. Tissue slices of 200 µm were obtained from mammary fat pad of SCID mice xenotransplanted with human MCF-7 breast cancer cells. Viability and proliferation were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay and Ki-67 immunohistochemistry,and apoptosis by cleaved caspase-3 immunohistochemistry. In vivo antitumor activity of trastuzumab and docetaxel was determined by caliper measurement of tumor volume and Ki-67 expression on explanted masses by immunohistochemistry. A Teflon support and normoxia were necessary experimental conditions to obtain high viability of excised breast cancer infiltrated mammary fat pad slices upon 48 h cultivation, as shown by MTT proliferation assay, and Ki-67 expression. Breast cancer tissue slices treated for 48 h with trastuzumab or docetaxel showed a significant dose-dependent reduction of viability by MTT assay. Consistently, both drugs down-modulated Ki-67 and increased cleaved caspase-3. Tumor masses collected from docetaxel-or trastuzumab-treated mice showed a similar reduction of proliferation markers. By contrast, MCF-7 cell cultures were significantly inhibited by docetaxel but not by trastuzumab. Tumor tissue slices represent a more predictive experimental cancer model compared to cell cultures for both small and large molecule antitumor efficacy. This observation

  16. Trastuzumab and docetaxel in a preclinical organotypic breast cancer model using tissue slices from mammary fat pad: Translational relevance.

    PubMed

    Vesci, Loredana; Carollo, Valeria; Roscilli, Giuseppe; Aurisicchio, Luigi; Ferrara, Fabiana Fosca; Spagnoli, Luigi; De Santis, Rita

    2015-09-01

    With the ever-increasing number of drugs approved to treat cancers, selection of the optimal treatment regimen for an individual patient is challenging. Breast cancer complexity requires novel predictive methods and tools. In the present study, we set up experimental conditions to obtain an 'ex vivo' organotypic culture from xenotransplanted mice aiming at recapitulating the human clinical condition. The effect of trastuzumab (large biological molecule) and docetaxel (small chemical entity) was subsequently investigated on this organotypic model and compared with in vivo and in vitro activity on tumor cells. Tissue slices of 200 µm were obtained from mammary fat pad of SCID mice xenotransplanted with human MCF-7 breast cancer cells. Viability and proliferation were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) colorimetric assay and Ki-67 immunohistochemistry,and apoptosis by cleaved caspase-3 immunohistochemistry. In vivo antitumor activity of trastuzumab and docetaxel was determined by caliper measurement of tumor volume and Ki-67 expression on explanted masses by immunohistochemistry. A Teflon support and normoxia were necessary experimental conditions to obtain high viability of excised breast cancer infiltrated mammary fat pad slices upon 48 h cultivation, as shown by MTT proliferation assay, and Ki-67 expression. Breast cancer tissue slices treated for 48 h with trastuzumab or docetaxel showed a significant dose‑dependent reduction of viability by MTT assay. Consistently, both drugs down-modulated Ki-67 and increased cleaved caspase-3. Tumor masses collected from docetaxel- or trastuzumab‑treated mice showed a similar reduction of proliferation markers. By contrast, MCF-7 cell cultures were significantly inhibited by docetaxel but not by trastuzumab. Tumor tissue slices represent a more predictive experimental cancer model compared to cell cultures for both small and large molecule antitumor efficacy. This

  17. Biobehavioral Approaches to Cancer Progression and Survival

    PubMed Central

    Lutgendorf, Susan K.; Andersen, Barbara L.

    2014-01-01

    Over the last decade, there have been groundbreaking strides in our understanding of the multiple biological pathways by which psychosocial and behavioral factors can affect cancer progression. It is now clear that biobehavioral factors not only affect cellular immunity but both directly and indirectly modulate fundamental processes in cancer growth, including inflammation, angiogenesis, invasion, and metastasis. There is also an emerging understanding of how psychological and behavioral factors used in interventions can impact these physiological processes. This review outlines our current understanding of the physiological mechanisms by which psychological, social, and behavioral processes can affect cancer progression. The intervention literature is discussed, along with recommendations for future research to move the field of biobehavioral oncology forward. PMID:25730724

  18. A Novel Effect of β-Adrenergic Receptor on Mammary Branching Morphogenesis and its Possible Implications in Breast Cancer.

    PubMed

    Gargiulo, Lucía; May, María; Rivero, Ezequiel M; Copsel, Sabrina; Lamb, Caroline; Lydon, John; Davio, Carlos; Lanari, Claudia; Lüthy, Isabel A; Bruzzone, Ariana

    2017-03-01

    Understanding the mechanisms that govern normal mammary gland development is crucial to the comprehension of breast cancer etiology. β-adrenergic receptors (β-AR) are targets of endogenous catecholamines such as epinephrine that have gained importance in the context of cancer biology. Differences in β2-AR expression levels may be responsible for the effects of epinephrine on tumor vs non-tumorigenic breast cell lines, the latter expressing higher levels of β2-AR. To study regulation of the breast cell phenotype by β2-AR, we over-expressed β2-AR in MCF-7 breast cancer cells and knocked-down the receptor in non-tumorigenic MCF-10A breast cells. In MCF-10A cells having knocked-down β2-AR, epinephrine increased cell proliferation and migration, similar to the response by tumor cells. In contrast, in MCF-7 cells overexpressing the β2-AR, epinephrine decreased cell proliferation and migration and increased adhesion, mimicking the response of the non-tumorigenic MCF-10A cells, thus underscoring that β2-AR expression level is a key player in cell behavior. β-adrenergic stimulation with isoproterenol induced differentiation of breast cells growing in 3-dimension cell culture, and also the branching of murine mammary epithelium in vivo. Branching induced by isoproterenol was abolished in fulvestrant or tamoxifen-treated mice, demonstrating that the effect of β-adrenergic stimulation on branching is dependent on the estrogen receptor (ER). An ER-independent effect of isoproterenol on lumen architecture was nonetheless found. Isoproterenol significantly increased the expression of ERα, Ephrine-B1 and fibroblast growth factors in the mammary glands of mice, and in MCF-10A cells. In a poorly differentiated murine ductal carcinoma, isoproterenol also decreased tumor growth and induced tumor differentiation. This study highlights that catecholamines, through β-AR activation, seem to be involved in mammary gland development, inducing mature duct formation. Additionally

  19. Experimental mammary carcinogenesis - Rat models.

    PubMed

    Alvarado, Antonieta; Faustino-Rocha, Ana I; Colaço, Bruno; Oliveira, Paula A

    2017-03-15

    Mammary cancer is one of the most common cancers, victimizing more than half a million of women worldwide every year. Despite all the studies in this field, the current therapeutic approaches are not effective and have several devastating effects for patients. In this way, the need to better understand the mammary cancer biopathology and find effective therapies led to the development of several rodent models over years. With this review, the authors intended to provide the readers with an overview of the rat models used to study mammary carcinogenesis, with a special emphasis on chemically-induced models.

  20. Caveolin-1 and prostate cancer progression.

    PubMed

    Freeman, Michael R; Yang, Wei; Di Vizio, Dolores

    2012-01-01

    Caveolin-1 was identified in the 1990s as a marker of aggressive prostate cancer. The caveolin-1 protein localizes to vesicular structures called caveolae and has been shown to bind and regulate many signaling proteins involved in oncogenesis. Caveolin-1 also has lipid binding properties and mediates aspects of cholesterol and fatty acid metabolism and can elicit biological responses in a paracrine manner when secreted. Caveolin-1 is also present in the serum of prostate cancer patients and circulating levels correlate with extent of disease. Current evidence indicates that increased expression of caveolin-1 in prostate adenocarcinoma cells and commensurate downregulation of the protein in prostate stroma, mediate progression to the castration-resistant phase of prostate cancer through diverse pathways. This chapter summarizes the current state of our understanding of the cellular and physiologic mechanisms in which caveolin-1 participates in the evolution of prostate cancer cell phenotypes.

  1. Computerized segmentation algorithm with personalized atlases of murine MRIs in a SV40 large T-antigen mouse mammary cancer model

    NASA Astrophysics Data System (ADS)

    Sibley, Adam R.; Markiewicz, Erica; Mustafi, Devkumar; Fan, Xiaobing; Conzen, Suzanne; Karczmar, Greg; Giger, Maryellen L.

    2016-03-01

    Quantities of MRI data, much larger than can be objectively and efficiently analyzed manually, are routinely generated in preclinical research. We aim to develop an automated image segmentation and registration pipeline to aid in analysis of image data from our high-throughput 9.4 Tesla small animal MRI imaging center. T2-weighted, fat-suppressed MRIs were acquired over 4 life-cycle time-points [up to 12 to 18 weeks] of twelve C3(1) SV40 Large T-antigen mice for a total of 46 T2-weighted MRI volumes; each with a matrix size of 192 x 256, 62 slices, in plane resolution 0.1 mm, and slice thickness 0.5 mm. These image sets were acquired with the goal of tracking and quantifying progression of mammary intraepithelial neoplasia (MIN) to invasive cancer in mice, believed to be similar to ductal carcinoma in situ (DCIS) in humans. Our segmentation algorithm takes 2D seed-points drawn by the user at the center of the 4 co-registered volumes associated with each mouse. The level set then evolves in 3D from these 2D seeds. The contour evolution incorporates texture information, edge information, and a statistical shape model in a two-step process. Volumetric DICE coefficients comparing the automatic with manual segmentations were computed and ranged between 0.75 and 0.58 for averages over the 4 life-cycle time points of the mice. Incorporation of these personalized atlases with intra and inter mouse registration is expected to enable locally and globally tracking of the morphological and textural changes in the mammary tissue and associated lesions of these mice.

  2. A new role of SNAI2 in postlactational involution of the mammary gland links it to luminal breast cancer development

    DOE PAGES

    Castillo-Lluva, Sonia; Hontecillas-Prieto, Lourdes; Blanco-Gómez, Adrian; ...

    2015-06-22

    Breast cancer is a major cause of mortality in women. The transcription factor SNAI2 has been implicated in the pathogenesis of several types of cancer, including breast cancer of basal origin. Here we show that SNAI2 is also important in the development of breast cancer of luminal origin in MMTV-ErbB2 mice. SNAI2 deficiency leads to longer latency and fewer luminal tumors, both of these being characteristics of pretumoral origin. These effects were associated with reduced proliferation and a decreased ability to generate mammospheres in normal mammary glands. However, the capacity to metastasize was not modified. Under conditions of increased ERBB2more » oncogenic activity after pregnancy plus SNAI2 deficiency, both pretumoral defects-latency and tumor load-were compensated. However, the incidence of lung metastases was dramatically reduced. Furthermore, SNAI2 was required for proper postlactational involution of the breast. At 3 days post lactational involution, the mammary glands of Snai2-deficient mice exhibited lower levels of pSTAT3 and higher levels of pAKT1, resulting in decreased apoptosis. Abundant noninvoluted ducts were still present at 30 days post lactation, with a greater number of residual ERBB2+ cells. These results suggest that this defect in involution leads to an increase in the number of susceptible target cells for transformation, to the recovery of the capacity to generate mammospheres and to an increase in the number of tumors. In conclusion, our work demonstrates the participation of SNAI2 in the pathogenesis of luminal breast cancer, and reveals an unexpected connection between the processes of postlactational involution and breast tumorigenesis in Snai2-null mutant mice.« less

  3. A new role of SNAI2 in postlactational involution of the mammary gland links it to luminal breast cancer development

    SciTech Connect

    Castillo-Lluva, Sonia; Hontecillas-Prieto, Lourdes; Blanco-Gómez, Adrian; del Mar Sáez-Freire, María; García-Cenador, Begona; García-Criado, Javier; Pérez-Andrés, Martín; Orfao, Alberto; Cañamero, Marta; Mao, Jian-Hua; Gridley, Thomas; Castellanos-Martín, Andres; Pérez-Losada, Jesus

    2015-06-22

    Breast cancer is a major cause of mortality in women. The transcription factor SNAI2 has been implicated in the pathogenesis of several types of cancer, including breast cancer of basal origin. Here we show that SNAI2 is also important in the development of breast cancer of luminal origin in MMTV-ErbB2 mice. SNAI2 deficiency leads to longer latency and fewer luminal tumors, both of these being characteristics of pretumoral origin. These effects were associated with reduced proliferation and a decreased ability to generate mammospheres in normal mammary glands. However, the capacity to metastasize was not modified. Under conditions of increased ERBB2 oncogenic activity after pregnancy plus SNAI2 deficiency, both pretumoral defects-latency and tumor load-were compensated. However, the incidence of lung metastases was dramatically reduced. Furthermore, SNAI2 was required for proper postlactational involution of the breast. At 3 days post lactational involution, the mammary glands of Snai2-deficient mice exhibited lower levels of pSTAT3 and higher levels of pAKT1, resulting in decreased apoptosis. Abundant noninvoluted ducts were still present at 30 days post lactation, with a greater number of residual ERBB2+ cells. These results suggest that this defect in involution leads to an increase in the number of susceptible target cells for transformation, to the recovery of the capacity to generate mammospheres and to an increase in the number of tumors. In conclusion, our work demonstrates the participation of SNAI2 in the pathogenesis of luminal breast cancer, and reveals an unexpected connection between the processes of postlactational involution and breast tumorigenesis in Snai2-null mutant mice.

  4. Developing a Novel Mouse Model for Breast Cancer by Targeting Oncogenes to Mammary Progenitor Cells

    DTIC Science & Technology

    2005-04-01

    obtained and rederived into our facility this line of mice from another investigator Tom O’Brien (1). We are in the process of testing this line for...Breed K6-rtTA transgenic mice with established tetO-c-Myc mice. Transplant the mammary cells from the resulting bi -transgenic mice into 10 inguinal...concentrated RCAS-K-RasG12D-IRES-Cre virus to inguinal mammary glands of 10 pubertal and 10 estrogen-stimulated K6-TVA /p53flox/flox bi -genic females. Monitor

  5. Maspin acts at the cell membrane to inhibit invasion and motility of mammary and prostatic cancer cells.

    PubMed Central

    Sheng, S; Carey, J; Seftor, E A; Dias, L; Hendrix, M J; Sager, R

    1996-01-01

    Maspin, a novel serine protease inhibitor (serpin), inhibits tumor invasion and metastasis of mammary carcinoma. We show here that recombinant maspin protein blocks the motility of these carcinoma cells in culture over 12 h, as demonstrated by time-lapse video microscopy. Lamellopodia are withdrawn but ruffling continues. Both exogenous recombinant maspin and maspin expressed by tumor transfectants exhibit inhibitory effects on cell motility and cell invasion as shown in modified Boyden chamber assays. In addition, three prostatic cancer cell lines treated with recombinant maspin exhibited similar inhibition of both invasion and motility, suggesting a similar mode of maspin action in these two glandular epithelial cancers. When mammary carcinoma cells were treated with recombinant maspin, the protein was shown by immunostaining to bind specifically to the cell surface, suggesting that maspin activity is membrane associated. When pretreated with antimaspin antibody, maspin loses its inhibitory effects on both invasion and motility. However, when maspin is added to these cells preceding antibody treatment, the activity of maspin is no longer inhibited by subsequent addition of the antibody. It is concluded therefore that the inhibition of invasion and motility by maspin is initially localized to the cell surface. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 6 Fig. 7 PMID:8876194

  6. In utero exposure of rats to high-fat diets perturbs gene-expression profiles and cancer susceptibility of prepubertal mammary glands

    PubMed Central

    Ying, Jun; Gear, Robin; Bornschein, Robert L; Medvedovic, Mario; Ho, Shuk-Mei

    2015-01-01

    Human studies suggest that high-fat diets (HFD) increase the risk of breast cancer. The 7,12 dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis rat model is commonly used to evaluate the effects of lifestyle factors such as HFD on mammary-tumor risk. Past studies focused primarily on the effects of continuous maternal exposure on the risk of offspring at the end of puberty (PND50). We assessed the effects of prenatal HFD exposure on cancer susceptibility in prepubertal mammary glands and identified key gene networks associated with such disruption. During pregnancy, dams were fed AIN93G-based diets with isocaloric high olive oil, butterfat, or safflower oil. The control group received AIN-93G. Female offspring were treated with DMBA on PND21. However, a significant increase in tumor volume and a trend of shortened tumor latency were observed in rats with HFD exposure against the controls (p=0.048 and p=0.067 respectively). Large-volume tumors harbored carcinoma in situ. Transcriptome profiling identified 43 differentially expressed genes in the mammary glands of the HFBUTTER group as compared with control. Rapid hormone signaling was the most dysregulated pathway. The diet also induced aberrant expression of Dnmt3a, Mbd1, and Mbd3, consistent with potential epigenetic disruption. Collectively, these findings provide the first evidence supporting susceptibility of prepubertal mammary glands to DMBA-induced tumorigenesis that can be modulated by dietary fat that involves aberrant gene expression and likely epigenetic dysregulation. PMID:26895667

  7. Progress Against Prostate Cancer | NIH MedlinePlus the Magazine

    MedlinePlus

    ... of this page please turn Javascript on. Feature: Prostate Cancer Progress Against Prostate Cancer Past Issues / Winter 2010 Table of Contents Click ... This can narrow the urethra, decreasing urine flow. Prostate cancer is made up of cells the body does ...

  8. Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells

    PubMed Central

    Wang, Yuan Yuan; Attané, Camille; Milhas, Delphine; Dirat, Béatrice; Dauvillier, Stéphanie; Guerard, Adrien; Gilhodes, Julia; Lazar, Ikrame; Alet, Nathalie; Laurent, Victor; Le Gonidec, Sophie; Hervé, Caroline; Bost, Frédéric; Ren, Guo Sheng; Bono, Françoise; Escourrou, Ghislaine; Prentki, Marc; Nieto, Laurence; Valet, Philippe

    2017-01-01

    In breast cancer, a key feature of peritumoral adipocytes is their loss of lipid content observed both in vitro and in human tumors. The free fatty acids (FFAs), released by adipocytes after lipolysis induced by tumor secretions, are transferred and stored in tumor cells as triglycerides in lipid droplets. In tumor cell lines, we demonstrate that FFAs can be released over time from lipid droplets through an adipose triglyceride lipase–dependent (ATGL-dependent) lipolytic pathway. In vivo, ATGL is expressed in human tumors where its expression correlates with tumor aggressiveness and is upregulated by contact with adipocytes. The released FFAs are then used for fatty acid β-oxidation (FAO), an active process in cancer but not normal breast epithelial cells, and regulated by coculture with adipocytes. However, in cocultivated cells, FAO is uncoupled from ATP production, leading to AMPK/acetyl-CoA carboxylase activation, a circle that maintains this state of metabolic remodeling. The increased invasive capacities of tumor cells induced by coculture are completely abrogated by inhibition of the coupled ATGL-dependent lipolysis/FAO pathways. These results show a complex metabolic symbiosis between tumor-surrounding adipocytes and cancer cells that stimulate their invasiveness, highlighting ATGL as a potential therapeutic target to impede breast cancer progression. PMID:28239646

  9. Tumor suppressor pten signaling is up-regulated in mammary epithelial cells by soy isoflavone genistein: implications for breast cancer protection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Epidemiological studies have shown lower occurrence of breast cancer in Asian women whose early intake of soy products is higher than their American counterparts. In a previous work, we showed protection against NMU-induced mammary tumors in rats exposed to dietary soy protein isolate (SPI) or casei...

  10. Dietary Regulation of PTEN Signaling and Mammary Tumor Initiating Cells: Implications for Breast Cancer Prevention

    DTIC Science & Technology

    2011-01-01

    ing for soybean oil. These diets are: (i) CAS diet, containing casein (New Zealand Milk Products, Santa Rosa, CA) as the only protein source and (ii...rat offspring from NMU-induced mammary tumorigenesis. Carcinogenesis, 28, 1046– 1051. 13.Hakkak,R. et al. (2000) Diets containing whey proteins or soy

  11. In-Silico Genomic Approaches To Understanding Lactation, Mammary Development, And Breast Cancer

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lactation-related traits are influenced by genetics. From a quantitative standpoint, these traits have been well studied in dairy species, but there has also been work on the genetics of lactation in humans and mice. In addition, there is evidence to support the notion that other mammary gland trait...

  12. Cancer Stem Cells Contribute to Cisplatin Resistance in Brca1/p53–Mediated Mouse Mammary Tumors

    PubMed Central

    Shafee, Norazizah; Smith, Christopher R.; Wei, Shuanzeng; Kim, Yoon; Mills, Gordon B.; Hortobagyi, Gabriel N.; Stanbridge, Eric J.; Lee, Eva Y-H. P.

    2010-01-01

    The majority of BRCA1-associated breast cancers are basal cell–like, which is associated with a poor outcome. Using a spontaneous mouse mammary tumor model, we show that platinum compounds, which generate DNA breaks during the repair process, are more effective than doxorubicin in Brca1/p53–mutated tumors. At 0.5 mg/kg of daily cisplatin treatment, 80% primary tumors (n = 8) show complete pathologic response. At greater dosages, 100% show complete response (n = 19). However, after 2 to 3 months of complete remission following platinum treatment, tumors relapse and become refractory to successive rounds of treatment. Approximately 3.8% to 8.0% (mean, 5.9%) of tumor cells express the normal mammary stem cell markers, CD29hi24med, and these cells are tumorigenic, whereas CD29med24–/lo and CD29med24hi cells have diminished tumorigenicity or are nontumorigenic, respectively. In partially platinum-responsive primary transplants, 6.6% to 11.0% (mean, 8.8%) tumor cells are CD29hi24med; these populations significantly increase to 16.5% to 29.2% (mean, 22.8%; P < 0.05) in platinum-refractory secondary tumor transplants. Further, refractory tumor cells have greater colony-forming ability than the primary transplant–derived cells in the presence of cisplatin. Expression of a normal stem cell marker, Nanog, is decreased in the CD29hi24med populations in the secondary transplants. Top2A expression is also down-regulated in secondary drug-resistant tumor populations and, in one case, was accompanied by genomic deletion of Top2A. These studies identify distinct cancer cell populations for therapeutic targeting in breast cancer and implicate clonal evolution and expansion of cancer stem-like cells as a potential cause of chemoresistance. PMID:18451150

  13. Financial Burden of Cancer Care - Life After Cancer Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  14. Epstein-Barr Virus, Human Papillomavirus and Mouse Mammary Tumour Virus as Multiple Viruses in Breast Cancer

    PubMed Central

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

    2012-01-01

    Background The purpose of this investigation is to determine if Epstein Barr virus (EBV), high risk human papillomavirus (HPV), and mouse mammary tumour viruses (MMTV) co-exist in some breast cancers. Materials and Methods All the specimens were from women residing in Australia. For investigations based on standard PCR, we used fresh frozen DNA extracts from 50 unselected invasive breast cancers. For normal breast specimens, we used DNA extracts from epithelial cells from milk donated by 40 lactating women. For investigations based on in situ PCR we used 27 unselected archival formalin fixed breast cancer specimens and 18 unselected archival formalin fixed normal breast specimens from women who had breast reduction surgery. Thirteen of these fixed breast cancer specimens were ductal carcinoma in situ (dcis) and 14 were predominantly invasive ductal carcinomas (idc). Results EBV sequences were identified in 68%, high risk HPV sequences in 50%, and MMTV sequences in 78% of DNA extracted from 50 invasive breast cancer specimens. These same viruses were identified in selected normal and breast cancer specimens by in situ PCR. Sequences from more than one viral type were identified in 72% of the same breast cancer specimens. Normal controls showed these viruses were also present in epithelial cells in human milk – EBV (35%), HPV, 20%) and MMTV (32%) of 40 milk samples from normal lactating women, with multiple viruses being identified in 13% of the same milk samples. Conclusions We conclude that (i) EBV, HPV and MMTV gene sequences are present and co-exist in many human breast cancers, (ii) the presence of these viruses in breast cancer is associated with young age of diagnosis and possibly an increased grade of breast cancer. PMID:23183846

  15. PRRX2 as a novel TGF-β-induced factor enhances invasion and migration in mammary epithelial cell and correlates with poor prognosis in breast cancer.

    PubMed

    Juang, Yu-Lin; Jeng, Yung-Ming; Chen, Chi-Long; Lien, Huang-Chun

    2016-12-01

    TGF-β and cancer progression share a multifaceted relationship. Despite the knowledge of TGF-β biology in the development of cancer, several factors that mediate the cancer-promoting role of TGF-β continue to be identified. This study aimed to identify and characterise novel factors potentially related to TGF-β-mediated tumour aggression in breast cells. We treated the human mammary epithelial cell line MCF10A with TGF-β and identified TGF-β-dependent upregulation of PRRX2, the gene encoding paired-related homeobox 2 transcription factor. Overexpression of PRRX2 enhanced migration, invasion and anchorage-independent growth of MCF10A cells and induced partial epithelial mesenchymal transition (EMT), as determined by partial fibroblastoid morphology of cells, upregulation of EMT markers and partially disrupted acinar structure in a three-dimensional culture. We further identified PLAT, the gene encoding tissue-type plasminogen activator (tPA), as the highest differentially expressed gene in PRRX2-overexpressing MCF10A cells, and demonstrated direct binding and transactivation of the PLAT promoter by PRRX2. Furthermore, PLAT knockdown inhibited PRRX2-mediated enhanced migration and invasion, suggesting that tPA may mediate PRRX2-induced migration and invasion. Finally, the significant correlation of PRRX2 expression with poor survival in 118 primary breast tumour samples (P = 0.027) and the increased PRRX2 expression in metaplastic breast carcinoma samples, which is pathogenetically related to EMT, validated the biological importance of PRRX2-enhanced migration and invasion and PRRX2-induced EMT. Thus, our data suggest that upregulation of PRRX2 may be a mechanism contributing to TGF-β-induced invasion and EMT in breast cancer. © 2016 Wiley Periodicals, Inc.

  16. Differential gene expression pattern in human mammary epithelial cells induced by realistic organochlorine mixtures described in healthy women and in women diagnosed with breast cancer.

    PubMed

    Rivero, Javier; Henríquez-Hernández, Luis Alberto; Luzardo, Octavio P; Pestano, José; Zumbado, Manuel; Boada, Luis D; Valerón, Pilar F

    2016-03-30

    Organochlorine pesticides (OCs) have been associated with breast cancer development and progression, but the mechanisms underlying this phenomenon are not well known. In this work, we evaluated the effects exerted on normal human mammary epithelial cells (HMEC) by the OC mixtures most frequently detected in healthy women (H-mixture) and in women diagnosed with breast cancer (BC-mixture), as identified in a previous case-control study developed in Spain. Cytotoxicity and gene expression profile of human kinases (n=68) and non-kinases (n=26) were tested at concentrations similar to those described in the serum of those cases and controls. Although both mixtures caused a down-regulation of genes involved in the ATP binding process, our results clearly indicate that both mixtures may exert a very different effect on the gene expression profile of HMEC. Thus, while BC-mixture up-regulated the expression of oncogenes associated to breast cancer (GFRA1 and BHLHB8), the H-mixture down-regulated the expression of tumor suppressor genes (EPHA4 and EPHB2). Our results indicate that the composition of the OC mixture could play a role in the initiation processes of breast cancer. In addition, the present results suggest that subtle changes in the composition and levels of pollutants involved in environmentally relevant mixtures might induce very different biological effects, which explain, at least partially, why some mixtures seem to be more carcinogenic than others. Nonetheless, our findings confirm that environmentally relevant pollutants may modulate the expression of genes closely related to carcinogenic processes in the breast, reinforcing the role exerted by environment in the regulation of genes involved in breast carcinogenesis.

  17. Mammary tumors

    SciTech Connect

    Weller, R.E.

    1988-10-01

    Mammary neoplasia is one of the more common malignancies affecting domestic species. Despite their importance, they are often over- diagnosed, undertreated and subject to several misconceptions propagated by veterinarians and pet owners alike. Mammary neoplasia is the most frequent tumor type encountered in the female accounting for almost half of all malignancies reported. The canine has the highest incidence of mammary tumors of all domestic species. In the dog, about 65 percent of mammary tumors are benign mixed tumors, and 25 percent are carcinomas. The rest are adenomas, myoepitheliomas, and malignant mixed tumors. The age distribution of mammary tumors closely follows the age distribution of most tumors in the dog. Mammary tumors are rare in dogs 2 years old, but incidence begins to increase sharply at approximately 6 years of age. Median age at diagnosis is about 10 years. No breed predilection has been consistently reported.

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

    PubMed

    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.

  19. Management of progressive metastatic prostate cancer.

    PubMed

    Waselenko, J K; Dawson, N A

    1997-10-01

    Metastatic prostate cancer is a growing health problem and is the second leading cause of cancer death in men. While the response of patients with metastatic prostate cancer to initial hormonal manipulation is excellent, the majority of patients eventually progress. As a result, a growing number of patients and their physicians need-to-find acceptable therapeutic alternatives. Fortunately, the number of therapies in the management armamentarium is growing and includes: alternative hormonal therapies, chemotherapy, radioisotopes, and investigational agents. The major focus of treatment has shifted to palliation and quality of life. The decline of prostate-specific antigen (PSA) has become another important end point as evidence supporting a correlation with prolonged survival mounts. Enrolling eligible patients in clinical trials is critical to the development of new treatment strategies for this difficult disease.

  20. Loss of the E3 ubiquitin ligase HACE1 results in enhanced Rac1 signaling contributing to breast cancer progression

    PubMed Central

    Goka, E T; Lippman, M E

    2015-01-01

    The transition from ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC) is a crucial step in breast cancer progression. The specific alterations that govern this transition have not been elucidated. HER2/neu is frequently overexpressed in DCIS but is less common in IBC, thereby suggesting additional requirements for transformation. To identify genes capable of cooperating with HER2/neu to fully transform mammary epithelial cells, we used an insertional mutagenesis screen on cells isolated from wild-type neu expressing mice and identified the E3 ligase HACE1 as HER2 cooperative tumor suppressor gene. Loss of HACE1 expression is commonly seen in clinical breast cancer data sets. HACE1 downregulation in normal human mammary epithelial cells (HMECs) results in the accumulation of the activated GTP-bound Rac1 partially transforming these cells. Overexpression of HER2 activates Rac1, which further accumulates upon HACE1 loss resulting in Rac1 hyperactivation. Although the knockdown of HACE1 or overexpression of HER2 alone in HMECs is not sufficient for tumorigenesis, HER2 overexpression combined with HACE1 downregulation fully transforms HMECs resulting in robust tumor formation. The pharmaceutical interference of Rac function abrogates the effects of HACE1 loss both in vitro and in vivo, resulting in marked reduction in tumor burden. Our work supports a critical role for HACE1 in breast cancer progression and identifies patients that may benefit from Rac-targeted therapies. PMID:25659579

  1. Mammary epithelial cell: Influence of extracellular matrix composition and organization during development and tumorigenesis

    PubMed Central

    Kass, Laura; Erler, Janine T.; Dembo, Micah; Weaver, Valerie M.

    2009-01-01

    Stromal–epithelial interactions regulate mammary gland development and are critical for the maintenance of tissue homeostasis. The extracellular matrix, which is a proteinaceous component of the stroma, regulates mammary epithelial growth, survival, migration and differentiation through a repertoire of transmembrane receptors, of which integrins are the best characterized. Integrins modulate cell fate by reciprocally transducing biochemical and biophysical cues between the cell and the extracellular matrix, facilitating processes such as embryonic branching morphogenesis and lactation in the mammary gland. During breast development and cancer progression, the extracellular matrix is dynamically altered such that its composition, turnover, processing and orientation change dramatically. These modifications influence mammary epithelial cell shape, and modulate growth factor and hormonal responses to regulate processes including branching morphogenesis and alveolar differentiation. Malignant transformation of the breast is also associated with significant matrix remodeling and a progressive stiffening of the stroma that can enhance mammary epithelial cell growth, perturb breast tissue organization, and promote cell invasion and survival. In this review, we discuss the role of stromal–epithelial interactions in normal and malignant mammary epithelial cell behavior. We specifically focus on how dynamic modulation of the biochemical and biophysical properties of the extracellular matrix elicit a dialogue with the mammary epithelium through transmembrane integrin receptors to influence tissue morphogenesis, homeostasis and malignant transformation. PMID:17719831

  2. Dehydroepiandrosterone inhibits the progression phase of mammary carcinogenesis by inducing cellular senescence via a p16-dependent but p53-independent mechanism

    PubMed Central

    Shilkaitis, Anne; Green, Albert; Punj, Vasu; Steele, Vernon; Lubet, Ronald; Christov, Konstantin

    2005-01-01

    Introduction Dehydroepiandrosterone (DHEA), an adrenal 17-ketosteroid, is a precursor of testosterone and 17β-estradiol. Studies have shown that DHEA inhibits carcinogenesis in mammary gland and prostate as well as other organs, a process that is not hormone dependent. Little is known about the molecular mechanisms of DHEA-mediated inhibition of the neoplastic process. Here we examine whether DHEA and its analog DHEA 8354 can suppress the progression of hyperplastic and premalignant (carcinoma in situ) lesions in mammary gland toward malignant tumors and the cellular mechanisms involved. Methods Rats were treated with N-nitroso-N-methylurea and allowed to develop mammary hyperplastic and premalignant lesions with a maximum frequency 6 weeks after carcinogen administration. The animals were then given DHEA or DHEA 8354 in the diet at 125 or 1,000 mg/kg diet for 6 weeks. The effect of these agents on induction of apoptosis, senescence, cell proliferation, tumor burden and various effectors of cellular signaling were determined. Results Both agents induced a dose-dependent decrease in tumor multiplicity and in tumor burden. In addition they induced a senescent phenotype in tumor cells, inhibited cell proliferation and increased the number of apoptotic cells. The DHEA-induced cellular effects were associated with increased expression of p16 and p21, but not p53 expression, implicating a p53-independent mechanism in their action. Conclusion We provide evidence that DHEA and DHEA 8354 can suppress mammary carcinogenesis by altering various cellular functions, inducing cellular senescence, in tumor cells with the potential involvement of p16 and p21 in mediating these effects. PMID:16457693

  3. Stabilin-1 is expressed in human breast cancer and supports tumor growth in mammary adenocarcinoma mouse model

    PubMed Central

    Riabov, Vladimir; Yin, Shuiping; Song, Bin; Avdic, Aida; Schledzewski, Kai; Ovsiy, Ilja; Gratchev, Alexei; Verdiell, Maria Llopis; Sticht, Carsten; Schmuttermaier, Christina; Schönhaber, Hiltrud; Weiss, Christel; Fields, Alan P.; Simon-Keller, Katja; Pfister, Frederick; Berlit, Sebastian; Marx, Alexander; Arnold, Bernd; Goerdt, Sergij; Kzhyshkowska, Julia

    2016-01-01

    Stabilin-1 is a multifunctional scavenger receptor expressed on alternatively-activated macrophages. Stabilin-1 mediates phagocytosis of “unwanted-self” components, intracellular sorting, and endocytic clearance of extracellular ligands including SPARC that modulates breast cancer growth. The expression of stabilin-1 was found on tumor-associated macrophages (TAM) in mouse and human cancers including melanoma, lymphoma, glioblastoma, and pancreatic insulinoma. Despite its tumor-promoting role in mouse models of melanoma and lymphoma the expression and functional role of stabilin-1 in breast cancer was unknown. Here, we demonstrate that stabilin-1 is expressed on TAM in human breast cancer, and its expression is most pronounced on stage I disease. Using stabilin-1 knockout (ko) mice we show that stabilin-1 facilitates growth of mouse TS/A mammary adenocarcinoma. Endocytosis assay on stabilin-1 ko TAM demonstrated impaired clearance of stabilin-1 ligands including SPARC that was capable of inducing cell death in TS/A cells. Affymetrix microarray analysis on purified TAM and reporter assays in stabilin-1 expressing cell lines demonstrated no influence of stabilin-1 expression on intracellular signalling. Our results suggest stabilin-1 mediated silent clearance of extracellular tumor growth-inhibiting factors (e.g. SPARC) as a mechanism of stabilin-1 induced tumor growth. Silent clearance function of stabilin-1 makes it an attractive candidate for delivery of immunomodulatory anti-cancer therapeutic drugs to TAM. PMID:27105498

  4. A prognosis classifier for breast cancer based on conserved gene regulation between mammary gland development and tumorigenesis: a multiscale statistical model.

    PubMed

    Tian, Yingpu; Chen, Baozhen; Guan, Pengfei; Kang, Yujia; Lu, Zhongxian

    2013-01-01

    Identification of novel cancer genes for molecular therapy and diagnosis is a current focus of breast cancer research. Although a few small gene sets were identified as prognosis classifiers, more powerful models are still needed for the definition of effective gene sets for the diagnosis and treatment guidance in breast cancer. In the present study, we have developed a novel statistical approach for systematic analysis of intrinsic correlations of gene expression between development and tumorigenesis in mammary gland. Based on this analysis, we constructed a predictive model for prognosis in breast cancer that may be useful for therapy decisions. We first defined developmentally associated genes from a mouse mammary gland epithelial gene expression database. Then, we found that the cancer modulated genes were enriched in this developmentally associated genes list. Furthermore, the developmentally associated genes had a specific expression profile, which associated with the molecular characteristics and histological grade of the tumor. These result suggested that the processes of mammary gland development and tumorigenesis share gene regulatory mechanisms. Then, the list of regulatory genes both on the developmental and tumorigenesis process was defined an 835-member prognosis classifier, which showed an exciting ability to predict clinical outcome of three groups of breast cancer patients (the predictive accuracy 64∼72%) with a robust prognosis prediction (hazard ratio 3.3∼3.8, higher than that of other clinical risk factors (around 2.0-2.8)). In conclusion, our results identified the conserved molecular mechanisms between mammary gland development and neoplasia, and provided a unique potential model for mining unknown cancer genes and predicting the clinical status of breast tumors. These findings also suggested that developmental roles of genes may be important criteria for selecting genes for prognosis prediction in breast cancer.

  5. The role of maintenance proteins in the preservation of epithelial cell identity during mammary gland remodeling and breast cancer initiation.

    PubMed

    Coradini, Danila; Oriana, Saro

    2014-02-01

    During normal postnatal mammary gland development and adult remodeling related to the menstrual cycle, pregnancy, and lactation, ovarian hormones and peptide growth factors contribute to the delineation of a definite epithelial cell identity. This identity is maintained during cell replication in a heritable but DNA-independent manner. The preservation of cell identity is fundamental, especially when cells must undergo changes in response to intrinsic and extrinsic signals. The maintenance proteins, which are required for cell identity preservation, act epigenetically by regulating gene expression through DNA methylation, histone modification, and chromatin remodeling. Among the maintenance proteins, the Trithorax (TrxG) and Polycomb (PcG) group proteins are the best characterized. In this review, we summarize the structures and activities of the TrxG and PcG complexes and describe their pivotal roles in nuclear estrogen receptor activity. In addition, we provide evidence that perturbations in these epigenetic regulators are involved in disrupting epithelial cell identity, mammary gland remodeling, and breast cancer initiation.

  6. Endogenous Mouse Mammary Tumor Viruses (Mtv): New Roles for an Old Virus in Cancer, Infection, and Immunity

    PubMed Central

    Holt, Michael P.; Shevach, Ethan M.; Punkosdy, George A.

    2013-01-01

    Mouse Mammary Tumor Viruses are beta-retroviruses that exist in both exogenous (MMTV) and endogenous (Mtv) forms. Exogenous MMTV is transmitted via the milk of lactating animals and is capable of inducing mammary gland tumors later in life. MMTV has provided a number of critical models for studying both viral infection as well as human breast cancer. In addition to the horizontally transmitted MMTV, most inbred mouse strains contain permanently integrated Mtv proviruses within their genome that are remnants of MMTV infection and vertically transmitted. Historically, Mtv have been appreciated for their role in shaping the T cell repertoire during thymic development via negative selection. In addition, more recent work has demonstrated a larger role for Mtv in modulating host immune responses due to its peripheral expression. The influence of Mtv on host response has been observed during experimental murine models of Polyomavirus- and ESb-induced lymphoma as well as Leishmania major and Plasmodium berghei ANKA infection. Decreased susceptibility to bacterial pathogens and virus-induced tumors has been observed among mice lacking all Mtv. We have also demonstrated a role for Mtv Sag in the expansion of regulatory T cells following chronic viral infection. The aim of this review is to summarize the latest research in the field regarding peripheral expression of Mtv with a particular focus on their role and influence on the immune system, infectious disease outcome, and potential involvement in tumor formation. PMID:24324930

  7. Kefir extracts suppress in vitro proliferation of estrogen-dependent human breast cancer cells but not normal mammary epithelial cells.

    PubMed

    Chen, Chujian; Chan, Hing Man; Kubow, Stan

    2007-09-01

    Anti-tumorigenic effects have been demonstrated in animal studies from the intake of kefir, a traditional fermented milk product believed to originate from the Caucasian mountains of Russia. In the present study, the antiproliferative effects of extracts of kefir, yogurt, and pasteurized cow's milk on human mammary cancer cells (MCF-7) and normal human mammary epithelial cells (HMECs) was investigated at doses of 0.31%, 0.63%, 1.25%, 2.5%, 5%, and 10% (vol/vol). After 6 days of culture, extracts of kefir-fermented milk depressed MCF-7 cell growth in a dose-dependent manner, showing 29% inhibition of proliferation at a concentration as low as 0.63%, whereas yogurt extracts began to show dose-dependent antiproliferative effects only at the 2.5% dose. Moreover, at the 2.5% dose, kefir extracts decreased the MCF-7 cell numbers by 56%, while yogurt extracts decreased MCF-7 cell proliferation by only 14%. No antiproliferative effects of kefir extracts were observed in the HMECs, while the yogurt extracts exerted antiproliferative effects on HMECs at the 5% and 10% doses. Unfermented milk extracts stimulated proliferation of MCF-7 cells and HMECs at concentrations above 0.31%. Peptide content and capillary electrophoresis analyses showed that kefir-mediated milk fermentation led to an increase in peptide concentrations and a change in peptide profiles relative to milk or yogurt. The present findings suggest that kefir extracts contain constituents that specifically inhibit the growth of human breast cancer cells, which might eventually be useful in the prevention or treatment of breast cancer.

  8. Repression of mammary adipogenesis by genistein limits mammosphere formation of human MCF-7 cells.

    PubMed

    Montales, Maria Theresa E; Rahal, Omar M; Nakatani, Hajime; Matsuda, Tsukasa; Simmen, Rosalia C M

    2013-07-01

    Mammary adipose tissue may contribute to breast cancer development and progression by altering neighboring epithelial cell behavior and phenotype through paracrine signaling. Dietary exposure to soy foods is associated with lower mammary tumor risk and reduced body weight and adiposity in humans and in rodent breast cancer models. Despite the suggested linkage between obesity and breast cancer, the local influence of bioactive dietary components on mammary adiposity for antitumor effects remains unknown. Herein, we report that post-weaning dietary exposure to soy protein isolate and its bioactive isoflavone genistein (GEN) lowered mammary adiposity and increased mammary tumor suppressor PTEN and E-cadherin expression in female mice, relative to control casein diet. To ascertain GEN's role in mammary adipose deposition that may affect underlying epithelial cell phenotype, we evaluated GEN's effects on SV40-immortalized mouse mammary stromal fibroblast-like (MSF) cells during differentiation into adipocytes. MSF cells cultured in a differentiation medium with 40 nM GEN showed reductions in mature adipocyte numbers, triglyceride accumulation, and Pparγ (Pparg) and fatty acid synthase transcript levels. GEN inhibition of adipose differentiation was accompanied by increased estrogen receptor β (Erβ (Esr2)) gene expression and was modestly recapitulated by ERβ-selective agonist 2,3-bis-(4-hydroxyphenyl)-propionitrile (DPN). Reduction of Erβ expression by siRNA targeting increased Pparγ transcript levels and stromal fibroblast differentiation into mature adipocytes; the latter was reversed by GEN but not by DPN. Conditioned medium from GEN-treated adipocytes diminished anchorage-independent mammosphere formation of human MCF-7 breast cancer cells. Our results suggest a mechanistic pathway to support direct regulation of mammary adiposity by GEN for breast cancer prevention.

  9. SMARCE1 is required for the invasive progression of in situ cancers.

    PubMed

    Sokol, Ethan S; Feng, Yu-Xiong; Jin, Dexter X; Tizabi, Minu D; Miller, Daniel H; Cohen, Malkiel A; Sanduja, Sandhya; Reinhardt, Ferenc; Pandey, Jai; Superville, Daphne A; Jaenisch, Rudolf; Gupta, Piyush B

    2017-04-04

    Advances in mammography have sparked an exponential increase in the detection of early-stage breast lesions, most commonly ductal carcinoma in situ (DCIS). More than 50% of DCIS lesions are benign and will remain indolent, never progressing to invasive cancers. However, the factors that promote DCIS invasion remain poorly understood. Here, we show that SMARCE1 is required for the invasive progression of DCIS and other early-stage tumors. We show that SMARCE1 drives invasion by regulating the expression of secreted proteases that degrade basement membrane, an ECM barrier surrounding all epithelial tissues. In functional studies, SMARCE1 promotes invasion of in situ cancers growing within primary human mammary tissues and is also required for metastasis in vivo. Mechanistically, SMARCE1 drives invasion by forming a SWI/SNF-independent complex with the transcription factor ILF3. In patients diagnosed with early-stage cancers, SMARCE1 expression is a strong predictor of eventual relapse and metastasis. Collectively, these findings establish SMARCE1 as a key driver of invasive progression in early-stage tumors.

  10. Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity

    PubMed Central

    Hernandez-Fernaud, Juan R.; Ruengeler, Elena; Casazza, Andrea; Neilson, Lisa J.; Pulleine, Ellie; Santi, Alice; Ismail, Shehab; Lilla, Sergio; Dhayade, Sandeep; MacPherson, Iain R.; McNeish, Iain; Ennis, Darren; Ali, Hala; Kugeratski, Fernanda G.; Al Khamici, Heba; van den Biggelaar, Maartje; van den Berghe, Peter V.E.; Cloix, Catherine; McDonald, Laura; Millan, David; Hoyle, Aoisha; Kuchnio, Anna; Carmeliet, Peter; Valenzuela, Stella M.; Blyth, Karen; Yin, Huabing; Mazzone, Massimiliano; Norman, Jim C.; Zanivan, Sara

    2017-01-01

    The secretome of cancer and stromal cells generates a microenvironment that contributes to tumour cell invasion and angiogenesis. Here we compare the secretome of human mammary normal and cancer-associated fibroblasts (CAFs). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminase-2 (TGM2). CLIC3 acts as a glutathione-dependent oxidoreductase that reduces TGM2 and regulates TGM2 binding to its cofactors. Finally, CLIC3 is also secreted by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers and its levels correlate with poor clinical outcome. This work reveals a previously undescribed invasive mechanism whereby the secretion of a glutathione-dependent oxidoreductase drives angiogenesis and cancer progression by promoting TGM2-dependent invasion. PMID:28198360

  11. Dietary Regulation of PTEN Signaling and Mammary Tumor Initiating Cells: Implications for Breast Cancer Prevention

    DTIC Science & Technology

    2012-07-01

    Results suggest that dietary SPI negatively regulates local (MaSC- enriched population) and systemic IL6 production . Based on the signaling pathways...Identified local (MaSC-enriched population) and systemic IL6 production as a central mediator of dietary effects on regulation of mammary stem...Epidemiological and case– control studies have shown a 2- to 8-fold lower occurrence of the disease in Asian women whose early intake of soy products is 10–20

  12. Genetic Manipulation Of Mammary Stem Cells to Reconcile Tumor Stem Cell Theory with Breast Cancer Heterogeneity

    DTIC Science & Technology

    2010-07-01

    analyzed by reverse transcription- polymerase chain reaction analysis (RT-PCR). GFP mRNA was not found in ΔN-p63-eGFPcre mammary gland. In the K14...transgene were selected by exploiting a neomycin resistance gene. The cells were then infected with an adenovirus bearing a gene for Cre- recombinase ...Successful genomic recombination was detected by polymerase chain reaction (PCR) analysis of genomic DNA. RT-PCR analysis was used to determine

  13. Breast Cancer and Early Onset Childhood Obesity: Cell Specific Gene Expression in Mammary Epithelia and Adipocytes

    DTIC Science & Technology

    2007-07-01

    hormone leptin (ob/ob mice) or its receptor (db/db mice, Zucker rat). These leptin signaling impaired animals are resistant to oncogene and...chemically induced mammary tumors (3,4). However, human obesity is not generally caused by mutations in leptin or its receptor (5). As expression of leptin ...morbidity factors associated with human obesity in the three groups of rats, including Leptin , Free fatty acids (FFA), triglycerides (TG) and insulin

  14. A rat model of bone cancer pain induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells

    SciTech Connect

    Mao-Ying, Q.-L.; Zhao Jun; Dong Zhiqiang; Wang Jun; Yu Jin; Yan Minfen; Zhang Yuqiu; Wu Gencheng; Wang Yanqing . E-mail: wangyanqing@shmu.edu.cn

    2006-07-14

    This study described a modified rat model of bone cancer pain. Syngeneic Walker 256 mammary gland carcinoma cells were injected into the tibia medullary cavity via intercondylar eminence. Series of tests were carried out including bone radiology, bone histology, ambulatory pain, thermal hyperalgesia, mechanical allodynia, weight bearing ability, and electrophysiological recording from primary afferent fibers. The rats inoculated with carcinoma cells showed significant ambulatory pain, mechanical allodynia, and reduction in weight bearing, as well as increased incidence of spontaneous activity in A{beta} fibers in affected limb, whereas PBS (vehicle) or heat-killed cells (sham) injected rats showed no significant difference in comparison to normal rats. The pain hypersensitive behaviors were aggravated with time and destruction of bone. Interestingly, mechanical allodynia was also observed in the contralateral limb, indicating the involvement of 'mirror image' pain in bone cancer pain. In summary, the present study provided a useful and easily established rat model of bone cancer pain which will contribute to further study of the mechanisms underlying cancer pain.

  15. ΔNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signalling.

    PubMed

    Chakrabarti, Rumela; Wei, Yong; Hwang, Julie; Hang, Xiang; Andres Blanco, Mario; Choudhury, Abrar; Tiede, Benjamin; Romano, Rose-Anne; DeCoste, Christina; Mercatali, Laura; Ibrahim, Toni; Amadori, Dino; Kannan, Nagarajan; Eaves, Connie J; Sinha, Satrajit; Kang, Yibin

    2014-10-01

    Emerging evidence suggests that cancer is populated and maintained by tumour-initiating cells (TICs) with stem-like properties similar to those of adult tissue stem cells. Despite recent advances, the molecular regulatory mechanisms that may be shared between normal and malignant stem cells remain poorly understood. Here we show that the ΔNp63 isoform of the Trp63 transcription factor promotes normal mammary stem cell (MaSC) activity by increasing the expression of the Wnt receptor Fzd7, thereby enhancing Wnt signalling. Importantly, Fzd7-dependent enhancement of Wnt signalling by ΔNp63 also governs tumour-initiating activity of the basal subtype of breast cancer. These findings establish ΔNp63 as a key regulator of stem cells in both normal and malignant mammary tissues and provide direct evidence that breast cancer TICs and normal MaSCs share common regulatory mechanisms.

  16. Examining the Pathogenesis of Breast Cancer Using a Novel Agent-Based Model of Mammary Ductal Epithelium Dynamics

    PubMed Central

    Chapa, Joaquin; Bourgo, Ryan J.; Greene, Geoffrey L.; Kulkarni, Swati; An, Gary

    2013-01-01

    The study of the pathogenesis of breast cancer is challenged by the long time-course of the disease process and the multi-factorial nature of generating oncogenic insults. The characterization of the longitudinal pathogenesis of malignant transformation from baseline normal breast duct epithelial dynamics may provide vital insight into the cascading systems failure that leads to breast cancer. To this end, extensive information on the baseline behavior of normal mammary epithelium and breast cancer oncogenesis was integrated into a computational model termed the Ductal Epithelium Agent-Based Model (DEABM). The DEABM is composed of computational agents that behave according to rules established from published cellular and molecular mechanisms concerning breast duct epithelial dynamics and oncogenesis. The DEABM implements DNA damage and repair, cell division, genetic inheritance and simulates the local tissue environment with hormone excretion and receptor signaling. Unrepaired DNA damage impacts the integrity of the genome within individual cells, including a set of eight representative oncogenes and tumor suppressors previously implicated in breast cancer, with subsequent consequences on successive generations of cells. The DEABM reproduced cellular population dynamics seen during the menstrual cycle and pregnancy, and demonstrated the oncogenic effect of known genetic factors associated with breast cancer, namely TP53 and Myc, in simulations spanning ∼40 years of simulated time. Simulations comparing normal to BRCA1-mutant breast tissue demonstrated rates of invasive cancer development similar to published epidemiologic data with respect to both cumulative incidence over time and estrogen-receptor status. Investigation of the modeling of ERα-positive (ER+) tumorigenesis led to a novel hypothesis implicating the transcription factor and tumor suppressor RUNX3. These data suggest that the DEABM can serve as a potentially valuable framework to augment the

  17. Examining the pathogenesis of breast cancer using a novel agent-based model of mammary ductal epithelium dynamics.

    PubMed

    Chapa, Joaquin; Bourgo, Ryan J; Greene, Geoffrey L; Kulkarni, Swati; An, Gary

    2013-01-01

    The study of the pathogenesis of breast cancer is challenged by the long time-course of the disease process and the multi-factorial nature of generating oncogenic insults. The characterization of the longitudinal pathogenesis of malignant transformation from baseline normal breast duct epithelial dynamics may provide vital insight into the cascading systems failure that leads to breast cancer. To this end, extensive information on the baseline behavior of normal mammary epithelium and breast cancer oncogenesis was integrated into a computational model termed the Ductal Epithelium Agent-Based Model (DEABM). The DEABM is composed of computational agents that behave according to rules established from published cellular and molecular mechanisms concerning breast duct epithelial dynamics and oncogenesis. The DEABM implements DNA damage and repair, cell division, genetic inheritance and simulates the local tissue environment with hormone excretion and receptor signaling. Unrepaired DNA damage impacts the integrity of the genome within individual cells, including a set of eight representative oncogenes and tumor suppressors previously implicated in breast cancer, with subsequent consequences on successive generations of cells. The DEABM reproduced cellular population dynamics seen during the menstrual cycle and pregnancy, and demonstrated the oncogenic effect of known genetic factors associated with breast cancer, namely TP53 and Myc, in simulations spanning ∼40 years of simulated time. Simulations comparing normal to BRCA1-mutant breast tissue demonstrated rates of invasive cancer development similar to published epidemiologic data with respect to both cumulative incidence over time and estrogen-receptor status. Investigation of the modeling of ERα-positive (ER+) tumorigenesis led to a novel hypothesis implicating the transcription factor and tumor suppressor RUNX3. These data suggest that the DEABM can serve as a potentially valuable framework to augment the

  18. NFAT Proteins: Emerging Roles in Cancer Progression

    PubMed Central

    Mancini, Maria; Toker, Alex

    2010-01-01

    Preface The roles of nuclear factor of activated T cells (NFAT) transcription factors have been extensively studied in the immune system. However, ubiquitous expression of NFAT isoforms in mammalian tissues has been recently observed, as well as an emerging role for these transcription factors in human cancer. Various NFAT isoforms are functional in tumor cells and multiple compartments in the tumor microenvironment including fibroblasts, endothelial cells and infiltrating immune cells. How do NFAT isoforms regulate the complex interplay between these compartments during carcinoma progression? The answers lie with the multiple functions attributed to NFAT including cell growth, survival, invasion and angiogenesis. In addition to sorting out the complex role of NFAT in cancer we face the challenge of targeting this pathway therapeutically. PMID:19851316

  19. Tumour progression and the nature of cancer.

    PubMed Central

    Clark, W. H.

    1991-01-01

    The nature of neoplasia and its sometime end result, cancer, has been studied by exposition and explanation of the sequential lesions of tumour progression. Neoplastic lesions were divided into four classes on the basis of growth characteristics and whether lesional growth is confined to one or more tissue compartments. Class IA, the initial lesion, an orderly, probably clonal growth, usually differentiates and disappears. Class IB: Failure to differentiate accompanied by disorderly growth. Class IC: Randomly dispersed atypical cells, constituting a precursor state. Class II, intermediate lesions, apparently arising from the atypical cells, show temporally unrestricted growth within the tissue compartment of origin. Class III lesions, primary invasive cancers, show temporally unrestricted growth in two or more tissue compartments and metastasise along different paths, a property associated with extracellular matrix interaction. The metastatic pathways may result from different subsets of cells in the primary cancer. Class IV lesions are the metastases. It was concluded that, all neoplasms develop in the same way, have the same general behavioural characteristics, and, when malignant, all interact with the extracellular matrix of the primary and the secondary sites. The origins and development of cancer are considered to be pluralistic and not due to a discrete change in a cell, whose progeny, as a result of that discrete change, carries all of the information required to explain the almost limitless events of a neoplastic system. Images Figure 4 PMID:1911211

  20. Wwox inactivation enhances mammary tumorigenesis.

    PubMed

    Abdeen, S K; Salah, Z; Maly, B; Smith, Y; Tufail, R; Abu-Odeh, M; Zanesi, N; Croce, C M; Nawaz, Z; Aqeilan, R I

    2011-09-08

    Breast cancer is the leading cause of cancer-related death in women worldwide. Expression of the WWOX tumor suppressor is absent or reduced in a large proportion of breast tumors suggesting that loss of WWOX may contribute to breast tumorigenesis. Wwox-deficient mice die by 3-4 weeks of age precluding adult tumor analysis. To evaluate the effect of WWOX-altered expression on mammary tumor formation, the Wwox-heterozygous allele was back crossed onto the C3H mammary tumor-susceptible genetic background (Wwox(C3H)+/-) and incidence of mammary tumor formation was evaluated. Although 50% of the female Wwox(C3H)+/- mice developed mammary carcinomas, only 7% of Wwox(C3H)+/+ mice did. Intriguingly, mammary tumors in Wwox(C3H)+/- mice frequently lost WWOX protein expression suggesting a genetic predisposition toward mammary tumorigenesis. Immunohistochemical staining of hormone receptors revealed loss of estrogen receptor-α (ER) and progesterone receptor in the majority of these tumors. In vitro, depletion of WWOX in MCF7 ER-positive cells led to reduced ER expression and reduced sensitivity to tamoxifen and estrogen treatment and was associated with enhanced survival and anchorage-independent growth. Finally, cDNA array analyses of murine normal mammary epithelial cells and mammary tumors identified 163 significantly downreguated and 129 upregulated genes in the tumors. The majority of differentially expressed genes were part of pathways involved in cellular movement, cell-to-cell signaling and interaction, cellular development, cellular growth and proliferation and cell death. These changes in gene expression of mouse mammary tumors in Wwox(C3H)+/- mice resemble, at least in part, human breast cancer development. Our findings demonstrate the critical role that the WWOX tumor suppressor gene has in preventing tumorigenesis in breast cancer.

  1. Rapidly progressive glomerulonephritis after immunotherapy for cancer.

    PubMed

    Parker, M G; Atkins, M B; Ucci, A A; Levey, A S

    1995-04-01

    Cytokines have been used in experimental and standard protocols for immune enhancement for cancer. The combination of interleukin-2 and interferon-alpha 2 beta has been used in experimental protocols for metastatic renal cell carcinoma. A man who developed rapidly progressive renal failure after receiving this combination therapy is reported. A renal biopsy revealed a pauci-immune crescentic glomerulonephritis. Antineutrophil cytoplasmic antibodies and antiglomerular basement membrane antibodies were absent. The spectrum of renal disease and potentially related extrarenal manifestations associated with interleukin-2 and inteferon-alpha are reviewed. A pathogenesis of altered cell-mediated immunity, consistent with abnormalities in extrarenal organs after immune enhancement, is proposed.

  2. Ductal barriers in mammary epithelium

    PubMed Central

    Owens, Mark B; Hill, Arnold DK; Hopkins, Ann M

    2013-01-01

    Tissue barriers play an integral role in the biology and pathobiology of mammary ductal epithelium. In normal breast physiology, tight and adherens junctions undergo dynamic changes in permeability in response to hormonal and other stimuli, while several of their proteins are directly involved in mammary tumorigenesis. This review describes first the structure of mammary ductal epithelial barriers and their role in normal mammary development, examining the cyclical changes in response to puberty, pregnancy, lactation and involution. It then examines the role of adherens and tight junctions and the participation of their constituent proteins in mammary tumorigenic functions such as migration, invasion and metastasis. Finally, it discusses the potential of these adhesion proteins as both prognostic biomarkers and potential therapeutic targets in breast cancer. PMID:24665412

  3. Mammary glands exhibit molecular laterality and undergo left-right asymmetric ductal epithelial growth in MMTV-cNeu mice.

    PubMed

    Robichaux, J P; Hallett, R M; Fuseler, J W; Hassell, J A; Ramsdell, A F

    2015-04-09

    Significant left-right (L-R) differences in tumor incidence and disease outcome occur for cancers of paired organs, including the breasts; however, the basis for this laterality is unknown. Here, we show that despite their morphologic symmetry, left versus right mammary glands in wild-type mice have baseline differences in gene expression that are L-R independently regulated during pubertal development, including genes that regulate luminal progenitor cell renewal, luminal cell differentiation, mammary tumorigenesis, tamoxifen sensitivity and chemotherapeutic resistance. In MMTV-cNeu(Tg/Tg) mice, which model HER2/Neu-amplified breast cancer, baseline L-R differences in mammary gene expression are amplified, sustained or inverted in a gene-specific manner and the mammary ductal epithelium undergoes L-R asymmetric growth and patterning. Comparative genomic analysis of mouse L-R mammary gene expression profiles with gene expression profiles of human breast tumors revealed significant linkage between right-sided gene expression and decreased breast cancer patient survival. Collectively, these findings are the first to demonstrate that mammary glands are lateralized organs, and, moreover, that mammary glands have L-R differential susceptibility to HER2/Neu oncogene-mediated effects on ductal epithelial growth and differentiation. We propose that intrinsic molecular laterality may have a role in L-R asymmetric breast tumor incidence and, furthermore, that interplay between the L-R molecular landscape and oncogene activity may contribute to the differential disease progression and patient outcome that are associated with tumor situs.

  4. Global gene expression profiles of canine macrophages and canine mammary cancer cells grown as a co-culture in vitro

    PubMed Central

    2012-01-01

    Background Solid tumours comprise various cells, including cancer cells, resident stromal cells, migratory haemopoietic cells and other. These cells regulate tumour growth and metastasis. Macrophages constitute probably the most important element of all interactions within the tumour microenvironment. However, the molecular mechanism, that guides tumour environment, still remains unknown. Exploring the underlying molecular mechanisms that orchestrate these phenomena has been the aim of our study. A co-culture of canine mammary cancer cells and macrophages was established and maintained for 72 hrs. Having sorted the cells, gene expression in cancer cells and macrophages, using DNA microarrays, was examined. The results were confirmed using real-time qPCR and confocal microscopy. Moreover, their ability for migration and invasion has been assessed. Results Microarray analysis showed that the up-regulated genes in the cancer cell lines are involved in 15 highly over-manifested pathways. The pathways that drew our diligent attention included: the inflammation pathway mediated by chemokine and cytokine, the Toll receptor signalling pathway and the B cell activation. The up-regulated genes in the macrophages were involved in only 18 significantly over-manifested pathways: the angiogenesis, the p53 pathway feedback loops2 and the Wnt signalling pathway. The microarray analysis revealed that co-culturing of cancer cells with macrophages initiated the myeloid-specific antigen expression in cancer cells, as well as cytokine/chemokine genes expression. This finding was confirmed at mRNA and protein level. Moreover, we showed that macrophages increase cancer migration and invasion. Conclusions The presence of macrophages in the cancer environment induces acquisition of the macrophage phenotype (specific antigens and chemokines/cytokines expression) in cancer cells. We presumed that cancer cells also acquire other myeloid features, such as: capabilities of cell rolling

  5. Cancer stem cells: progress and challenges in lung cancer

    PubMed Central

    Templeton, Amanda K.; Miyamoto, Shinya; Babu, Anish; Munshi, Anupama

    2014-01-01

    The identification of a subpopulation of tumor cells with stem cell-like characteristics first in hematological malignancies and later in solid tumors has emerged into a novel field of cancer research. It has been proposed that this aberrant population of cells now called “cancer stem cells” (CSCs) drives tumor initiation, progression, metastasis, recurrence, and drug resistance. CSCs have been shown to have the capacity of self-renewal and multipotency. Adopting strategies from the field of stem cell research has aided in identification, localization, and targeting of CSCs in many tumors. Despite the huge progress in other solid tumors such as brain, breast, and colon cancers no substantial advancements have been made in lung cancer. This is most likely due to the current rudimentary understanding of lung stem cell hierarchy and heterogeneous nature of lung disease. In this review, we will discuss the most recent findings related to identification of normal lung stem cells and CSCs, pathways involved in regulating the development of CSCs, and the importance of the stem cell niche in development and maintenance of CSCs. Additionally, we will examine the development and feasibility of novel CSC-targeted therapeutic strategies aimed at eradicating lung CSCs. PMID:27358855

  6. Bisphenol A (BPA) Exposure In Utero Leads to Immunoregulatory Cytokine Dysregulation in the Mouse Mammary Gland: A Potential Mechanism Programming Breast Cancer Risk.

    PubMed

    Fischer, Catha; Mamillapalli, Ramanaiah; Goetz, Laura G; Jorgenson, Elisa; Ilagan, Ysabel; Taylor, Hugh S

    2016-08-01

    Bisphenol-A (BPA) is a ubiquitous estrogen-like endocrine disrupting compound (EDC). BPA exposure in utero has been linked to breast cancer and abnormal mammary gland development in mice. The recent rise in incidence of human breast cancer and decreased age of first detection suggests a possible environmental etiology. We hypothesized that developmental programming of carcinogenesis may involve an aberrant immune response. Both innate and adaptive immunity play a role in tumor suppression through cytolytic CD8, NK, and Th1 T-cells. We hypothesized that BPA exposure in utero would lead to dysregulation of both innate and adaptive immunity in the mammary gland. CD1 mice were exposed to BPA in utero during gestation (days 9-21) via osmotic minipump. At 6 weeks, the female offspring were ovariectomized and estradiol was given at 8 weeks. RNA and protein were extracted from the posterior mammary glands, and the mRNA and protein levels were measured by PCR array, qRT-PCR, and western blot. In mouse mammary tissue, BPA exposure in utero significantly decreased the expression of members of the chemokine CXC family (Cxcl2, Cxcl4, Cxcl14, and Ccl20), interleukin 1 (Il1) gene family (Il1β and Il1rn), interleukin 2 gene family (Il7 receptor), and interferon gene family (interferon regulatory factor 9 (Irf9), as well as immune response gene 1 (Irg1). Additionally, BPA exposure in utero decreased Esr1 receptor gene expression and increased Esr2 receptor gene expression. In utero exposure of BPA resulted in significant changes to inflammatory modulators within mammary tissue. We suggest that dysregulation of inflammatory cytokines, both pro-inflammatory and anti-inflammatory, leads to a microenvironment that may promote disordered cell growth through inhibition of the immune response that targets cancer cells.

  7. Mammary gland development.

    PubMed

    Macias, Hector; Hinck, Lindsay

    2012-01-01

    The mammary gland develops through several distinct stages. The first transpires in the embryo as the ectoderm forms a mammary line that resolves into placodes. Regulated by epithelial–mesenchymal interactions, the placodes descend into the underlying mesenchyme and produce the rudimentary ductal structure of the gland present at birth. Subsequent stages of development—pubertal growth, pregnancy, lactation, and involution—occur postnatally under the regulation of hormones. Puberty initiates branching morphogenesis, which requires growth hormone (GH) and estrogen, as well as insulin-like growth factor 1 (IGF1), to create a ductal tree that fills the fat pad. Upon pregnancy, the combined actions of progesterone and prolactin generate alveoli, which secrete milk during lactation. Lack of demand for milk at weaning initiates the process of involution whereby the gland is remodeled back to its prepregnancy state. These processes require numerous signaling pathways that have distinct regulatory functions at different stages of gland development. Signaling pathways also regulate a specialized subpopulation of mammary stem cells that fuel the dramatic changes in the gland occurring with each pregnancy. Our knowledge of mammary gland development and mammary stem cell biology has significantly contributed to our understanding of breast cancer and has advanced the discovery of therapies to treat this disease.

  8. A nomogram based on mammary ductoscopic indicators for evaluating the risk of breast cancer in intraductal neoplasms with nipple discharge.

    PubMed

    Lian, Zhen-Qiang; Wang, Qi; Zhang, An-Qin; Zhang, Jiang-Yu; Han, Xiao-Rong; Yu, Hai-Yun; Xie, Si-Mei

    2015-04-01

    Mammary ductoscopy (MD) is commonly used to detect intraductal lesions associated with nipple discharge. This study investigated the relationships between ductoscopic image-based indicators and breast cancer risk, and developed a nomogram for evaluating breast cancer risk in intraductal neoplasms with nipple discharge. A total of 879 consecutive inpatients (916 breasts) with nipple discharge who underwent selective duct excision for intraductal neoplasms detected by MD from June 2008 to April 2014 were analyzed retrospectively. A nomogram was developed using a multivariate logistic regression model based on data from a training set (687 cases) and validated in an independent validation set (229 cases). A Youden-derived cut-off value was assigned to the nomogram for the diagnosis of breast cancer. Color of discharge, location, appearance, and surface of neoplasm, and morphology of ductal wall were independent predictors for breast cancer in multivariate logistic regression analysis. A nomogram based on these predictors performed well. The P value of the Hosmer-Lemeshow test for the prediction model was 0.36. Area under the curve values of 0.812 (95 % confidence interval (CI) 0.763-0.860) and 0.738 (95 % CI 0.635-0.841) was obtained in the training and validation sets, respectively. The accuracies of the nomogram for breast cancer diagnosis were 71.2 % in the training set and 75.5 % in the validation set. We developed a nomogram for evaluating breast cancer risk in intraductal neoplasms with nipple discharge based on MD image findings. This model may aid individual risk assessment and guide treatment in clinical practice.

  9. Grb2 and Shc Adapter Proteins Play Distinct Roles in Neu (ErbB-2)-Induced Mammary Tumorigenesis: Implications for Human Breast Cancer

    PubMed Central

    Dankort, David; Maslikowski, Bart; Warner, Neil; Kanno, Nubufumi; Kim, Harold; Wang, Zhixiang; Moran, Michael F.; Oshima, Robert G.; Cardiff, Robert D.; Muller, William J.

    2001-01-01

    Amplification of the Neu (ErbB-2 or HER-2) receptor tyrosine kinase occurs in 20 to 30% of human mammary carcinomas, correlating with a poor clinical prognosis. We have previously demonstrated that four (Y1144 Y1201, Y1227 and Y1253) of the five known Neu autophosphorylation sites can independently mediate transforming signals. The transforming potential of two of these mutants correlates with their capacity to recruit Grb2 directly to Y1144 (YB) or indirectly through Shc to Y1227 (YD). Here, we demonstrate that these transformation-competent neu mutants activate extracellular signal-regulated kinases and stimulate Ets-2-dependent transcription. Although the transforming potential of three of these mutants (YB, YD, and YE) was susceptible to inhibition by Rap1A, a genetic antagonist of Ras, the transforming potential of YC was resistant to inhibition by Rap1A. To further address the significance of these ErbB-2-coupled signaling molecules in induction of mammary cancers, transgenic mice expressing mutant Neu receptors lacking the known autophosphorylation sites (NYPD) or those coupled directly to either Grb2 (YB) or Shc (YD) adapter molecules were derived. In contrast to the NYPD strains, which developed focal mammary tumors after a long latency period with low penetrance, all female mice derived from YB and YD strains rapidly developed mammary tumors. Although female mice from several independent YB or YD lines developed mammary tumors, the YB strains developed lung metastases at substantially higher rates than the YD strains. These observations argue that Grb2 and Shc play important and distinct roles in ErbB-2/Neu-induced mammary tumorigenesis and metastasis. PMID:11238891

  10. Incidence and Mortality Tables | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  11. Diet - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  12. Smoke-free Home Rules | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  13. UV Exposure and Sun Protective Practices | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  14. Sun-Protective Behavior | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  15. Medicaid Coverage of Tobacco Dependency Treatments | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  16. Tobacco Policy/Regulatory Factors | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  17. Diet, Physical Activity, and Weight | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  18. Clinicians' Advice to Quit Smoking | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  19. Fruit and Vegetable Consumption | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  20. Person-Years of Life Lost | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  1. Secondhand Smoke - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  2. Smoking Cessation - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  3. Recent Updates and Archive | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  4. Tobacco Company Marketing Expenditures | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  5. HPV Immunization - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  6. Chemical Exposures - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  7. Methodology for Characterizing Trends | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  8. Trends at a Glance | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  9. Tobacco Use - Prevention Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  10. Stromal matrix metalloproteinase-11 is involved in the mammary gland postnatal development.

    PubMed

    Tan, J; Buache, E; Alpy, F; Daguenet, E; Tomasetto, C-L; Ren, G-S; Rio, M-C

    2014-07-31

    MMP-11 is a bad prognosis paracrine factor in invasive breast cancers. However, its mammary physiological function remains largely unknown. In the present study we have investigated MMP-11 function during postnatal mammary gland development and function using MMP-11-deficient (MMP-11-/-) mice. Histological and immunohistochemical analyses as well as whole-mount mammary gland staining show alteration of the mammary gland in the absence of MMP-11, where ductal tree, alveolar structures and milk production are reduced. Moreover, a series of transplantation experiments allowed us to demonstrate that MMP-11 exerts an essential local paracrine function that favors mammary gland branching and epithelial cell outgrowth and invasion through adjacent connective tissues. Indeed, MMP-11-/- cleared fat pads are not permissive for wild-type epithelium development, whereas MMP-11-/- epithelium transplants grow normally when implanted in wild-type cleared fat pads. In addition, using primary mammary epithelial organoids, we show in vitro that this MMP-11 pro-branching effect is not direct, suggesting that MMP-11 acts via production/release of stroma-associated soluble factor(s). Finally, the lack of MMP-11 leads to decreased periductal collagen content, suggesting that MMP-11 has a role in collagen homeostasis. Thus, local stromal MMP-11 might also regulate mammary epithelial cell behavior mechanically by promoting extracellular matrix stiffness. Collectively, the present data indicate that MMP-11 is a paracrine factor involved during postnatal mammary gland morphogenesis, and support the concept that the stroma strongly impact epithelial cell behavior. Interestingly, stromal MMP-11 has previously been reported to favor malignant epithelial cell survival and promote cancer aggressiveness. Thus, MMP-11 has a paracrine function during mammary gland development that might be harnessed to promote tumor progression, exposing a new link between development and malignancy.

  11. Molecular characterization of cancer reveals interactions between ionizing radiation and chemicals on rat mammary carcinogenesis.

    PubMed

    Imaoka, Tatsuhiko; Nishimura, Mayumi; Doi, Kazutaka; Tani, Shusuke; Ishikawa, Ken-ichi; Yamashita, Satoshi; Ushijima, Toshikazu; Imai, Takashi; Shimada, Yoshiya

    2014-04-01

    Although various mechanisms have been inferred for combinatorial actions of multiple carcinogens, these mechanisms have not been well demonstrated in experimental carcinogenesis models. We evaluated mammary carcinogenesis initiated by combined exposure to various doses of radiation and chemical carcinogens. Female rats at 7 weeks of age were γ-irradiated (0.2-2 Gy) and/or exposed to 1-methyl-1-nitrosourea (MNU) (20 or 40 mg/kg, single intraperitoneal injection) or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) (40 mg/kg/day by gavage for 10 days) and were observed until 50 weeks of age. The incidence of mammary carcinoma increased steadily as a function of radiation dose in the absence of chemicals; mathematical analysis supported an additive increase when radiation was combined with a chemical carcinogen, irrespective of the chemical species and its dose. Hras mutations were characteristic of carcinomas that developed after chemical carcinogen treatments and were overrepresented in carcinomas induced by the combination of radiation and MNU (but not PhIP), indicating an interaction of radiation and MNU at the level of initiation. The expression profiles of seven classifier genes, previously shown to distinguish two classes of rat mammary carcinomas, categorized almost all examined carcinomas that developed after individual or combined treatments with radiation (1 Gy) and chemicals as belonging to a single class; more comprehensive screening using microarrays and a separate test sample set failed to identify differences in gene expression profiles among these carcinomas. These results suggest that a complex, multilevel interaction underlies the combinatorial action of radiation and chemical carcinogens in the experimental model.

  12. Cancer stem cell targeted therapy: progress amid controversies.

    PubMed

    Wang, Tao; Shigdar, Sarah; Gantier, Michael P; Hou, Yingchun; Wang, Li; Li, Yong; Shamaileh, Hadi Al; Yin, Wang; Zhou, Shu-Feng; Zhao, Xinhan; Duan, Wei

    2015-12-29

    Although cancer stem cells have been well characterized in numerous malignancies, the fundamental characteristics of this group of cells, however, have been challenged by some recent observations: cancer stem cells may not necessary to be rare within tumors; cancer stem cells and non-cancer stem cells may undergo reversible phenotypic changes; and the cancer stem cells phenotype can vary substantially between patients. Here the current status and progresses of cancer stem cells theory is illustrated and via providing a panoramic view of cancer therapy, we addressed the recent controversies regarding the feasibility of cancer stem cells targeted anti-cancer therapy.

  13. Cancer stem cell targeted therapy: progress amid controversies

    PubMed Central

    Wang, Tao; Shigdar, Sarah; Gantier, Michael P.; Hou, Yingchun; Wang, Li; Li, Yong; Shamaileh, Hadi Al; Yin, Wang; Zhou, Shu-Feng; Zhao, Xinhan; Duan, Wei

    2015-01-01

    Although cancer stem cells have been well characterized in numerous malignancies, the fundamental characteristics of this group of cells, however, have been challenged by some recent observations: cancer stem cells may not necessary to be rare within tumors; cancer stem cells and non-cancer stem cells may undergo reversible phenotypic changes; and the cancer stem cells phenotype can vary substantially between patients. Here the current status and progresses of cancer stem cells theory is illustrated and via providing a panoramic view of cancer therapy, we addressed the recent controversies regarding the feasibility of cancer stem cells targeted anti-cancer therapy. PMID:26496035

  14. Antioxidants accelerate lung cancer progression in mice.

    PubMed

    Sayin, Volkan I; Ibrahim, Mohamed X; Larsson, Erik; Nilsson, Jonas A; Lindahl, Per; Bergo, Martin O

    2014-01-29

    Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. We show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production.

  15. Molecular profiling of human mammary gland links breast cancer risk to a p27(+) cell population with progenitor characteristics.

    PubMed

    Choudhury, Sibgat; Almendro, Vanessa; Merino, Vanessa F; Wu, Zhenhua; Maruyama, Reo; Su, Ying; Martins, Filipe C; Fackler, Mary Jo; Bessarabova, Marina; Kowalczyk, Adam; Conway, Thomas; Beresford-Smith, Bryan; Macintyre, Geoff; Cheng, Yu-Kang; Lopez-Bujanda, Zoila; Kaspi, Antony; Hu, Rong; Robens, Judith; Nikolskaya, Tatiana; Haakensen, Vilde D; Schnitt, Stuart J; Argani, Pedram; Ethington, Gabrielle; Panos, Laura; Grant, Michael; Clark, Jason; Herlihy, William; Lin, S Joyce; Chew, Grace; Thompson, Erik W; Greene-Colozzi, April; Richardson, Andrea L; Rosson, Gedge D; Pike, Malcolm; Garber, Judy E; Nikolsky, Yuri; Blum, Joanne L; Au, Alfred; Hwang, E Shelley; Tamimi, Rulla M; Michor, Franziska; Haviv, Izhak; Liu, X Shirley; Sukumar, Saraswati; Polyak, Kornelia

    2013-07-03

    Early full-term pregnancy is one of the most effective natural protections against breast cancer. To investigate this effect, we have characterized the global gene expression and epigenetic profiles of multiple cell types from normal breast tissue of nulliparous and parous women and carriers of BRCA1 or BRCA2 mutations. We found significant differences in CD44(+) progenitor cells, where the levels of many stem cell-related genes and pathways, including the cell-cycle regulator p27, are lower in parous women without BRCA1/BRCA2 mutations. We also noted a significant reduction in the frequency of CD44(+)p27(+) cells in parous women and showed, using explant cultures, that parity-related signaling pathways play a role in regulating the number of p27(+) cells and their proliferation. Our results suggest that pathways controlling p27(+) mammary epithelial cells and the numbers of these cells relate to breast cancer risk and can be explored for cancer risk assessment and prevention.

  16. The Immune System as a New Possible Cell Target for AFP 464 in a Spontaneous Mammary Cancer Mouse Model.

    PubMed

    Callero, Mariana A; Rodriguez, Cristina E; Sólimo, Aldana; Bal de Kier Joffé, Elisa; Loaiza Perez, Andrea I

    2017-02-16

    Aminoflavone (AFP 464, NSC 710464), an antitumor agent which recently entered phase II clinical trials, acts against estrogen-positive breast cancer (ER +). AFP 464, which has a unique mechanism of action by activating aryl hydrocarbon receptor (AhR) signaling pathway, decreased tumor size and growth rate in the estrogen dependent, Tamoxifen-sensitive spontaneous M05 mouse model. Considering that AhR has recently emerged as a physiological regulator of the innate and adaptive immune responses, we investigated whether AFP 464 modulates the immune response in our mouse model. Studies on the effect of AFP 464 on the immune system were carried in BALB/c mice bearing M05 semi-differentiated mammary adenocarcinomas that express estrogen and progesterone receptors. Splenic cells and tumor inflammatory infiltrates were studied by cytometric analyses. The modulation of splenocytes cytotoxic activity by AFP 464 was also evaluated. We further investigated the effects of AFP 464 on peritoneal macrophages by evaluating metalloproteinase, arginase and iNOS activities. We found that AFP 464 increased splenic cytotoxic activity, diminished the number of systemic and local Treg lymphocytes and MDSCs, and induced a M1 phenotype in peritoneal macrophages of M05 tumor bearing mice. Therefore, we conclude that AFP 464 modulates immune response which collaborates with its anti-tumor activity. Our results place the immune system as a novel target for this anti-cancer agent to strengthen the rationale for its inclusion in breast cancer treatment regimens. This article is protected by copyright. All rights reserved.

  17. Castration Induced Neuroendocrine Mediated Progression of Prostate Cancer

    DTIC Science & Technology

    2007-09-01

    androgen -insensitive prostate cancer patients based upon our work. 15. SUBJECT TERMS Prostate Cancer , Neuroendocrine, Progression...two androgen - ines PC-3 and DU-145 by examining the status of publication. a Src kinase inhibitor AZ independent prostate cancer cell l...differentiation in prostate cancer . AR activation. Together with our studies in the chimeric growth of androgen -sensitive and androgen -insensitive cells,

  18. Non-autonomous cell proliferation in the mammary gland and cancer.

    PubMed

    Weber, Robert J; Desai, Tejal A; Gartner, Zev J

    2017-03-14

    Cells decide whether to grow and divide by integrating internal and external signals. Non-autonomous cell growth and proliferation occurs when microenvironmental signals from neighboring cells, both physical and secreted, license this decision. Understanding these processes is vital to developing an accurate framework for cell-cell interactions and cellular decision-making, and is useful for advancing new therapeutic strategies to prevent dysregulated growth. Here, we review some recent examples of non-autonomous cell growth in the mammary gland and tumor cell proliferation.

  19. Role of GGAP/PIKE-A in prostate cancer progression

    DTIC Science & Technology

    2009-05-01

    isoform which also contains a COOH-terminal Arf-GAP domain and two ankyrin repeats . Both of these proteins can bind PI3-K via their proline-rich...may contribute to increased activity of GGAP2 in prostate cancer. In summary, GGAP2 may promote prostate cancer growth and progression via...that they may contribute to the functions of GGAP2 in prostate cancer. In summary, GGAP2 may promote prostate cancer growth and progression via

  20. Nuclear repartitioning of galectin-1 by an extracellular glycan switch regulates mammary morphogenesis.

    PubMed

    Bhat, Ramray; Belardi, Brian; Mori, Hidetoshi; Kuo, Peiwen; Tam, Andrew; Hines, William C; Le, Quynh-Thu; Bertozzi, Carolyn R; Bissell, Mina J

    2016-08-16

    Branching morphogenesis in the mammary gland is achieved by the migration of epithelial cells through a microenvironment consisting of stromal cells and extracellular matrix (ECM). Here we show that galectin-1 (Gal-1), an endogenous lectin that recognizes glycans bearing N-acetyllactosamine (LacNAc) epitopes, induces branching migration of mammary epithelia in vivo, ex vivo, and in 3D organotypic cultures. Surprisingly, Gal-1's effects on mammary patterning were independent of its glycan-binding ability and instead required localization within the nuclei of mammary epithelia. Nuclear translocation of Gal-1, in turn, was regulated by discrete cell-surface glycans restricted to the front of the mammary end buds. Specifically, α2,6-sialylation of terminal LacNAc residues in the end buds masked Gal-1 ligands, thereby liberating the protein for nuclear translocation. Within mammary epithelia, Gal-1 localized within nuclear Gemini bodies and drove epithelial invasiveness. Conversely, unsialylated LacNAc glycans, enriched in the epithelial ducts, sequestered Gal-1 in the extracellular environment, ultimately attenuating invasive potential. We also found that malignant breast cells possess higher levels of nuclear Gal-1 and α2,6-SA and lower levels of LacNAc than nonmalignant cells in culture and in vivo and that nuclear localization of Gal-1 promotes a transformed phenotype. Our findings suggest that differential glycosylation at the level of tissue microanatomy regulates the nuclear function of Gal-1 in the context of mammary gland morphogenesis and in cancer progression.

  1. Targeted Overexpression of EZH2 in the Mammary Gland Disrupts Ductal Morphogenesis and Causes Epithelial Hyperplasia

    PubMed Central

    Li, Xin; Gonzalez, Maria E.; Toy, Katherine; Filzen, Tracey; Merajver, Sofia D.; Kleer, Celina G.

    2009-01-01

    The Polycomb group protein enhancer of zeste homolog 2 (EZH2), which has roles during development of numerous tissues, is a critical regulator of cell type identity. Overexpression of EZH2 has been detected in invasive breast carcinoma tissue samples and is observed in human breast tissue samples of morphologically normal lobules up to 12 years before the development of breast cancer. The function of EZH2 during preneoplastic progression in the mammary gland is unknown. To investigate the role of EZH2 in the mammary gland, we targeted the expression of EZH2 to mammary epithelial cells using the mouse mammary tumor virus long terminal repeat. EZH2 overexpression resulted in aberrant terminal end bud architecture. By the age of 4 months, 100% of female mouse mammary tumor virus-EZH2 virgin mice developed intraductal epithelial hyperplasia resembling the human counterpart accompanied by premature differentiation of ductal epithelial cells and up-regulation of the luminal marker GATA-3. In addition, remodeling of the mammary gland after parturition was impaired and EZH2 overexpression caused delayed involution. Mechanistically, we found that EZH2 physically interacts with β-catenin, inducing β-catenin nuclear accumulation in mammary epithelial cells and activating Wnt/β-catenin signaling. The biological significance of these data to human hyperplasias is demonstrated by EZH2 up-regulation and colocalization with β-catenin in human intraductal epithelial hyperplasia, the earliest histologically identifiable precursor of breast carcinoma. PMID:19661437

  2. Breast Cancer Prevention by Hormonally Induced Mammary Gland Differentiation: The Role of a Novel Mammary Growth Inhibitor and Differentiation Factor MRG

    DTIC Science & Technology

    2000-10-01

    growth in vivo. Here, the effects of MRG on mammary gland differentiation and its interaction with omega - 3 polyunsaturated fatty acids ( omega - 3 PUFA) on...with omega - 3 PUFA DRA resulted in a differential growth inhibition proportional to their MRG expression. MRG transfected cells or MRG protein treated...is a candidate mediator of the differentiating effect of pregnancy on breast epithelial cells and may play a major role in omega - 3 PUFA-mediated tumor suppression.

  3. RANKL/RANK control Brca1 mutation-driven mammary tumors

    PubMed Central

    Sigl, Verena; Owusu-Boaitey, Kwadwo; Joshi, Purna A; Kavirayani, Anoop; Wirnsberger, Gerald; Novatchkova, Maria; Kozieradzki, Ivona; Schramek, Daniel; Edokobi, Nnamdi; Hersl, Jerome; Sampson, Aishia; Odai-Afotey, Ashley; Lazaro, Conxi; Gonzalez-Suarez, Eva; Pujana, Miguel A; CIMBA, for; Heyn, Holger; Vidal, Enrique; Cruickshank, Jennifer; Berman, Hal; Sarao, Renu; Ticevic, Melita; Uribesalgo, Iris; Tortola, Luigi; Rao, Shuan; Tan, Yen; Pfeiler, Georg; Lee, Eva YHP; Bago-Horvath, Zsuzsanna; Kenner, Lukas; Popper, Helmuth; Singer, Christian; Khokha, Rama; Jones, Laundette P; Penninger, Josef M

    2016-01-01

    Breast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that genetic inactivation of the key osteoclast differentiation factor RANK in the mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brca1 mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. In addition, genome variations within the RANK locus were significantly associated with risk of developing breast cancer in women with BRCA1 mutations. Thus, RANKL/RANK control progenitor cell expansion and tumorigenesis in inherited breast cancer. These results present a viable strategy for the possible prevention of breast cancer in BRCA1 mutant patients. PMID:27241552

  4. Ink4a/Arf(-/-) and HRAS(G12V) transform mouse mammary cells into triple-negative breast cancer containing tumorigenic CD49f(-) quiescent cells.

    PubMed

    Kai, K; Iwamoto, T; Kobayashi, T; Arima, Y; Takamoto, Y; Ohnishi, N; Bartholomeusz, C; Horii, R; Akiyama, F; Hortobagyi, G N; Pusztai, L; Saya, H; Ueno, N T

    2014-01-23

    Intratumoral heterogeneity within individual breast tumors is a well-known phenomenon that may contribute to drug resistance. This heterogeneity is dependent on several factors, such as types of oncogenic drivers and tumor precursor cells. The purpose of our study was to engineer a mouse mammary tumor model with intratumoral heterogeneity by using defined genetic perturbations. To achieve this, we used mice with knockout (-/-) of Ink4a/Arf, a tumor suppressor locus; these mice are known to be susceptible to non-mammary tumors such as fibrosarcoma. To induce mammary tumors, we retrovirally introduced an oncogene, HRAS(G12V), into Ink4a/Arf(-/-) mammary cells in vitro, and those cells were inoculated into syngeneic mice mammary fat pads. We observed 100% tumorigenesis. The tumors formed were negative for estrogen receptor, progesterone receptor and HER2. Further, they had pathological features similar to those of human triple-negative breast cancer (TNBC) (for example, pushing borders, central necrosis). The tumors were found to be heterogeneous and included two subpopulations: CD49f(-) quiescent cells and CD49f(+)cells. Contrary to our expectation, CD49f(-) quiescent cells had high tumor-initiating potential and CD49f(+)cells had relatively low tumor-initiating potential. Gene expression analysis revealed that CD49f(-) quiescent cells overexpressed epithelial-to-mesenchymal transition-driving genes, reminiscent of tumor-initiating cells and claudin-low breast cancer. Our animal model with intratumoral heterogeneity, derived from defined genetic perturbations, allows us to test novel molecular targeted drugs in a setting that mimics the intratumoral heterogeneity of human TNBC.

  5. Canine mammary gland tumors.

    PubMed

    Sorenmo, Karin

    2003-05-01

    The National Consensus Group recommends that all women with tumors larger than 1 cm be offered chemotherapy regardless of tumor histology of lymph node status. This recommendation is to ensure that everyone at risk for failing, even though the risk may be low in women with relatively small tumors and favorable histology, has a choice and receives the benefit of adjuvant chemotherapy. This type of treatment recommendation may also be made in dogs based on recognized, well-accepted prognostic factors such as tumor size, stage, type, and histologic differentiation. Based on the limited clinical information available in veterinary medicine, the drugs that are effective in human breast cancer, such as cyclophosphamide, 5-fluorouracil, and doxorubicin, may also have a role in the treatment of malignant mammary gland tumors in dogs. Randomized prospective studies are needed, however, to evaluate the efficacy of chemotherapy in dogs with high-risk mammary gland tumors and to determine which drugs and protocols are the most efficacious. Until such studies are performed, the treatment of canine mammary gland tumors will be based on the individual oncologist's understanding of tumor biology, experience, interpretation of the available studies, and a little bit of gut-feeling. Table 2 is a proposal for treatment guidelines for malignant canine mammary gland tumors according to established prognostic factors, results from published veterinary studies, and current recommendations for breast cancer treatment in women.

  6. Anticancer and Cancer Prevention Effects of Piperine-Free Piper nigrum Extract on N-nitrosomethylurea-Induced Mammary Tumorigenesis in Rats.

    PubMed

    Sriwiriyajan, Somchai; Tedasen, Aman; Lailerd, Narissara; Boonyaphiphat, Pleumjit; Nitiruangjarat, Anupong; Deng, Yan; Graidist, Potchanapond

    2016-01-01

    Piper nigrum (P. nigrum) is commonly used in traditional medicine. This current study aimed to investigate the anticancer and cancer preventive activity of a piperine-free P. nigrum extract (PFPE) against breast cancer cells and N-nitrosomethylurea (NMU)-induced mammary tumorigenesis in rats. The cytotoxic effects and the mechanism of action were investigated in breast cancer cells using the MTT assay and Western blot analysis, respectively. An acute toxicity study was conducted according to the Organization for Economic Co-operation and Development guideline. Female Sprague-Dawley rats with NMU-induced mammary tumors were used in preventive and anticancer studies. The results showed that PFPE inhibited the growth of luminal-like breast cancer cells more so than the basal-like ones by induction of apoptosis. In addition, PFPE exhibited greater selectivity against breast cancer cells than colorectal cancer, lung cancer, and neuroblastoma cells. In an acute toxicity study, a single oral administration of PFPE at a dose of 5,000 mg/kg body weight resulted in no mortality and morbidity during a 14-day observation period. For the cancer preventive study, the incidence of tumor-bearing rats was 10% to 20% in rats treated with PFPE. For the anticancer activity study, the growth rate of tumors in the presence of PFPE-treated groups was much slower when compared with the control and vehicle groups. The extract itself caused no changes to the biochemical and hematologic parameters when compared with the control and vehicle groups. In conclusion, PFPE had a low toxicity and a potent antitumor effect on mammary tumorigenesis in rats.

  7. ‘The charmingest place’: non-coding RNA, lineage tracing, tumor heterogeneity, metastasis and metabolism - new methods in mammary gland development and cancer: the fifth ENBDC Workshop

    PubMed Central

    2013-01-01

    The European Network for Breast Development and Cancer (ENBDC) Workshop on ‘Methods in Mammary Gland Development and Cancer’ has grown into the essential, international technical discussion forum for scientists with interests in the normal and neoplastic breast. The fifth ENBDC meeting was held in Weggis, Switzerland in April, 2013, and focussed on emerging, state-of-the-art techniques for the study of non-coding RNA, lineage tracing, tumor heterogeneity, metastasis and metabolism. PMID:24103450

  8. Can Breast Tumors Affect the Oxidative Status of the Surrounding Environment? A Comparative Analysis among Cancerous Breast, Mammary Adjacent Tissue, and Plasma

    PubMed Central

    Panis, C.; Victorino, V. J.; Herrera, A. C. S. A.; Cecchini, A. L.; Simão, A. N. C.; Tomita, L. Y.; Cecchini, R.

    2016-01-01

    In this paper, we investigated the oxidative profile of breast tumors in comparison with their normal adjacent breast tissue. Our study indicates that breast tumors present enhanced oxidative/nitrosative stress, with concomitant augmented antioxidant capacity when compared to the adjacent normal breast. These data indicate that breast cancers may be responsible for the induction of a prooxidant environment in the mammary gland, in association with enhanced TNF-α and nitric oxide. PMID:26697139

  9. Can Breast Tumors Affect the Oxidative Status of the Surrounding Environment? A Comparative Analysis among Cancerous Breast, Mammary Adjacent Tissue, and Plasma.

    PubMed

    Panis, C; Victorino, V J; Herrera, A C S A; Cecchini, A L; Simão, A N C; Tomita, L Y; Cecchini, R

    2015-01-01

    In this paper, we investigated the oxidative profile of breast tumors in comparison with their normal adjacent breast tissue. Our study indicates that breast tumors present enhanced oxidative/nitrosative stress, with concomitant augmented antioxidant capacity when compared to the adjacent normal breast. These data indicate that breast cancers may be responsible for the induction of a prooxidant environment in the mammary gland, in association with enhanced TNF-α and nitric oxide.

  10. Biological and genetic properties of the p53 null preneoplastic mammary epithelium

    NASA Technical Reports Server (NTRS)

    Medina, Daniel; Kittrell, Frances S.; Shepard, Anne; Stephens, L. Clifton; Jiang, Cheng; Lu, Junxuan; Allred, D. Craig; McCarthy, Maureen; Ullrich, Robert L.

    2002-01-01

    The absence of the tumor suppressor gene p53 confers an increased tumorigenic risk for mammary epithelial cells. In this report, we describe the biological and genetic properties of the p53 null preneoplastic mouse mammary epithelium in a p53 wild-type environment. Mammary epithelium from p53 null mice was transplanted serially into the cleared mammary fat pads of p53 wild-type BALB/c female to develop stable outgrowth lines. The outgrowth lines were transplanted for 10 generations. The outgrowths were ductal in morphology and progressed through ductal hyperplasia and ductal carcinoma in situ before invasive cancer. The preneoplastic outgrowth lines were immortal and exhibited activated telomerase activity. They are estrogen and progesterone receptor-positive, and aneuploid, and had various levels of tumorigenic potential. The biological and genetic properties of these lines are distinct from those found in most hyperplastic alveolar outgrowth lines, the form of mammary preneoplasia occurring in most traditional models of murine mammary tumorigenesis. These results indicate that the preneoplastic cell populations found in this genetically engineered model are similar in biological properties to a subset of precurser lesions found in human breast cancer and provide a unique model to identify secondary events critical for tumorigenicity and invasiveness.

  11. Tumor-derived mesenchymal stem cells and orthotopic site increase the tumor initiation potential of putative mouse mammary cancer stem cells derived from MMTV-PyMT mice.

    PubMed

    Lanza, Denise Grant; Ma, Jun; Guest, Ian; Uk-Lim, Chang; Glinskii, Anna; Glinsky, Gennadi; Sell, Stewart

    2012-12-01

    The ability to transplant mammary cancer stem cells, identified by the phenotype CD24(+)CD29(+)CD49f(+)Sca-1(low), is dependent on the microenvironment in which the cells are placed. Using the MMTV-PyMT mouse model of mammary cancer, we now report two methods of tumor growth enhancement: contributions of tumor stroma in the form of tumor-derived mesenchymal stem cells and orthotopic vs. heterotopic transplantation sites. To support evidence of stem cell function, tumor-derived mesenchymal stem cells differentiated into adipocyte- and osteocyte-like cells after culture in specific medium. Co-injection of tumor-initiating cells with tumor-derived mesenchymal stem cells significantly increased tumor initiation compared to subcutaneous injection of TICs alone; co-injection also allowed tumor initiation with a single TIC. Interestingly, we observed the formation of sarcomas after co-injections of tumor-derived mesenchymal stem cells or mouse embryonic fibroblasts with TICs; sarcomas are not observed in spontaneous MMTV-PyMT tumors and rarely observed in injections of TICs alone. Tumor initiation was also significantly increased in the orthotopic injection site compared to heterotopic injections. We conclude that tumor stroma and orthotopic sites both enhance tumor initiation by mammary cancer stem cells.

  12. Autophagy in malignant transformation and cancer progression

    PubMed Central

    Galluzzi, Lorenzo; Pietrocola, Federico; Bravo-San Pedro, José Manuel; Amaravadi, Ravi K; Baehrecke, Eric H; Cecconi, Francesco; Codogno, Patrice; Debnath, Jayanta; Gewirtz, David A; Karantza, Vassiliki; Kimmelman, Alec; Kumar, Sharad; Levine, Beth; Maiuri, Maria Chiara; Martin, Seamus J; Penninger, Josef; Piacentini, Mauro; Rubinsztein, David C; Simon, Hans-Uwe; Simonsen, Anne; Thorburn, Andrew M; Velasco, Guillermo; Ryan, Kevin M; Kroemer, Guido

    2015-01-01

    Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy. PMID:25712477

  13. Autophagy in malignant transformation and cancer progression.

    PubMed

    Galluzzi, Lorenzo; Pietrocola, Federico; Bravo-San Pedro, José Manuel; Amaravadi, Ravi K; Baehrecke, Eric H; Cecconi, Francesco; Codogno, Patrice; Debnath, Jayanta; Gewirtz, David A; Karantza, Vassiliki; Kimmelman, Alec; Kumar, Sharad; Levine, Beth; Maiuri, Maria Chiara; Martin, Seamus J; Penninger, Josef; Piacentini, Mauro; Rubinsztein, David C; Simon, Hans-Uwe; Simonsen, Anne; Thorburn, Andrew M; Velasco, Guillermo; Ryan, Kevin M; Kroemer, Guido

    2015-04-01

    Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy.

  14. Dietary lignin, and insoluble fiber, enhance uterine cancer but did not influence mammary cancer induced by N-methyl-N-nitrosourea in rats.

    PubMed

    Birt, D F; Markin, R S; Blackwood, D; Harvell, D M; Shull, J D; Pennington, K L

    1998-01-01

    Previous investigations suggested potential breast cancer-preventive properties of dietary fiber from cabbage. The purpose of the present investigation was to determine whether lignin, a component of cabbage fiber, would protect against mammary carcinogenesis by N-methyl-N-nitrosourea (MNU) in Sprague-Dawley rats. A six-week study was conducted using diets containing 0.5-5% dietary wood lignin (a readily available, purified source). These diets were well tolerated by the rats, and a carcinogenesis study using 5 mg MNU/100 g body wt i.v. at 50 days of age was conducted, with the 2.5% lignin diet fed from 6 through 8 weeks of age followed by 5% lignin diet until 20 weeks after MNU. Dietary lignin and MNU treatment increased food consumption (p < 0.05), and body weight was slightly reduced at 10 and 20 weeks after MNU in the MNU-5% lignin diet group (p < 0.05). Serum estradiol was not altered by dietary lignin or MNU treatment, but uterine weights were highest in the MNU-control diet group 4 and 12 weeks after MNU. Expression of creatine kinase B, and estrogen-responsive gene, was lower in eh uteri of the MNU-lignin diet group than in other groups at 20 weeks. Mammary carcinogenesis was not altered by dietary lignin. However, uterine endometrial adenocarcinoma was observed only in the MNU-lignin diet group (4 carcinomas/40 effective rats) (p < 0.05).

  15. RUNX2 correlates with subtype-specific breast cancer in a human tissue microarray, and ectopic expression of Runx2 perturbs differentiation in the mouse mammary gland.

    PubMed

    McDonald, Laura; Ferrari, Nicola; Terry, Anne; Bell, Margaret; Mohammed, Zahra M; Orange, Clare; Jenkins, Alma; Muller, William J; Gusterson, Barry A; Neil, James C; Edwards, Joanne; Morris, Joanna S; Cameron, Ewan R; Blyth, Karen

    2014-05-01

    RUNX2, a master regulator of osteogenesis, is oncogenic in the lymphoid lineage; however, little is known about its role in epithelial cancers. Upregulation of RUNX2 in cell lines correlates with increased invasiveness and the capacity to form osteolytic disease in models of breast and prostate cancer. However, most studies have analysed the effects of this gene in a limited number of cell lines and its role in primary breast cancer has not been resolved. Using a human tumour tissue microarray, we show that high RUNX2 expression is significantly associated with oestrogen receptor (ER)/progesterone receptor (PR)/HER2-negative breast cancers and that patients with high RUNX2 expression have a poorer survival rate than those with negative or low expression. We confirm RUNX2 as a gene that has a potentially important functional role in triple-negative breast cancer. To investigate the role of this gene in breast cancer, we made a transgenic model in which Runx2 is specifically expressed in murine mammary epithelium under the control of the mouse mammary tumour virus (MMTV) promoter. We show that ectopic Runx2 perturbs normal development in pubertal and lactating animals, delaying ductal elongation and inhibiting lobular alveolar differentiation. We also show that the Runx2 transgene elicits age-related, pre-neoplastic changes in the mammary epithelium of older transgenic animals, suggesting that elevated RUNX2 expression renders such tissue more susceptible to oncogenic changes and providing further evidence that this gene might have an important, context-dependent role in breast cancer.

  16. Selection of chemotherapy for metastatic mammary cancer by effect on cesium-131 uptake.

    PubMed

    Ferguson, D J; Harper, P V

    1977-09-01

    Cesium-131 was administered intravenously to 39 patients with superficial metastases of mammary carcinoma and the concentration in tumor was compared with that in normal tissue by application of a detector in vivo, before and after 1 to 5 days of chemotherapy with cyclophosphamide (CP), 5-fluorouracil (FU), or diethylstilbestrol. A change of the cesium concentration ratio (tumor/normal tissue) greater than 15% after brief treatment correctly predicted the therapeutic effect after 1 to 39 months on the tumors that were tested in 30 of 33 tests. No reliable correlation could be made in the remaining 21 tests in which the change of ratio was less than 15%. The concentration of cesium-131 in the skin, fat, and skeletal muscle of mice was not appreciably altered by treatment for 5 days with CP or FU.

  17. Mammary cancer in humans and mice: a tutorial for comparative pathology. The CD-ROM.

    PubMed

    Cardiff, R D; Wagner, U; Hennighausen, L

    2000-04-01

    This article introduces a CD-ROM containing whole-mount and histological images of normal growth and development of both the mouse mammary gland and the human breast. It also covers nonneoplastic lesions and neoplasias in both species including a catalog of lesions in genetically engineered mice. Instructions, with examples, on techniques such as whole-mount preparation, immunohistochemistry, in situ hybridization, and common histological stains are provided. The images are based on full-scale 1996 x 1640 pixel images at 300 pixels/ inch and are annotated. Every genetically engineered model has one or more accompanying citations. Tables are provided for orientation and organization. The CD includes zoom capabilities, a search engine, and a help mode.

  18. Validation study for the hypothesis of internal mammary sentinel lymph node lymphatic drainage in breast cancer.

    PubMed

    Cong, Bin-Bin; Qiu, Peng-Fei; Liu, Yan-Bing; Zhao, Tong; Chen, Peng; Cao, Xiao-Shan; Wang, Chun-Jian; Zhang, Zhao-Peng; Sun, Xiao; Yu, Jin-Ming; Wang, Yong-Sheng

    2016-07-05

    According to axilla sentinel lymph node lymphatic drainage pattern, we hypothesized that internal mammary sentinel lymph node (IM-SLN) receives lymphatic drainage from not only the primary tumor area, but also the entire breast parenchyma. Based on the hypothesis a modified radiotracer injection technique was established and could increase the visualization rate of the IM-SLN significantly. To verify the hypothesis, two kinds of tracers were injected at different sites of breast. The radiotracer was injected with the modified technique, and the fluorescence tracer was injected in the peritumoral intra-parenchyma. The location of IM-SLN was identified by preoperative lymphoscintigraphy and intraoperative gamma probe. Then, internal mammary sentinel lymph node biopsy (IM-SLNB) was performed. The fluorescence status of IM-SLN was identified by the fluorescence imaging system. A total of 216 patients were enrolled from September 2013 to July 2015. The overall visualization rate of IM-SLN was 71.8% (155/216). The success rate of IM-SLNB was 97.3% (145/149). The radiotracer and the fluorescence tracer were identified in the same IM-SLN in 127 cases, the correlation and the agreement is significant (Case-base, rs=0.836, P<0.001; Kappa=0.823, P<0.001). Different tracers injected into the different sites of the intra-parenchyma reached the same IM-SLN, which demonstrates the hypothesis that IM-SLN receives the lymphatic drainage from not only the primary tumor area but also the entire breast parenchyma.

  19. Hedgehog signaling in the normal and neoplastic mammary gland.

    PubMed

    Visbal, Adriana P; Lewis, Michael T

    2010-09-01

    The hedgehog signal transduction network is a critical regulator of metazoan development. Inappropriate activation of this network is implicated in several different cancers, including breast. Genetic evidence in mice as well as molecular biological studies in human cells clearly indicate that activated signaling can lead to mammary hyperplasia and, in some cases, tumor formation. However, the exact role(s) activated hedgehog signaling plays in the development or progression of breast cancer also remain unclear. In this review, we have discussed recent data regarding the mechanism(s) by which the hedgehog network may signal in the mammary gland, as well as the data implicating activated signaling as a contributing factor to breast cancer development. Finally, we provide a brief update on the available hedgehog signaling inhibitors with respect to ongoing clinical trials, some of which will include locally advanced or metastatic breast cancers. Given the growing intensity with which the hedgehog signaling network is being studied in the normal and neoplastic mammary gland, a more complete understanding of this network should allow more effective targeting of its activities in breast cancer treatment or prevention.

  20. Growth hormone and insulin-like growth factor-I in the transition from normal mammary development to preneoplastic mammary lesions.

    PubMed

    Kleinberg, David L; Wood, Teresa L; Furth, Priscilla A; Lee, Adrian V

    2009-02-01

    Adult female mammary development starts at puberty and is controlled by tightly regulated cross-talk between a group of hormones and growth factors. Although estrogen is the initial driving force and is joined by luteal phase progesterone, both of these hormones require GH-induced IGF-I in the mammary gland in order to act. The same group of hormones, when experimentally perturbed, can lead to development of hyperplastic lesions and increase the chances, or be precursors, of mammary carcinoma. For example, systemic administration of GH or IGF-I causes mammary hyperplasia, and overproduction of IGF-I in transgenic animals can cause the development of usual or atypical hyperplasias and sometimes carcinoma. Although studies have clearly demonstrated the transforming potential of both GH and IGF-I receptor in cell culture and in animals, debate remains as to whether their main role is actually instructive or permissive in progression to cancer in vivo. Genetic imprinting has been shown to occur in precursor lesions as early as atypical hyperplasia in women. Thus, the concept of progression from normal development to cancer through precursor lesions sensitive to hormones and growth factors discussed above is gaining support in humans as well as in animal models. Indeed, elevation of estrogen receptor, GH, IGF-I, and IGF-I receptor during progression suggests a role for these pathways in this process. New agents targeting the GH/IGF-I axis may provide a novel means to block formation and progression of precursor lesions to overt carcinoma. A novel somatostatin analog has recently been shown to prevent mammary development in rats via targeted IGF-I action inhibition at the mammary gland. Similarly, pegvisomant, a GH antagonist, and other IGF-I antagonists such as IGF binding proteins 1 and 5 also block mammary gland development. It is, therefore, possible that inhibition of IGF-I action, or perhaps GH, in the mammary gland may eventually play a role in breast cancer

  1. Comparative value of clinical, cytological, and histopathological features in feline mammary gland tumors; an experimental model for the study of human breast cancer

    PubMed Central

    2013-01-01

    Background The diagnosis of breast lesions is usually confirmed by fine-needle aspiration cytology (FNAC) or histological biopsy. Although there is increasing literature regarding the advantages and limitations of both modalities, there is no literature regarding the accuracy of these modalities for diagnosing breast lesions in high-risk patients, who usually have lesions detected by screening. Moreover, few studies have been published regarding the cytopathology of mammary tumors in cats despite widespread use of the animal model for breast cancer formation and inhibition. The objective of the present study was to evaluate the diagnostic interest of cytological and histopathological analysis in feline mammary tumours (FMTs), in order to evaluate its possible value as an animal model. Methods The study was performed in 3 female cats submitted to surgical resections of mammary tumours. The mammary tumours were excised by simple mastectomy or regional mastectomy, with or without the superficial inguinal lymph nodes. Female cats were of different breeds (1 siamese and 2 persians). Before surgical excision of the tumour, FNA cytology was performed using a 0.4 mm diameter needle attached to a 8 ml syringe held in a standard metal syringe holder. The cytological sample was smeared onto a glass slide and either air-dried for May-Grünwald-stain and masses were surgically removed, the tumours were grossly examined and tissue samples were fixed in 10%-buffered-formalin and embedded in paraffin. Sections 4 μm thick were obtained from each sample and H&E stained. Results Cytologically, atypical epithelial cells coupled to giant nucleus, chromatin anomalies, mitotic figures, spindle shape cells, anisocytosis with anisokaryosis and hyperchromasia were found. Histologically, these tumors are characterized by pleomorphic and polygonal cell population together with mitotic figures, necrotic foci and various numbers inflammatory foci. Also, spindle shaped cells, haemorrhage

  2. Role of Reactive Stroma in Prostate Cancer Progression

    DTIC Science & Technology

    2008-02-01

    AD_________________ Award Number: W81XWH-04-1-0189 TITLE: Role of Reactive Stroma in Prostate Cancer Progression PRINCIPAL INVESTIGATOR: David R...REPORT TYPE Final 3. DATES COVERED 12 JAN 2004 - 11 JAN 2008 4. TITLE AND SUBTITLE Role of Reactive Stroma in Prostate Cancer Progression 5a. CONTRACT...the reactive stroma of experimental prostate cancer . Using a modified approach, we are placing an inducible Cre recombinase behind the FAP gene

  3. Role of MicroRNA Genes in Breast Cancer Progression

    DTIC Science & Technology

    2006-08-01

    AD_________________ Award Number: W81XWH-05-1-0483 TITLE: Role of microRNA Genes in Breast Cancer ...proposal, we asked if miRNA expression is altered as cells progress through the different stages of cancer . Through our microarray experiments, we have...shown that many miRNAs are differentially regulated as cells progress through cancer stages. A general trend in miRNA expression emerges from this work

  4. Signs of proinflammatory/genotoxic switch (adipogenotoxicosis) in mammary fat of breast cancer patients: role of menopausal status, estrogens and hyperglycemia.

    PubMed

    Berstein, Lev M; Kovalevskij, Anatolij Y; Poroshina, Tatjana E; Kotov, Alexander V; Kovalenko, Irina G; Tsyrlina, Evgenia V; Leenman, Elena E; Revskoy, Sergey Y; Semiglazov, Vladimir F; Pozharisski, Kazimir M

    2007-08-01

    The abundance of fat tissue surrounding normal and malignant epithelial mammary cells raises the questions whether such "adipose milieu" is important in the local proinflammatory/genotoxic shift, which apparently promotes tumor development and worsens prognosis, and what conditions stimulate this shift, or "adipogenotoxicosis." We studied 95 mammary fat samples from 70 postmenopausal and 25 premenopausal breast cancer (BC) patients at a distance of 1.5-2.0 cm from tumors. The levels of leptin, adiponectin, TNFalpha and IL-6 release after 4-hr incubation of the samples were evaluated with ELISA, nitric oxide (NO) production by Griess reaction and lipid peroxidation by determination of thiobarbiturate-reactive products (TBRP). Infiltration of fat with macrophages (CD68-positive cells) and expression of cytochrome P450 1B1/estrogen 4-hydroxylase (CYP1B1) were detected by immunohistochemistry. Aromatase (CYP19) activity in mammary fat was measured by (3)H(2)O release from (3)H-1beta-androstenedione. In the postmenopausal BC patients, NO and TNFalpha production by adipose tissue explants increased independent of BMI and in parallel with decreasing leptin and, especially, adiponectin release. In the premenopausal patients, higher CYP1B1 expression and TBRP level were found in mammary fat, while higher aromatase activity was combined with higher CYP1B1 expression as well as NO and IL-6 production. In the postmenopausal group, impaired glucose tolerance was associated with higher IL-6 release production by fat and with higher IL-6/adiponectin ratio. Thus, signs of adipogenotoxicosis in mammary fat can be found in both pre- and postmenopausal BC patients. This condition is likely being maintained through estrogen- and glucose-related factors and mechanisms presumably associated with less favorable types of hormonal carcinogenesis.

  5. [Research progress on mechanisms of modern medicine in cancer metastasis].

    PubMed

    Chen, Hui; Qu, Jing-Lian; Gong, Jie-Ning

    2014-08-01

    Cancer metastasis is the most dangerous stage of tumorigenesis and evolution, the primary cause of death in cancer patients. Clinically, more than 60% of cancer patients have found metastasis at the time of examination. Modern medicine has made significant progress on the mechanisms of cancer metastasis in recent years, from the simple "anatomy and machinery" theory forward to the "seed and soil" theory, then to the "microenvironmental" theory and the "cancer stem cell" theory. The emerging "cancer stem cell" theory successfully explains phenomenon such as tumor genetic heterogeneity, anoikis resistance, tumor dormancy, providing more new targets and ideas for the diagnosis and treatment of cancer metastasis.

  6. Morphine does not facilitate breast cancer progression in two preclinical mouse models for human invasive lobular and HER2⁺ breast cancer.

    PubMed

    Doornebal, Chris W; Vrijland, Kim; Hau, Cheei-Sing; Coffelt, Seth B; Ciampricotti, Metamia; Jonkers, Jos; de Visser, Karin E; Hollmann, Markus W

    2015-08-01

    Morphine and other opioid analgesics are potent pain-relieving agents routinely used for pain management in patients with cancer. However, these drugs have recently been associated with a worse relapse-free survival in patients with surgical cancer, thus suggesting that morphine adversely affects cancer progression and relapse. In this study, we evaluated the impact of morphine on breast cancer progression, metastatic dissemination, and outgrowth of minimal residual disease. Using preclinical mouse models for metastatic invasive lobular and HER2 breast cancer, we show that analgesic doses of morphine do not affect mammary tumor growth, angiogenesis, and the composition of tumor-infiltrating immune cells. Our studies further demonstrate that morphine, administered in the presence or absence of surgery-induced tissue damage, neither facilitates de novo metastatic dissemination nor promotes outgrowth of minimal residual disease after surgery. Together, these findings indicate that opioid analgesics can be used safely for perioperative pain management in patients with cancer and emphasize that current standards of "good clinical practice" should be maintained.

  7. Generation of breast cancer stem cells by steroid hormones in irradiated human mammary cell lines.

    PubMed

    Vares, Guillaume; Cui, Xing; Wang, Bing; Nakajima, Tetsuo; Nenoi, Mitsuru

    2013-01-01

    Exposure to ionizing radiation was shown to result in an increased risk of breast cancer. There is strong evidence that steroid hormones influence radiosensitivity and breast cancer risk. Tumors may be initiated by a small subpopulation of cancer stem cells (CSCs). In order to assess whether the modulation of radiation-induced breast cancer risk by steroid hormones could involve CSCs, we measured by flow cytometry the proportion of CSCs in irradiated breast cancer cell lines after progesterone and estrogen treatment. Progesterone stimulated the expansion of the CSC compartment both in progesterone receptor (PR)-positive breast cancer cells and in PR-negative normal cells. In MCF10A normal epithelial PR-negative cells, progesterone-treatment and irradiation triggered cancer and stemness-associated microRNA regulations (such as the downregulation of miR-22 and miR-29c expression), which resulted in increased proportions of radiation-resistant tumor-initiating CSCs.

  8. Induction of cells with cancer stem cell properties from nontumorigenic human mammary epithelial cells by defined reprogramming factors.

    PubMed

    Nishi, M; Sakai, Y; Akutsu, H; Nagashima, Y; Quinn, G; Masui, S; Kimura, H; Perrem, K; Umezawa, A; Yamamoto, N; Lee, S W; Ryo, A

    2014-01-30

    Cancer stem cells (CSCs), a small and elusive population of undifferentiated cancer cells within tumors that drive tumor growth and recurrence, are believed to resemble normal stem cells. Although surrogate markers have been identified and compelling CSC theoretical models abound, actual proof for the existence of CSCs can only be had retrospectively. Hence, great store has come to be placed in isolating CSCs from cancers for in-depth analysis. On the other hand, although induced pluripotent stem cells (iPSCs) hold great promise for regenerative medicine, concern exists over the inadvertent co-transplantation of partially or undifferentiated stem cells with tumorigenic capacity. Here we demonstrate that the introduction of defined reprogramming factors (OCT4, SOX2, Klf4 and c-Myc) into MCF-10A nontumorigenic mammary epithelial cells, followed by partial differentiation, transforms the bulk of cells into tumorigenic CD44(+)/CD24(low) cells with CSC properties, termed here as induced CSC-like-10A or iCSCL-10A cells. These reprogrammed cells display a malignant phenotype in culture and form tumors of multiple lineages when injected into immunocompromised mice. Compared with other transformed cell lines, cultured iCSCL-10A cells exhibit increased resistance to the chemotherapeutic compounds, Taxol and Actinomycin D, but higher susceptibility to the CSC-selective agent Salinomycin and the Pin1 inhibitor Juglone. Restored expression of the cyclin-dependent kinase inhibitor p16INK4a abrogated the CSC properties of iCSCL-10A cells, by inducing cellular senescence. This study provides some insight into the potential oncogenicity that may arise via cellular reprogramming, and could represent a valuable in vitro model for studying the phenotypic traits of CSCs per se.

  9. Myeloperoxidase in the Progression of Breast Cancer

    DTIC Science & Technology

    2012-09-01

    We have crossed mice that carry the polyoma virus middle T oncogene (PyMT) and develop mammary tumors with mice that carry a human MPO (huMPO...glands affected) Cumulative Tumor Burden 6285 + 1486 3971 + 1310 0.06 (mm3 at 23 woa) Male PyMT mice were crossed with females carrying one copy of the...human MPO-G transgene. Tumor development was followed in cohorts of virgin, female littermates. All mice were in the C57Bl/6 background. P

  10. [Establishment of a mammary cancer cell line Ca 761-86 and its biologic characteristics in inbred 615 mice].

    PubMed

    Cheng, Y D

    1988-11-01

    A cell line designated as Ca761-86 has been established from the solid mouse mammary cancer (Ca761) by suspension culture. It has been passaged for more than 200 generations. Moderate round cells were predominant and most of them were mononuclear. Some characteristics of malignant cells and A-type viral-like particles were observed by electron microscopy. The results of cytochemical studies (DNA, RNA, SDH, 5'AMPase, ACP etc) were comparable to the ultramicroscopic results. It multiplied approximately 27.4 fold on Day 5 with mitotic index reaching 1.8% on Day 3. This cell line was a hyperdiploid with karyotype of 45 or 43, -2X, tri12, tri17, +M1-5. Cell agglutination was observed when treated with ConA (greater than or equal to 7 micrograms/ml). Spontaneous agglutination might also take place without adding any ConA. After 5 x 10(6) cells of Ca761-86 suspension were transplanted into the normal inbred 615 mice by different ways (subcutaneous, intrafoot pad or intraperitoneal), the transplantability rate reached 100%. Spontaneous remission was never observed and its metastatic ability reserved. PPLO were not detected. Ca761-86 may be of value for practical purposes.

  11. Importance of dietary fat during initiation versus promotion in rat mammary cancer

    SciTech Connect

    Hasler, C.M.; Bennink, M.R.

    1986-03-05

    This study was designed to determine if the fat content of the diet would alter 7,12-dimethylbenzanthracene (DMBA) initiation of mammary carcinogenesis. Female Sprague-Dawley rats were fed the AIN-76 (high carbohydrate, HC) diet or a modified AIN-76 diet (high fat (37/sup 5/), HF) prior to initiation. The HF diet had the same energy to nutrient ratio as the HC diet. Two groups were fed either the HC or the HF diet during the initiation and promotion phase (HC-HC and HF-HF groups). A third group was fed the HF diet 20 days before and 12 days after initiation and then were fed the HC diet during the promotion phase (HF-HC group). Weight gain during promotion was similar for the HC-HC and HF-HC groups, but the HF-HF group gained 41% more weight. The HC-HC group had significantly fewer tumors than the HF-HF or HF-HC groups (HC-HC = 1.45 tumors/rat; HF-HF = 2.75 and HF-HC = 3.63). Surprisingly, feeding the HC diet during promotion did not cause a decrease in tumorigenesis (there was actually a non-significant increase). This work demonstrates that the fat (energy) content of the diet during DMBA initiation is critical. Furthermore, the fat (energy) content of the diet during initiation was more critical than during promotion.

  12. Exposure to excess estradiol or leptin during pregnancy increases mammary cancer risk and prevents parity-induced protective genomic changes in rats.

    PubMed

    de Assis, Sonia; Wang, Mingyue; Jin, Lu; Bouker, Kerrie B; Hilakivi-Clarke, Leena A

    2013-11-01

    Using a preclinical model, we investigated whether excess estradiol (E2) or leptin during pregnancy affects maternal mammary tumorigenesis in rats initiated by administering carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) on day 50. Two weeks later, rats were mated, and pregnant dams were treated daily with 10 μg of 17β-estradiol, 15 μg of leptin, or vehicle from gestation day 8 to 19. Tumor development was assessed separately during weeks 1 to 12 and 13 to 22 after DMBA administration, because pregnancy is known to induce a transient increase in breast cancer risk, followed by a persistent reduction. Parous rats developed less (32%) mammary tumors than nulliparous rats (59%, P < 0.001), and the majority (93%) of tumors in the parous rats appeared before week 13 (vs. 41% in nulliparous rats), indicating that pregnancy induced a transient increase in breast cancer risk. Parous rats exposed to leptin (final tumor incidence 65%) or E2 (45%) during pregnancy developed mammary tumors throughout the tumor-monitoring period, similar to nulliparous control rats, and the incidence was significantly higher in both the leptin- and E2-exposed dams after week 12 than in the vehicle-exposed parous dams (P < 0.001). The mammary glands of the exposed parous rats contained significantly more proliferating cells (P < 0.001). In addition, the E2- or leptin-treated parous rats did not exhibit the protective genomic signature induced by pregnancy and seen in the parous control rats. Specifically, these rats exhibited downregulation of genes involved in differentiation and immune functions and upregulation of genes involved in angiogenesis, growth, and epithelial-to-mesenchymal transition.

  13. Genetic instability favoring transversions associated with ErbB2-induced mammary tumorigenesis.

    PubMed

    Liu, Shiquan; Liu, Wenjing; Jakubczak, John L; Erexson, Gregory L; Tindall, Kenneth R; Chan, Richard; Muller, William J; Adhya, Sankar; Garges, Susan; Merlino, Glenn

    2002-03-19

    It has been argued that genetic instability is required to generate the myriad mutations that fuel tumor initiation and progression and, in fact, patients with heritable cancer susceptibility syndromes harbor defects in specific genes that normally maintain DNA integrity. However, the vast majority of human cancers arise sporadically, in the absence of deficiencies in known "mutator" genes. We used a cII-based mutation detection assay to show that the mean frequency of forward mutations in primary mammary adenocarcinomas arising in mouse mammary tumor virus-c-erbB2 transgenic mice harboring multiple copies of the lambda bacteriophage genome was significantly higher than in aged-matched, wild-type mammary tissue. Analysis of the cII mutational spectrum within the mammary tumor genomic DNA demonstrated a >6-fold elevation in transversion mutation frequency, resulting in a highly unusual inversion of the transition/transversion ratio characteristic of normal epithelium; frameshift mutation frequencies were unaltered. Arising oncogenic point mutations within the c-erbB2 transgene of such tumors were predominantly transversions as well. Data from this model system support the notion that elaboration of a mutator phenotype is a consequential event in breast cancer and suggest that a novel DNA replication/repair gene is a relatively early mutational target in c-erbB2-induced mammary tumorigenesis.

  14. STX140, but not paclitaxel, inhibits mammary tumour initiation and progression in C3(1)/SV40 T/t-antigen transgenic mice.

    PubMed

    Meyer-Losic, Florence; Newman, Simon P; Day, Joanna M; Reed, Michael J; Kasprzyk, Philip G; Purohit, Atul; Foster, Paul A

    2013-01-01

    Despite paclitxael's clinical success, treating hormone-refractory breast cancer remains challenging. Paclitaxel has a poor pharmacological profile, characterized by a low therapeutic index (TIX) caused by severe dose limiting toxicities, such as neutropenia and peripheral neuropathy. Consequently, new drugs are urgently required. STX140, a compound previously shown to have excellent efficacy against many tumors, is here compared to paclitaxel in three translational in vivo breast cancer models, a rat model of peripheral neuropathy, and through pharmacological testing. Three different in vivo mouse models of breast cancer were used; the metastatic 4T1 orthotopic model, the C3(1)/SV40 T-Ag model, and the MDA-MB-231 xenograft model. To determine TIX and pharmacological profile of STX140, a comprehensive dosing regime was performed in mice bearing MDA-MD-231 xenografts. Finally, peripheral neuropathy was examined using a rat plantar thermal hyperalgesia model. In the 4T1 metastatic model, STX140 and paclitaxel significantly inhibited primary tumor growth and lung metastases. All C3(1)/SV40 T-Ag mice in the control and paclitaxel treated groups developed palpable mammary cancer. STX140 blocked 47% of tumors developing and significantly inhibited growth of tumors that did develop. STX140 treatment caused a significant (P<0.001) survival advantage for animals in early and late intervention groups. Conversely, in C3(1)/SV40 T-Ag mice, paclitaxel failed to inhibit tumor growth and did not increase survival time. Furthermore, paclitaxel, but not STX140, induced significant peripheral neuropathy and neutropenia. These results show that STX140 has a greater anti-cancer efficacy, TIX, and reduced neurotoxicity compared to paclitaxel in C3(1)/SV40 T-Ag mice and therefore may be of significant benefit to patients with breast cancer.

  15. The methyltransferase EZH2 is not required for mammary cancer development, although high EZH2 and low H3K27me3 correlate with poor prognosis of ER-positive breast cancers.

    PubMed

    Bae, Woo Kyun; Yoo, Kyung Hyun; Lee, Ji Shin; Kim, Young; Chung, Ik-Joo; Park, Min Ho; Yoon, Jung Han; Furth, Priscilla A; Hennighausen, Lothar

    2015-10-01

    Enhancer of zeste homolog 2 (EZH2) catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) and its demethylation is catalyzed by UTX. EZH2 levels are frequently elevated in breast cancer and have been proposed to control gene expression through regulating repressive H3K27me3 marks. However, it is not fully established whether breast cancers with different levels of H3K27me3, EZH2 and UTX exhibit different biological behaviors. Levels of H3K27me3, EZH2 and UTX and their prognostic significance were evaluated in 146 cases of breast cancer. H3K27me3 levels were higher in HER2-negative samples. EZH2 expression was higher in cancers that were LN+, size > 20mm, and with higher tumor grade and stage. Using a Cox regression model, H3K27me3 levels and EZH2 expression were identified as independent prognostic factors for overall survival for all the breast cancers studied as well as the ER-positive subgroup. The combination of low H3K27me3 and high EZH2 expression levels were significantly associated with shorter survival. UTX expression was not significantly associated with prognosis and there were no correlations between H3K27me3 levels and EZH2/UTX expression. To determine if EZH2 is required to establish H3K27me3 marks in mammary cancer, Brca1 and Ezh2 were deleted in mammary stem cells in mice. Brca1-deficient mammary cancers with unaltered H3K27me3 levels developed in the absence of EZH2, demonstrating that EZH2 is not a mandatory H3K27 methyltransferase in mammary neoplasia and providing genetic evidence for biological independence between H3K27me3 and EZH2 in this tissue.

  16. Breast Cancer Prevention by Fatty Acid Binding Protein MRG-Induced Pregnancy Like Mammary Gland Differentiation

    DTIC Science & Technology

    2005-08-01

    Annual Summary 3. DATES COVERED (From - To) 1 AUG 2004 - 31 JUL 2005 4. TITLE AND SUBTITLE Breast Cancer Prevention by Fatty Acid Binding Protein...differentiation. Overexpression of MRG in human breast cancer cells induced differentiation with changes in cellular morphology and a significant increase

  17. Common Integration Sites for MMTV in Viral Induced Mouse Mammary Tumors

    PubMed Central

    Callahan, Robert

    2011-01-01

    The paradigm of mammary cancer induction by the mouse mammary tumor virus (MMTV) is used to illustrate the body of evidence that supports the hypothesis that mammary epithelial stem/progenitor cells represent targets for oncogenic transformation. It is argued that this is not a special case applicable only to MMTV-induced mammary cancer, because MMTV acts as an environmental mutagen producing random interruptions in the somatic DNA of infected cells by insertion of proviral DNA copies. In addition to disrupting the host genome, the proviral DNA also influences gene expression through its associated enhancer sequences over significant inter-genomic distances. Genes commonly affected by MMTV insertion in multiple individual tumors include, the Wnt, FGF, RSpo gene families as well as eIF3e and Notch4. All of these gene families are known to play essential roles in stem cell maintenance and behavior in a variety of organs. The MMTV-induced mutations accumulate in cells that are long-lived and possess the properties of stem cells, namely, self-renewal and the capacity to produce divergent epithelial progeny through asymmetric division. The evidence shows that epithelial cells with these properties are present in normal mammary glands, may be infected with MMTV, become transformed to produce epithelial hyperplasia through MMTV-induced mutagenesis and progress to frank mammary malignancy. Retroviral marking via MMTV proviral insertion demonstrates that this process progresses from a single mammary epithelial cell that possesses all of the features ascribed to tissue-specific stem cells. PMID:18709449

  18. Mouse Models of Follicular and Papillary Thyroid Cancer Progression

    PubMed Central

    Russo, Marika A.; Arciuch, Valeria G. Antico; Di Cristofano, Antonio

    2011-01-01

    A significant number of well-differentiated thyroid cancers progress or recur, becoming resistant to current therapeutic options. Mouse models recapitulating the genetic and histological features of advanced thyroid cancer have been an invaluable tool to dissect the mechanisms involved in the progression from indolent, well differentiated tumors to aggressive, poorly differentiated carcinomas, and to identify novel therapeutic targets. In this review, we focus on the lessons learned from models of epithelial cell-derived thyroid cancer showing progression from hyperplastic lesions to locally invasive and metastatic carcinomas. PMID:22654848

  19. Regulated lysosomal exocytosis mediates cancer progression

    PubMed Central

    Machado, Eda; White-Gilbertson, Shai; van de Vlekkert, Diantha; Janke, Laura; Moshiach, Simon; Campos, Yvan; Finkelstein, David; Gomero, Elida; Mosca, Rosario; Qiu, Xiaohui; Morton, Christopher L.; Annunziata, Ida; d’Azzo, Alessandra

    2015-01-01

    Understanding how tumor cells transition to an invasive and drug-resistant phenotype is central to cancer biology, but the mechanisms underlying this transition remain unclear. We show that sarcomas gain these malignant traits by inducing lysosomal exocytosis, a ubiquitous physiological process. During lysosomal exocytosis, the movement of exocytic lysosomes along the cytoskeleton and their docking at the plasma membrane involve LAMP1, a sialylated membrane glycoprotein and target of the sialidase NEU1. Cleavage of LAMP1 sialic acids by NEU1 limits the extent of lysosomal exocytosis. We found that by down-regulation of NEU1 and accumulation of oversialylated LAMP1, tumor cells exacerbate lysosomal exocytosis of soluble hydrolases and exosomes. This facilitates matrix invasion and propagation of invasive signals, and purging of lysosomotropic chemotherapeutics. In Arf−⁄− mice, Neu1 haploinsufficiency fostered the development of invasive, pleomorphic sarcomas, expressing epithelial and mesenchymal markers, and lysosomal exocytosis effectors, LAMP1 and Myosin-11. These features are analogous to those of metastatic, pleomorphic human sarcomas, where low NEU1 levels correlate with high expression of lysosomal exocytosis markers. In a therapeutic proof of principle, we demonstrate that inhibiting lysosomal exocytosis reversed invasiveness and chemoresistance in aggressive sarcoma cells. Thus, we reveal that this unconventional, lysosome-regulated pathway plays a primary role in tumor progression and chemoresistance. PMID:26824057

  20. A compendium of the mouse mammary tumor biologist: from the initial observations in the house mouse to the development of genetically engineered mice.

    PubMed

    Cardiff, Robert D; Kenney, Nicholas

    2011-06-01

    For over a century, mouse mammary tumor biology and the associated mouse mammary tumor virus (MMTV) have served as the foundation for experimental cancer research, in general, and, in particular, experimental breast cancer research. Spontaneous mouse mammary tumors were the basis for studies of the natural history of neoplasia, oncogenic viruses, host responses, endocrinology and neoplastic progression. However, lacking formal proof of a human mammary tumor virus, the preeminence of the mouse model faded in the 1980s. Since the late 1980s, genetically engineered mice (GEM) have proven extremely useful for studying breast cancer and have become the animal model for human breast cancer. Hundreds of mouse models of human breast cancer have been developed since the first demonstration in 1984. The GEM have attracted a new generation of molecular and cellular biologists eager to apply their skill sets to these surrogates of the human disease. Newcomers often enter the field without an appreciation of the origins of mouse mammary tumor biology and the basis for many of the prevailing concepts. Our purpose in writing this compendium is to extend an "olive branch" while simultaneously deepen the knowledge of the novice mouse mammary tumor biologist as they journey into a field rich in pathology and genetics spanning several centuries.

  1. miR-221/222 control luminal breast cancer tumor progression by regulating different targets.

    PubMed

    Dentelli, Patrizia; Traversa, Matteo; Rosso, Arturo; Togliatto, Gabriele; Olgasi, Cristina; Marchiò, Caterina; Provero, Paolo; Lembo, Antonio; Bon, Giulia; Annaratone, Laura; Sapino, Anna; Falcioni, Rita; Brizzi, Maria Felice

    2014-01-01

    α6β4 integrin is an adhesion molecule for laminin receptors involved in tumor progression. We present a link between β4 integrin expression and miR-221/222 in the most prevalent human mammary tumor: luminal invasive carcinomas (Lum-ICs). Using human primary tumors that display different β4 integrin expression and grade, we show that miR-221/222 expression inversely correlates with tumor proliferating index, Ki67. Interestingly, most high-grade tumors express β4 integrin and low miR-221/222 levels. We ectopically transfected miR-221/222 into a human-derived mammary tumor cell line that recapitulates the luminal subtype to investigate whether miR-221/222 regulates β4 expression. We demonstrate that miR-221/222 overexpression results in β4 expression downregulation, breast cancer cell proliferation, and invasion inhibition. The role of miR-221/222 in driving β4 integrin expression is also confirmed via mutating the miR-221/222 seed sequence for β4 integrin 3'UTR. Furthermore, we show that these 2 miRNAs are also key breast cancer cell proliferation and invasion regulators, via the post-transcriptional regulation of signal transducer and activator of transcription 5A (STAT5A) and of a disintegrin and metalloprotease-17 (ADAM-17). We further confirm these data by silencing ADAM-17, using a dominant-negative or an activated STAT5A form. miR-221/222-driven β4 integrin, STAT5A, and ADAM-17 did not occur in MCF-10A cells, denoted "normal" breast epithelial cells, indicating that the mechanism is cancer cell-specific.   These results provide the first evidence of a post-transcriptional mechanism that regulates β4 integrin, STAT5A, and ADAM-17 expression, thus controlling breast cancer cell proliferation and invasion. Pre-miR-221/222 use in the aggressive luminal subtype may be a powerful therapeutic anti-cancer strategy.

  2. PTEN is required to maintain luminal epithelial homeostasis and integrity in the adult mammary gland.

    PubMed

    Shore, Amy N; Chang, Chi-Hsuan; Kwon, Oh-Joon; Weston, Matthew C; Zhang, Mei; Xin, Li; Rosen, Jeffrey M

    2016-01-01

    In the mammary gland, PTEN loss in luminal and basal epithelial cells results in differentiation defects and enhanced proliferation, leading to the formation of tumors with basal epithelial characteristics. In breast cancer, PTEN loss is associated with a hormone receptor-negative, basal-like subtype that is thought to originate in a luminal epithelial cell. Here, we show that luminal-specific PTEN loss results in distinct effects on epithelial homeostasis and mammary tumor formation. Luminal PTEN loss increased proliferation of hormone receptor-negative cells, thereby decreasing the percentage of hormone receptor-positive cells. Moreover, luminal PTEN loss led to misoriented cell divisions and mislocalization of cells to the intraluminal space of mammary ducts. Despite their elevated levels of activated AKT, Pten-null intraluminal cells showed increased levels of apoptosis. One year after Pten deletion, the ducts had cleared and no palpable mammary tumors were detected. These data establish PTEN as a critical regulator of luminal epithelial homeostasis and integrity in the adult mammary gland, and further show that luminal PTEN loss alone is not sufficient to promote the progression of mammary tumorigenesis.

  3. Gr-1+CD11b+ cells are responsible for tumor promoting effect of TGF-β in breast cancer progression.

    PubMed

    Li, Zhaoyang; Pang, Yanli; Gara, Sudheer Kumar; Achyut, B R; Heger, Christopher; Goldsmith, Paul K; Lonning, Scott; Yang, Li

    2012-12-01

    One great challenge in our understanding of TGF-β cancer biology and the successful application of TGF-β-targeted therapy is that TGF-β works as both a tumor suppressor and a tumor promoter. The underlying mechanisms for its functional change remain to be elucidated. Using 4T1 mammary tumor model that shares many characteristics with human breast cancer, particularly its ability to spontaneously metastasize to the lungs, we demonstrate that Gr-1+CD11b+ cells or myeloid derived suppressor cells are important mediators in TGF-β regulation of mammary tumor progression. Depletion of Gr-1+CD11b+ cells diminished the antitumor effect of TGF-β neutralization. Two mechanisms were involved: first, treatment with TGF-β neutralization antibody (1D11) significantly decreased the number of Gr-1+CD11b+ cells in tumor tissues and premetastatic lung. This is mediated through increased Gr-1+CD11b+ cell apoptosis. In addition, 1D11 treatment significantly decreased the expression of Th2 cytokines and Arginase 1. Interestingly, the number and property of Gr-1+CD11b+ cells in peripheral blood/draining lymph nodes correlated with tumor size and metastases in response to 1D11 treatment. Our data suggest that the efficacy of TGF-β neutralization depends on the presence of Gr-1+CD11b+ cells, and these cells could be good biomarkers for TGF-β-targeted therapy.

  4. Heme oxygenase-1 in macrophages controls prostate cancer progression.

    PubMed

    Nemeth, Zsuzsanna; Li, Mailin; Csizmadia, Eva; Döme, Balazs; Johansson, Martin; Persson, Jenny Liao; Seth, Pankaj; Otterbein, Leo; Wegiel, Barbara

    2015-10-20

    Innate immune cells strongly influence cancer growth and progression via multiple mechanisms including regulation of epithelial to mesenchymal transition (EMT). In this study, we investigated whether expression of the metabolic gene, heme oxygenase-1 (HO-1) in tumor microenvironment imparts significant effects on prostate cancer progression.We showed that HO-1 is expressed in MARCO-positive macrophages in prostate cancer (PCa) xenografts and human prostate cancers. We demonstrated that macrophage specific (LyzM-Cre) conditional deletion of HO-1 suppressed growth of PC3 xenografts in vivo and delayed progression of prostate intraepithelial neoplasia (PIN) in TRAMP mice. However, initiation and progression of cancer xenografts in the presence of macrophages lacking HO-1 resulted in loss of E-cadherin, a known marker of poor prognosis as well as EMT. Application of CO, a product of HO-1 catalysis, increased levels of E-cadherin in the adherens junctions between cancer cells. We further showed that HO-1-driven expression of E-cadherin in cancer cells cultured in the presence of macrophages is dependent on mitochondrial activity of cancer cells.In summary, these data suggest that HO-1-derived CO from tumor-associated macrophages influences, in part, E-cadherin expression and thus tumor initiation and progression.

  5. Progesterone receptor gene maps to human chromosome band 11q13, the site of the mammary oncogene int-2

    SciTech Connect

    Law, M.L.; Kao, F.T.; Wei, Q.; Hartz, J.A.; Greene, G.L.; Zarucki-Schulz, T.; Conneely, O.M.; Jones, C.; Puck, T.T.; O'Malley, B.W.; Horwitz, K.B.

    1987-05-01

    Progesterone is involved in the development and progression of breast cancers, and progesterone receptors (PR) are important markers of hormone dependence and disease prognosis. The authors have used a human PR cDNA probe, genomic DNA blotting of a series of Chinese hamster-human cell hybrids, and in situ hybridization to map the human PR gene to chromosome 11, band q13. This band also contains the human homolog of the mouse mammary tumor virus integration site, int-2, which surrounds a protooncogene thought to be involved in the development of murine mammary cancers. That these two genes share the same chromosomal location raises important questions about their possible linkage and about the relationship between the mammary-specific oncogene and the steroid hormone in the development, growth, and hormone dependence of human breast cancers.

  6. NY-BR-1 protein expression in breast carcinoma: a mammary gland differentiation antigen as target for cancer immunotherapy.

    PubMed

    Theurillat, Jean-Philippe; Zürrer-Härdi, Ursina; Varga, Zsuzsanna; Storz, Martina; Probst-Hensch, Nicole M; Seifert, Burkhardt; Fehr, Mathias K; Fink, Daniel; Ferrone, Soldano; Pestalozzi, Bernhard; Jungbluth, Achim A; Chen, Yao-Tseng; Jäger, Dirk; Knuth, Alexander; Moch, Holger

    2007-11-01

    NY-BR-1 is a recently identified differentiation antigen of the mammary gland. To use NY-BR-1 for T-cell-based immunotherapy, analysis of its co-expression with HLA class I antigens is required. In the present tissue microarray study, primary breast cancers (n = 1,444), recurrences (n = 88), lymph node (n = 525) and distant metastases (n = 91) were studied for NY-BR-1 expression using a novel monoclonal antibody. NY-BR-1 expression was compared with prognosis, estrogen receptor, HER2-status, EGFR and HLA class I antigen expression. NY-BR-1 was more frequently expressed in grade 1 (82%) than in grade 2 (69%) and grade 3 (46%) carcinomas (P < 0.0001). Moreover, NY-BR-1 expression correlated directly with estrogen receptor expression (P < 0.0001) and inversely correlated with HER2-status and EGFR expression (P < 0.0001 for both). Considering high expression level of co-expression, 198/1,321 (15%) primary breast carcinomas and 4/65 (6%) distant metastases expressed NY-BR-1 and HLA class I, suggesting that active immunotherapy can be applied to about 10% of breast cancer patients. Survival analysis showed an association of NY-BR-1 expression with better patient outcome (P = 0.015). No difference between NY-BR-1 expression of primary tumors and metastases could be found, indicating that the presence of NY-BR-1 in metastases can be deduced from their corresponding primary. Forty-three paired biopsies taken from patients before and after chemotherapy suggest that NY-BR-1 expression is not influenced by preceding chemotherapy (kappa = 0.89, P < 0.0001). In summary, the co-expression of NY-BR-1 with HLA class I antigens and its expression in metastases without modification by chemotherapy suggest that NY-BR-1 targeted immunotherapy represents a viable strategy in addition to other targeted cancer drug therapies of breast cancer.

  7. Role of Hunk and Punc in Breast Cancer and Mammary Development

    DTIC Science & Technology

    2000-08-01

    control, and the Caenorhabditis elegans restricted to subsets of cells within a variety of organs SNF-1 related kinase, PAR-i, in the establishment of...transcripts provides that mutations in the C. elegans SNF1-related kinase evidence that we have isolated the entire ORF and that PAR-1 result in an inability...Whether HUNK and PNCK are Amplified, Overexpressed or Mutated in Human Breast Cancers Protein kinases function as oncogenes in a variety of human cancers

  8. Survival, Smoking, Physical Activity, and Obesity - Life After Cancer Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  9. Bladder, Breast, and Colorectal Cancer- Treatment Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  10. Kidney, Lung, Ovarian, and Prostate Cancer - Treatment Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  11. Breast, Cervical, and Colorectal Cancers - Early Detection Summary Table | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  12. Leptin and Cancer: From Cancer Stem Cells to Metastasis (Preprint)

    DTIC Science & Technology

    2011-01-01

    1 Endocrine-Related Cancer Commentary Leptin and Cancer: From Cancer Stem Cells to Metastasis Jiyoung Park 1 and Philipp E. Scherer...REPORT DATE JUN 2011 2. REPORT TYPE 3. DATES COVERED 00-00-2011 to 00-00-2011 4. TITLE AND SUBTITLE Leptin And Cancer: From Cancer Stem Cells To...interest. Recently several groups have addressed the functional roles of leptin , an adipocyte-derived adipokine, for mammary tumor progression. In this

  13. Progress in neutron capture therapy for cancer

    SciTech Connect

    Allen, B.J.; Harrington, B.V. ); Moore, D.E. )

    1992-01-01

    Prognosis for some cancers is good, but for others, few patients will survive 12 months. This latter group of cancers is characterised by a proclivity to disseminate malignant cells in the host organ. In some cases systemic metastases occur, but in other cases, failure to achieve local control results in death. First among these cancers are the high grade brain tumours, astrocytoma 3,4 and glioblastoma multiforme. Local control of these tumors should lead to cure. Other cancers melanoma metastatic to the brain, for which a useful palliative therapy is not yet available, and pancreatic cancer for which localised control at an early stage could bring about improved prognosis. Patients with these cancers have little grounds for hope. Our primary objective is to reverse this situation with Neutron Capture Therapy (NCT). The purpose of this fourth symposium is to hasten the day whereby patients with these cancers can reasonably hope for substantial remissions.

  14. Progress in neutron capture therapy for cancer

    SciTech Connect

    Allen, B.J.; Harrington, B.V.; Moore, D.E.

    1992-09-01

    Prognosis for some cancers is good, but for others, few patients will survive 12 months. This latter group of cancers is characterised by a proclivity to disseminate malignant cells in the host organ. In some cases systemic metastases occur, but in other cases, failure to achieve local control results in death. First among these cancers are the high grade brain tumours, astrocytoma 3,4 and glioblastoma multiforme. Local control of these tumors should lead to cure. Other cancers melanoma metastatic to the brain, for which a useful palliative therapy is not yet available, and pancreatic cancer for which localised control at an early stage could bring about improved prognosis. Patients with these cancers have little grounds for hope. Our primary objective is to reverse this situation with Neutron Capture Therapy (NCT). The purpose of this fourth symposium is to hasten the day whereby patients with these cancers can reasonably hope for substantial remissions.

  15. Neem leaf extract inhibits mammary carcinogenesis by altering cell proliferation, apoptosis, and angiogenesis

    PubMed Central

    Arumugam, Arunkumar; Agullo, Pamela; Boopalan, Thiyagarajan; Nandy, Sushmita; Lopez, Rebecca; Gutierrez, Christina; Narayan, Mahesh; Rajkumar, Lakshmanaswamy

    2014-01-01

    Plant-based medicines are useful in the treatment of cancer. Many breast cancer patients use complementary and alternative medicine in parallel with conventional treatments. Neem is historically well known in Asia and Africa as a versatile medicinal plant with a wide spectrum of biological activities. The experiments reported herein determined whether the administration of an ethanolic fraction of Neem leaf (EFNL) inhibits progression of chemical carcinogen-induced mammary tumorigenesis in rat models. Seven-week-old female Sprague Dawley rats were given a single intraperitoneal injection of N-methyl-N-nitrosourea (MNU). Upon the appearance of palpable mammary tumors, the rats were divided into vehicle-treated control groups and EFNL-treated groups. Treatment with EFNL inhibited MNU-induced mammary tumor progression. EFNL treatment was also highly effective in reducing mammary tumor burden and in suppressing mammary tumor progression even after the cessation of treatment. Further, we found that EFNL treatment effectively upregulated proapoptotic genes and proteins such as p53, B cell lymphoma-2 protein (Bcl-2)-associated X protein (Bax), Bcl-2-associated death promoter protein (Bad) caspases, phosphatase and tensin homolog gene (PTEN), and c-Jun N-terminal kinase (JNK). In contrast, EFNL treatment caused downregulation of anti-apoptotic (Bcl-2), angiogenic proteins (angiopoietin and vascular endothelial growth factor A [VEGF-A]), cell cycle regulatory proteins (cyclin D1, cyclin-dependent kinase 2 [Cdk2], and Cdk4), and pro-survival signals such as NFκB, mitogen-activated protein kinase 1 (MAPK1). The data obtained in this study demonstrate that EFNL exert a potent anticancer effect against mammary tumorigenesis by altering key signaling pathways. PMID:24146019

  16. A Genetic Interaction Screen for Breast Cancer Progression Driver Genes

    DTIC Science & Technology

    2013-06-01

    AD_________________ Award Number: W81XWH-12-1-0082 TITLE: A Genetic Interaction Screen for Breast...COVERED 1 2012 - 3 2013 4. TITLE AND SUBTITLE A Genetic Interaction Screen for Breast Cancer Progression Driver Genes 5a. CONTRACT NUMBER...analysis of genetic alterations in human breast cancers has revealed that individual tumors accumulate mutations in approximately ninety different genes

  17. Analysis of microRNA expression in canine mammary cancer stem-like cells indicates epigenetic regulation of transforming growth factor-beta signaling.

    PubMed

    Rybicka, A; Mucha, J; Majchrzak, K; Taciak, B; Hellmen, E; Motyl, T; Krol, M

    2015-02-01

    Cancer stem cells (CSCs) display both unique self-renewal ability as well as the ability to differentiate into many kinds of cancer cells. They are supposed to be responsible for cancer initiation, recurrence and drug resistance. Despite the fact that a variety of methods are currently employed in order to target CSCs, little is known about the regulation of their phenotype and biology by miRNAs. The aim of our study was to assess miRNA expression in canine mammary cancer stem-like cells (expressing stem cell antigen 1, Sca-1; CD44 and EpCAM) sorted from canine mammary tumour cell lines (CMT-U27, CMT-309 and P114). In order to prove their stem-like phenotype, we conducted a colony formation assay that confirmed their ability to form colonies from a single cell. Profiles of miRNA expression were investigated using Agilent custom-designed microarrays. The results were further validated by real-time rt-PCR analysis of expression of randomly selected miRNAs. Target genes were indicated and analysed using Kioto Encyclopedia of Genes and Genomes (KEGG) and BioCarta databases. The results revealed 24 down-regulated and nine up-regulated miRNAs in cancer stem-like cells compared to differentiated tumour cells. According to KEGG and BioCarta databases, target genes (n=240) of significantly down-regulated miRNAs were involved in transforming growth factor-beta signaling, mitogen-activated protein kinases (MAPK) signaling pathway, anaplastic lymphoma receptor tyrosine kinase (ALK) and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1A) pathways. The analysis of single-gene overlapping with different pathways showed that the most important genes were: TGFBR1, TGFBR2, SOS1, CHUK, PDGFRA, SMAD2, MEF2A, MEF2C and MEF2D. All of them are involved in tumor necrosis factor-beta signaling and may indicate its important role in cancer stem cell biology. Increased expression of TGFBR2, SMAD2, MEF2A and MEF2D in canine mammary cancer stem-like cells was further

  18. Role of Mammary Adenocarcinoma Cell Transterrin Response In Breast Cancer Metastasis

    DTIC Science & Technology

    1995-09-21

    for identifying dividing cells. Int. J. Cancer, 27::329-334. 13. Wrba, F., Ritzinger, E., Reiner, A., and Holzner , J.H. Transferrin receptor (TrfR...A., and Holzner , J.H. Transferrin receptor (TrfR) expression in breast carcinoma and its possible relationship to prognosis. An immunohistochemical

  19. Genes Involved in Oxidation and Prostate Cancer Progression

    DTIC Science & Technology

    2008-01-01

    association of genes and prostate cancer progression from these simulated nested case - control studies to what would be observed if the entire...Control Sampling: Methods for Nested Case - Control Studies of Candidate Genes and Prostate Cancer Progression”. This work forms one aim of MS Wang’s...prostate cancer risk: results from two large nested case - control studies . Carcinogenesis. 2007 Nov 13; [Epub ahead of print] PMID: 17999989 Dr

  20. Negative regulation of CDC42 expression and cell cycle progression by miR-29a in breast cancer

    PubMed Central

    Zhang, Mingliang; Guo, Wei; Qian, Jun

    2016-01-01

    Abstract Objective The inhibitory role of microRNA-29a (miR-29a) has been assessed in breast cancer cells. Herein, we analyze the underlying mechanisms of its role in cell cycle progression in breast cancer cells. Methods We applied real-time polymerase chain reaction (PCR) to detect the expression of miR-29 in breast cancer cell lines. Then one of the cell lines, MDA-MB-453, was transfected with mimics of miR-29a. The cell cycle was analyzed by fluorescence-activated cell sorting after staining the cells with propidium iodide. Real-time PCR, luciferase assay and western blot were used together to verify the regulation of the predicted target, cell division cycle 42 (CDC42) by miR-29a. Results MiR-29s were decreased in our selected mammary cell lines, among which miR-29a was the dominant isoform. Overexpression of miR-29a caused cell cycle arrest at the G0/G1 phase. We further found that miR-29a could target the expression of CDC42, which is a small GTPase associated with cell cycle progression. Conclusion We suggest that miR-29a exerts its tumor suppressor role in breast cancer cells partially by arresting the cell cycle through negative regulation of CDC42.

  1. Simvastatin exhibits antiproliferative effects on spheres derived from canine mammary carcinoma cells.

    PubMed

    Torres, Cristian G; Olivares, Araceli; Stoore, Caroll

    2015-05-01

    Mammary cancer is the most frequent type of tumor in the female canine. Treatments are mainly limited to surgery and chemotherapy; however, these tumors may develop clinical recurrence, metastasis and chemoresistance. The existence of a subpopulation of cancer cells with stemness features called cancer stem-like cells, may explain in part these characteristics of tumor progression. The statins, potent blockers of cholesterol synthesis, have also shown antitumor effects on cancer mammary cells, changes mediated by a decrease in the isoprenylation of specific proteins. Few studies have shown that simvastatin, a lipophilic statin, sensitizes cancer stem-like cells eliminating drug resistance. The aim of the present study was to evaluate the effects of simvastatin on spheres derived from CF41.Mg canine mammary tumor cells, which were characterized by phenotypic and functional analyses. Spheres exhibited characteristics of stemness, primarily expressing a CD44⁺/CD24⁻/low phenotype, displaying auto-renewal and relative chemoresistance. Exposure to simvastatin induced a decrease in the sphere-forming capacity and cell viability, accompanied by a concentration- and time-dependent increase in caspase-3/7 activity. In addition, modulation of β-catenin and p53 expression was observed. Simvastatin triggered a synergistic effect with doxorubicin, sensitizing the spheres to the cytotoxic effect exerted by the drug. Invasiveness of spheres was decreased in response to simvastatin and this effect was counteracted by the presence of geranylgeranyl pyrophosphate. Our results suggest that simvastatin targets canine mammary cancer stem-like cells, supporting its therapeutical application as a novel agent to treat canine mammary cancer.

  2. Protein tyrosine kinase 6 promotes ERBB2-induced mammary gland tumorigenesis in the mouse

    PubMed Central

    Peng, M; Ball-Kell, S M; Tyner, A L

    2015-01-01

    Protein tyrosine kinase 6 (PTK6) expression, activation, and amplification of the PTK6 gene have been reported in ERBB2/HER2-positive mammary gland cancers. To explore contributions of PTK6 to mammary gland tumorigenesis promoted by activated ERBB2, we crossed Ptk6−/− mice with the mouse mammary tumor virus-ERBB2 transgenic mouse line expressing activated ERBB2 and characterized tumor development and progression. ERBB2-induced tumorigenesis was significantly delayed and diminished in mice lacking PTK6. PTK6 expression was induced in the mammary glands of ERBB2 transgenic mice before tumor development and correlated with activation of signal transducer and activator of transcription 3 (STAT3) and increased proliferation. Disruption of PTK6 impaired STAT3 activation and proliferation. Phosphorylation of the PTK6 substrates focal adhesion kinase (FAK) and breast cancer anti-estrogen resistance 1 (BCAR1; p130CAS) was decreased in Ptk6−/− mammary gland tumors. Reduced numbers of metastases were detected in the lungs of Ptk6−/− mice expressing activated ERBB2, compared with wild-type ERBB2 transgenic mice. PTK6 activation was detected at the edges of ERBB2-positive tumors. These data support roles for PTK6 in both ERBB2-induced mammary gland tumor initiation and metastasis, and identify STAT3, FAK, and BCAR1 as physiologically relevant PTK6 substrates in breast cancer. Including PTK6 inhibitors as part of a treatment regimen could have distinct benefits in ERBB2/HER2-positive breast cancers. PMID:26247733

  3. Inhibition of STAT3 signaling blocks obesity-induced mammary hyperplasia in a mouse model

    PubMed Central

    Park, Jeong Won; Zhao, Li; Willingham, Mark C; Cheng, Sheue-Yann

    2017-01-01

    Compelling epidemiologic evidence indicates that obesity is a risk factor for human cancers, including breast. However, molecular mechanisms by which obesity could contribute to the development of breast cancer remain unclear. To understand the impact of obesity on breast cancer development, we used a mutant mouse that expresses a mutated thyroid hormone receptor β (denoted as PV) with haplodeficiency of the Pten gene (ThrbPV/PVPten+/- mice). We previously showed that adult nulliparous female ThrbPV/PVPten+/- mice developed extensive mammary hyperplasia and breast tumors. In this study, we induced obesity in ThrbPV/PVPten+/- mice by feeding them a high fat diet (HFD). We found HFD exacerbated the extent of mammary hyperplasia in ThrbPV/PVPten+/- mice. HFD elevated serum leptin levels but had no effect on the levels of serum thyroid stimulating hormone, thyroid hormones, and estrogens. Molecular analysis showed that the obesity-induced hyperplasia was mediated by the leptin/leptin receptor-JAK1-STAT3 pathway to increase key cell cycle regulators to stimulate mammary epithelial cell proliferation. Activated STAT3 signaling led to altered expression in the key regulators of epithelial-mesenchymal-transition (EMT) to augment invasiveness and migration of mammary proliferating epithelial cells. Moreover, treatment of HFD-ThrbPV/PVPten+/- mice with a STAT3 inhibitor, S3I-201, markedly reversed the obesity-induced mammary hyperplasia and reduced EMT signals to lessen cell invasiveness and migration. Our studies not only elucidated how obesity could contribute to mammary hyperplasia at the molecular level, but also, importantly, demonstrated that inhibition of the STAT3 activity could be a novel treatment strategy for obesity-induced breast cancer progression.

  4. Histopathological and in vivo evidence of regucalcin as a protective molecule in mammary gland carcinogenesis

    SciTech Connect

    Marques, Ricardo; Vaz, Cátia V.; Maia, Cláudio J.; Gomes, Madalena; Gama, Adelina; Alves, Gilberto; Santos, Cecília R.; Schmitt, Fernando; Socorro, Sílvia

    2015-01-15

    Regucalcin (RGN) is a calcium-binding protein, which has been shown to be underexpressed in cancer cases. This study aimed to determine the association of RGN expression with clinicopathological parameters of human breast cancer. In addition, the role of RGN in malignancy of mammary gland using transgenic rats overexpressing the protein (Tg-RGN) was investigated. Wild-type (Wt) and Tg-RGN rats were treated with 7,12-dimethylbenz[α]anthracene (DMBA). Carcinogen-induced tumors were histologically classified and the Ki67 proliferation index was estimated. Immunohistochemistry analysis showed that RGN immunoreactivity was negatively correlated with the histological grade of breast infiltrating ductal carcinoma suggesting that progression of breast cancer is associated with loss of RGN. Tg-RGN rats displayed lower incidence of carcinogen-induced mammary gland tumors, as well as lower incidence of invasive forms. Moreover, higher proliferation was observed in non-invasive tumors of Wt animals comparatively with Tg-RGN. Overexpression of RGN was associated with diminished expression of cell-cycle inhibitors and increased expression of apoptosis inducers. Augmented activity of apoptosis effector caspase-3 was found in the mammary gland of Tg-RGN. RGN overexpression protected from carcinogen-induced mammary gland tumor development and was linked with reduced proliferation and increased apoptosis. These findings indicated the protective role of RGN in the carcinogenesis of mammary gland. - Highlights: • RGN immunoreactivity was negatively correlated with breast cancer differentiation. • Transgenic overexpression of RGN diminished incidence of carcinogen-induced tumors. • Transgenic overexpression of RGN restricted proliferation and fostered apoptosis. • RGN has a protective role in the carcinogenesis of mammary gland.

  5. Dietary Regulation of PTEN Signaling and Mammary Tumor Initiating Cells: Implications for Breast Cancer Prevention

    DTIC Science & Technology

    2012-01-01

    Institutional Animal Care and Use Committee. Time-mated Sprague Dawley rats ( Charles River Laboratories, Wilmington, MA) were individually housed in...collected at PND21 and PND50 were measured using a rat APN ELISA kit (Linco Research, St. Charles , MO). The assay sensi- tivity was 0.15 ng/ml, and intra...Stampfer MJ, Hunter DJ, Manson JE, Hennekens CH, Rosner B, Speizer FE, Willett WC 1997 Dual effects of weight and weight gain on breast cancer risk

  6. Pubertal Social Isolation and Hypervigilance Regulate Gene Expression Mechanisms of Mammary Differentiation and Cancer Risks

    DTIC Science & Technology

    2010-08-01

    tasks itemized below. Each contributed to all reportable outcomes. Together, these transdisciplinary studies show for the first time that an...model of naturally developing breast cancer Together, these transdisciplinary studies show for the first time that an adverse social environment is...accelerated growth of invasive ductal carcinomas inevitably induced by the SV40-T-Antigen. Together, these transdisciplinary studies show for the

  7. Role of Aquaporin 1 Signalling in Cancer Development and Progression

    PubMed Central

    Tomita, Yoko; Dorward, Hilary; Yool, Andrea J.; Smith, Eric; Townsend, Amanda R.; Price, Timothy J.; Hardingham, Jennifer E.

    2017-01-01

    Cancer is a major health burden worldwide. Despite the advances in our understanding of its pathogenesis and continued improvement in cancer management and outcomes, there remains a strong clinical demand for more accurate and reliable biomarkers of metastatic progression and novel therapeutic targets to abrogate angiogenesis and tumour progression. Aquaporin 1 (AQP1) is a small hydrophobic integral transmembrane protein with a predominant role in trans-cellular water transport. Recently, over-expression of AQP1 has been associated with many types of cancer as a distinctive clinical prognostic factor. This has prompted researchers to evaluate the link between AQP1 and cancer biological functions. Available literature implicates the role of AQP1 in tumour cell migration, invasion and angiogenesis. This article reviews the current understanding of AQP1-facilitated tumour development and progression with a focus on regulatory mechanisms and downstream signalling pathways. PMID:28146084

  8. Inflammation in prostate cancer progression and therapeutic targeting

    PubMed Central

    Stark, Timothy; Livas, Lydia

    2015-01-01

    Chronic inflammation contributes to the onset and progression of human cancer, via modifications in the tumor microenvironment by remodeling the extracellular matrix (ECM) and initiating epithelial mesenchymal transition (EMT). At the biological level, chronically inflamed cells release cytokines that are functionally dictating a constitutively active stroma, promoting tumor growth and metastasis. In prostate cancer, inflammation correlates with increased development of “risk factor” lesions or proliferative inflammatory atrophy (PIA). Chronic inflammation in benign prostate biopsy specimens can be associated with high-grade prostate tumors in adjacent areas. In this article, we discuss the current understanding of the incidence of inflammation in prostate cancer progression and the significance of the process in therapeutic targeting of specific inflammatory signaling pathways and critical effectors during tumor progression. Further understanding of the process of chronic inflammation in prostate tumor progression to metastasis will enable development and optimization of novel therapeutic modalities for the treatment of high-risk patients with advanced disease. PMID:26816843

  9. GPR56 in cancer progression: current status and future perspective.

    PubMed

    Yang, Liquan; Xu, Lei

    2012-04-01

    Cell adhesion is a critical process during cancer progression and is mediated by transmembrane receptors. Recently, GPR56, a member of the adhesion family of G protein-coupled receptors, was established as a new type of adhesion receptor that binds to extracellular matrix proteins and shown to play inhibitory roles in melanoma progression. Further studies revealed that the extracellular portion and the seven transmembrane domains of GPR56 function antagonistically to regulate VEGF production and angiogenesis via a signaling pathway mediated by PKCα. Tissue transglutaminase was identified as the first extracellular matrix protein that binds to GPR56. It is a crosslinking enzyme in the extracellular matrix but is also expressed in the cytosol. Tissue transglutaminase plays pleiotropic roles in cancer progression. Whether and how it might mediate GPR56-regulated cancer progression awaits further investigation.

  10. Detection of in situ mammary cancer in a transgenic mouse model: in vitro and in vivo MRI studies demonstrate histopathologic correlation

    NASA Astrophysics Data System (ADS)

    Jansen, S. A.; Conzen, S. D.; Fan, X.; Krausz, T.; Zamora, M.; Foxley, S.; River, J.; Newstead, G. M.; Karczmar, G. S.

    2008-10-01

    Improving the prevention and detection of preinvasive ductal carcinoma in situ (DCIS) is expected to lower both morbidity and mortality from breast cancer. Transgenic mouse models can be used as a 'test bed' to develop new imaging methods and to evaluate the efficacy of candidate preventive therapies. We hypothesized that despite its microscopic size, early murine mammary cancer, including DCIS, might be accurately detected by MRI. C3(1) SV40 TAg female mice (n = 23) between 10 and 18 weeks of age were selected for study. Eleven mice were subjected to in vitro imaging using a T2-weighted spin echo sequence and 12 mice were selected for in vivo imaging using a T1-weighted gradient echo, a T2-weighted spin echo and high spectral and spatial resolution imaging sequences. The imaged glands were carefully dissected, formalin fixed and paraffin embedded, and then H&E stained sections were obtained. The ratio of image-detected versus histologically detected cancers was obtained by reviewing the MR images and H&E sections independently and using histology as the gold standard. MR images were able to detect 12/12 intramammary lymph nodes, 1/1 relatively large (~5 mm) tumor, 17/18 small (~1 mm) tumors and 13/16 ducts distended with DCIS greater than 300 µm. Significantly, there were no false positives—i.e., image detection always corresponded to a histologically detectable cancer in this model. These results indicate that MR imaging can reliably detect both preinvasive in situ and early invasive mammary cancers in mice with high sensitivity. This technology is an important step toward the more effective use of non-invasive imaging in pre-clinical studies of breast cancer prevention, detection and treatment.

  11. Epigenetic reduction of DNA repair in progression to gastrointestinal cancer

    PubMed Central

    Bernstein, Carol; Bernstein, Harris

    2015-01-01

    Deficiencies in DNA repair due to inherited germ-line mutations in DNA repair genes cause increased risk of gastrointestinal (GI) cancer. In sporadic GI cancers, mutations in DNA repair genes are relatively rare. However, epigenetic alterations that reduce expression of DNA repair genes are frequent in sporadic GI cancers. These epigenetic reductions are also found in field defects that give rise to cancers. Reduced DNA repair likely allows excessive DNA damages to accumulate in somatic cells. Then either inaccurate translesion synthesis past the un-repaired DNA damages or error-prone DNA repair can cause mutations. Erroneous DNA repair can also cause epigenetic alterations (i.e., epimutations, transmitted through multiple replication cycles). Some of these mutations and epimutations may cause progression to cancer. Thus, deficient or absent DNA repair is likely an important underlying cause of cancer. Whole genome sequencing of GI cancers show that between thousands to hundreds of thousands of mutations occur in these cancers. Epimutations that reduce DNA repair gene expression and occur early in progression to GI cancers are a likely source of this high genomic instability. Cancer cells deficient in DNA repair are more vulnerable than normal cells to inactivation by DNA damaging agents. Thus, some of the most clinically effective chemotherapeutic agents in cancer treatment are DNA damaging agents, and their effectiveness often depends on deficient DNA repair in cancer cells. Recently, at least 18 DNA repair proteins, each active in one of six DNA repair pathways, were found to be subject to epigenetic reduction of expression in GI cancers. Different DNA repair pathways repair different types of DNA damage. Evaluation of which DNA repair pathway(s) are deficient in particular types of GI cancer and/or particular patients may prove useful in guiding choice of therapeutic agents in cancer therapy. PMID:25987950

  12. Epigenetic reduction of DNA repair in progression to gastrointestinal cancer.

    PubMed

    Bernstein, Carol; Bernstein, Harris

    2015-05-15

    Deficiencies in DNA repair due to inherited germ-line mutations in DNA repair genes cause increased risk of gastrointestinal (GI) cancer. In sporadic GI cancers, mutations in DNA repair genes are relatively rare. However, epigenetic alterations that reduce expression of DNA repair genes are frequent in sporadic GI cancers. These epigenetic reductions are also found in field defects that give rise to cancers. Reduced DNA repair likely allows excessive DNA damages to accumulate in somatic cells. Then either inaccurate translesion synthesis past the un-repaired DNA damages or error-prone DNA repair can cause mutations. Erroneous DNA repair can also cause epigenetic alterations (i.e., epimutations, transmitted through multiple replication cycles). Some of these mutations and epimutations may cause progression to cancer. Thus, deficient or absent DNA repair is likely an important underlying cause of cancer. Whole genome sequencing of GI cancers show that between thousands to hundreds of thousands of mutations occur in these cancers. Epimutations that reduce DNA repair gene expression and occur early in progression to GI cancers are a likely source of this high genomic instability. Cancer cells deficient in DNA repair are more vulnerable than normal cells to inactivation by DNA damaging agents. Thus, some of the most clinically effective chemotherapeutic agents in cancer treatment are DNA damaging agents, and their effectiveness often depends on deficient DNA repair in cancer cells. Recently, at least 18 DNA repair proteins, each active in one of six DNA repair pathways, were found to be subject to epigenetic reduction of expression in GI cancers. Different DNA repair pathways repair different types of DNA damage. Evaluation of which DNA repair pathway(s) are deficient in particular types of GI cancer and/or particular patients may prove useful in guiding choice of therapeutic agents in cancer therapy.

  13. Bone morphogenetic protein-4 strongly potentiates growth factor-induced proliferation of mammary epithelial cells

    SciTech Connect

    Montesano, Roberto Sarkoezi, Rita; Schramek, Herbert

    2008-09-12

    Bone morphogenetic proteins (BMPs) are multifunctional cytokines that elicit pleiotropic effects on biological processes such as cell proliferation, cell differentiation and tissue morphogenesis. With respect to cell proliferation, BMPs can exert either mitogenic or anti-mitogenic activities, depending on the target cells and their context. Here, we report that in low-density cultures of immortalized mammary epithelial cells, BMP-4 did not stimulate cell proliferation by itself. However, when added in combination with suboptimal concentrations of fibroblast growth factor (FGF)-2, FGF-7, FGF-10, epidermal growth factor (EGF) or hepatocyte growth factor (HGF), BMP-4 potently enhanced growth factor-induced cell proliferation. These results reveal a hitherto unsuspected interplay between BMP-4 and growth factors in the regulation of mammary epithelial cell proliferation. We suggest that the ability of BMP-4 to potentiate the mitogenic activity of multiple growth factors may contribute to mammary gland ductal morphogenesis as well as to breast cancer progression.

  14. The extracellular matrix: A dynamic niche in cancer progression

    PubMed Central

    Lu, Pengfei; Weaver, Valerie M.

    2012-01-01

    The local microenvironment, or niche, of a cancer cell plays important roles in cancer development. A major component of the niche is the extracellular matrix (ECM), a complex network of macromolecules with distinctive physical, biochemical, and biomechanical properties. Although tightly controlled during embryonic development and organ homeostasis, the ECM is commonly deregulated and becomes disorganized in diseases such as cancer. Abnormal ECM affects cancer progression by directly promoting cellular transformation and metastasis. Importantly, however, ECM anomalies also deregulate behavior of stromal cells, facilitate tumor-associated angiogenesis and inflammation, and thus lead to generation of a tumorigenic microenvironment. Understanding how ECM composition and topography are maintained and how their deregulation influences cancer progression may help develop new therapeutic interventions by targeting the tumor niche. PMID:22351925

  15. DISCOIDIN DOMAIN RECEPTOR TYROSINE KINASES: NEW PLAYERS IN CANCER PROGRESSION

    PubMed Central

    Valiathan, Rajeshwari R.; Marco, Marta; Leitinger, Birgit; Kleer, Celina G.; Fridman, Rafael

    2012-01-01

    Almost all human cancers display dysregulated expression and/or function of one or more receptor tyrosine kinases (RTKs). The strong causative association between altered RTK function and cancer progression has translated into novel therapeutic strategies that target these cell surface receptors in the treatment of cancer. Yet, the full spectrum of RTKs that may alter the oncogenic process is not completely understood. Accumulating evidence suggests that a unique set of RTKs known as the Discoidin Domain Receptors (DDRs) play a role in cancer progression by regulating the interactions of tumor cells with their surrounding collagen matrix. The DDRs are the only RTKs that specifically bind to, and are activated by collagen. Hence, the DDRs are part of the signaling networks that translate information from the extracellular matrix thereby acting as key regulators of cell-matrix interactions. Under physiological conditions, DDRs control cell and tissue homeostasis by acting as collagen sensors, transducing signals that regulate cell polarity, tissue morphogenesis, and cell differentiation. In cancer, DDRs are hijacked by tumor cells to disrupt normal cell-matrix communication and initiate pro-migratory and pro-invasive programs. Importantly, several cancer types exhibit DDR mutations, which are thought to alter receptor function and contribute to cancer progression. Other evidence suggests that the actions of DDRs in cancer are complex, either promoting or suppressing tumor cell behavior in a DDR type/isoform specific and context dependent manner. Thus, there is still a considerable gap in our knowledge of DDR actions in cancer tissues. This review summarizes the current knowledge on DDR expression and function in cancer and discusses the potential implications of DDRs in cancer biology. It is hoped that this effort will encourage more research into these poorly understood but unique RTKs, which have the potential of becoming novel therapeutics targets in cancer. PMID

  16. Estrogen decreases chemokine levels in murine mammary tissue: implications for the regulatory role of MIP-1 alpha and MCP-1/JE in mammary tumor formation.

    PubMed

    Fanti, Peter; Nazareth, Michael; Bucelli, Robert; Mineo, Michael; Gibbs, Kathleen; Kumin, Michael; Grzybek, Kevin; Hoeltke, Janice; Raiber, Lisa; Poppenberg, Kristin; Janis, Kelly; Schwach, Catherine; Aronica, Susan M

    2003-11-01

    Estrogen contributes to the development of breast cancer through mechanisms that are not completely understood. Estrogen influences the function of immune effector cells, primarily through alterations in cytokine expression. Chemokines are proinflammatory cytokines that attract various immune cells to the site of tissue injury or inflammation, and activate many cell types, including T lymphocytes and monocytes. As an initial step toward ultimately determining whether regulation of chemokine expression and/or biological activity by estrogen could potentially be a contributing factor to the development and progression of mammary tumors, we evaluated the effect of estrogen on the expression of specific chemokines in murine mammary tissue. We also evaluated whether exposure of female mice to various chemokines could alter the growth of mammary tumors in the presence of estrogen. We report here that estrogen significantly decreases levels of the chemokines MIP-1alpha and MCP-1/JE in murine mammary tissue. Co-treatment with 4-hydroxytamoxifen partially reverses the suppressive effect of estrogen on MIP-1alpha levels. Estrogen increases the growth of CCL- 51 cell-based tumors in the mammary glands of female mice. Co-treatment with the chemokine MIP-1alpha or MCP- 1/JE substantially decreases the ability of estrogen to stimulate the formation of CCL-51 cell-based tumors. Our results show that estrogen might influence the bioactivity of specific chemokines through alteration of chemokine expression in mammary tissue, and further suggest that decreases in murine chemokines evoked by estrogen exposure could contribute to the promotion of mammary tumor growth.

  17. Metabotropic glutamate receptor 1 disrupts mammary acinar architecture and initiates malignant transformation of mammary epithelial cells

    PubMed Central

    Teh, Jessica L. F.; Shah, Raj; La Cava, Stephanie; Dolfi, Sonia C.; Mehta, Madhura S.; Kongara, Sameera; Price, Sandy; Ganesan, Shridar; Reuhl, Kenneth R.; Hirshfield, Kim M.

    2016-01-01

    Metabotropic glutamate receptor 1 (mGluR1/Grm1) is a member of the G-protein-coupled receptor superfamily, which was once thought to only participate in synaptic transmission and neuronal excitability, but has more recently been implicated in non-neuronal tissue functions. We previously described the oncogenic properties of Grm1 in cultured melanocytes in vitro and in spontaneous melanoma development with 100 % penetrance in vivo. Aberrant mGluR1 expression was detected in 60–80 % of human melanoma cell lines and biopsy samples. As most human cancers are of epithelial origin, we utilized immortalized mouse mammary epithelial cells (iMMECs) as a model system to study the transformative properties of Grm1. We introduced Grm1 into iMMECs and isolated several stable mGluR1-expressing clones. Phenotypic alterations in mammary acinar architecture were assessed using three-dimensional morphogenesis assays. We found that mGluR1-expressing iMMECs exhibited delayed lumen formation in association with decreased central acinar cell death, disrupted cell polarity, and a dramatic increase in the activation of the mitogen-activated protein kinase pathway. Orthotopic implantation of mGluR1-expressing iMMEC clones into mammary fat pads of immunodeficient nude mice resulted in mammary tumor formation in vivo. Persistent mGluR1 expression was required for the maintenance of the tumorigenic phenotypes in vitro and in vivo, as demonstrated by an inducible Grm1-silencing RNA system. Furthermore, mGluR1 was found be expressed in human breast cancer cell lines and breast tumor biopsies. Elevated levels of extracellular glutamate were observed in mGluR1-expressing breast cancer cell lines and concurrent treatment of MCF7 xenografts with glutamate release inhibitor, riluzole, and an AKT inhibitor led to suppression of tumor progression. Our results are likely relevant to human breast cancer, highlighting a putative role of mGluR1 in the pathophysiology of breast cancer and the potential

  18. [Epigenetic alterations in cervical cancer progression].

    PubMed

    Ríos-Romero, Magdalena; Soto-Valladares, Ana Guadalupe; Piña-Sánchez, Patricia

    2015-01-01

    Despite the use of the screening test, such as Papanicolaou, and the detection of human papillomavirus (HPV), cervical cancer remains as a public health problem in México and it is the second leading cause of death for malignant neoplasias among women. High-risk HPV infection is the main risk factor for the development of premalignant lesions and cervical cancer; however, HPV infection is not the only factor; there are various genetic and epigenetic alterations required for the development of neoplasias; some of them have been described and even in some cases they have been suggested as biomarkers for prognosis. However, in contrast with other cancer types, such as breast cancer, in cervical cancer the use of biomarkers has not been established for clinical applications. Unlike genetic alterations, epigenetic alterations are potentially reversible; in this sense, their characterization is important, since they have not only a potential use as biomarkers, but they also could represent new therapeutic targets for treatment of cervical cancer. This review describes some of the more common epigenetic alterations in cervical cancer and its potential use in routine clinical practice.

  19. Akt isoform specific effects in ovarian cancer progression

    PubMed Central

    Linnerth-Petrik, Nicolle M.; Santry, Lisa A.; Moorehead, Roger; Jücker, Manfred

    2016-01-01

    Ovarian cancer remains a significant therapeutic problem and novel, effective therapies are needed. Akt is a serine-threonine kinase that is overexpressed in numerous cancers, including ovarian. Mammalian cells express three Akt isoforms which are encoded by distinct genes. Although there are several Akt inhibitors in clinical trials, most indiscriminately target all isoforms. Current in vitro data and animal knockout experiments suggest that the Akt isoforms may have divergent roles. In this paper, we determined the isoform-specific functions of Akt in ovarian cancer cell proliferation in vitro and in ovarian cancer progression in vivo. For in vitro experiments, murine and human ovarian cancer cells were treated with Akt inhibitors and cell viability was assessed. We used two different in vivo approaches to identify the roles of Akt isoforms in ovarian cancer progression and their influence on the primary tumor and tumor microenvironment. In one experiment, wild-type C57Bl6 mice were orthotopically injected with ID8 cells with stable knockdown of Akt isoforms. In a separate experiment, mice null for Akt 1-3 were orthotopically injected with WT ID8 cells (Figure 1). Our data show that inhibition of Akt1 significantly reduced ovarian cancer cell proliferation and inhibited tumor progression in vivo. Conversely, disruption of Akt2 increased tumor growth. Inhibition of Akt3 had an intermediate phenotype, but also increased growth of ovarian cancer cells. These data suggest that there is minimal redundancy between the Akt isoforms in ovarian cancer progression. These findings have important implications in the design of Akt inhibitors for the effective treatment of ovarian cancer. PMID:27533079

  20. A new role of SNAI2 in post-lactational involution of the mammary gland links it to luminal breast cancer development

    PubMed Central

    Castillo-Lluva, Sonia; Hontecillas-Prieto, Lourdes; Blanco-Gómez, Adrián; Sáez-Freire, María del Mar; García-Cenador, Begoña; García-Criado, Javier; Pérez-Andrés, Martín; de Matos, Alberto Orfao; Cañamero, Marta; Mao, Jian-Hua; Gridley, Thomas; Castellanos-Martín, Andrés; Pérez-Losada, Jesús

    2015-01-01

    Breast cancer is a major cause of mortality in women. The transcription factor SNAI2 has been implicated in the pathogenesis of several types of cancer, including breast cancer of basal origin. Here we show that SNAI2 is also important in the development of breast cancer of luminal origin in MMTV-ErbB2 mice. SNAI2 deficiency leads to longer latency and fewer luminal tumors, both of these being characteristics of pre-tumoral origin. These effects were associated with reduced proliferation and a decreased ability to generate mammospheres in normal mammary glands. However, the capacity to metastasize was not modified. Under conditions of increased ERBB2 oncogenic activity after pregnancy plus SNAI2 deficiency, both pretumoral defects-latency and tumor load- were compensated. However, the incidence of lung metastases was dramatically reduced. Furthermore, SNAI2 was required for proper post-lactational involution of the breast. At three days post-lactational involution, the mammary glands of Snai2-deficient mice exhibited lower levels of pSTAT3 and higher levels pAKT1, resulting in decreased apoptosis. The presence of abundant non-involuted ducts was still present at 30 days post-lactation, with a greater number of residual ERBB2+ cells. These results suggest that this defect in involution leads to an increase in the number of susceptible target cells for transformation, to the recovery of the capacity to generate mammospheres, and to an increase in the number of tumors. Our work demonstrates the participation of SNAI2 in the pathogenesis of luminal breast cancer, and reveals an unexpected connection between the processes of post-lactational involution and breast tumorigenesis in Snai2-null mutant mice. PMID:26096931

  1. Use of the immune adherence hemagglutination test for titration of breast cancer patients' sea cross-reacting with purified mouse mammary tumor virus.

    PubMed

    Nagayoshi, S; Imai, M; Tsutsui, Y; Saga, S; Takahashi, M; Hoshino, M

    1981-02-01

    Ninety-two sera from patients with breast cancer, 42 sera from patients with neoplastic diseases other than breast cancer and 59 sera from apparently healthy women were examined by means of the immune adherence hemagglutination (IAHA) test using purified mouse mammary tumor virus (MMTV) fron RII mouse milk. It was found that 36.4% (34/96) of the sera from breast cancer patients, 7.1% (3/42) of the sera from patients with other neoplastic diseases and 5.1% (3/59) of the sera from apparently healthy women showed a positive reaction. Among the IAHA positive sera from breast cancer patients, 82.9% (29/35) showed a titer of more than 1:16. On the other hand, none of the positive sera from patients with cancers other than breast cancer showed a titer of more than 1:16. The sera from 4 breast cancer patients, which showed a positive reaction with RII MMTV in the IAHA test, were tested to examine the specificity of the reaction by using milk samples from sources other than RII mice, including C57BL mice, dogs, cattle and humans. None of the 4 sera showed a positive reaction with milk samples from sources other than the RIII mouse.

  2. FACS Sorting Mammary Stem Cells.

    PubMed

    Iriondo, Oihana; Rábano, Miriam; Vivanco, María D M

    2015-01-01

    Fluorescent-activated cell sorting (FACS) represents one of the key techniques that have been used to isolate and characterize stem cells, including cells from the mammary gland. A combination of approaches, including recognition of cell surface antigens and different cellular activities, has facilitated the identification of stem cells from the healthy mammary gland and from breast tumors. In this chapter we describe the protocol to use FACS to separate breast cancer stem cells, but most of the general principles discussed could be applied to sort other types of cells.

  3. Does Lactation Mitigate Triple Negative/Basal Breast Cancer Progression?

    DTIC Science & Technology

    2012-09-01

    cells. Science 1994, 263(5146):526-529. 11. Li JH, Man YG: Dual usages of single Wilms ’ tumor 1 immunohistochemistry in evaluation of breast tumors : a...mammary tumor cells (MCF10ADCIS.com and HCC70 cell lines) directly through the intact mouse teat into the correct anatomical location for ductal...may be preferentially compromised by tumors formed in postpartum involuting mammary glands but maintained by pregnancy. Our murine mammary

  4. Algorithmic methods to infer the evolutionary trajectories in cancer progression

    PubMed Central

    Graudenzi, Alex; Ramazzotti, Daniele; Sanz-Pamplona, Rebeca; De Sano, Luca; Mauri, Giancarlo; Moreno, Victor; Antoniotti, Marco; Mishra, Bud

    2016-01-01

    The genomic evolution inherent to cancer relates directly to a renewed focus on the voluminous next-generation sequencing data and machine learning for the inference of explanatory models of how the (epi)genomic events are choreographed in cancer initiation and development. However, despite the increasing availability of multiple additional -omics data, this quest has been frustrated by various theoretical and technical hurdles, mostly stemming from the dramatic heterogeneity of the disease. In this paper, we build on our recent work on the “selective advantage” relation among driver mutations in cancer progression and investigate its applicability to the modeling problem at the population level. Here, we introduce PiCnIc (Pipeline for Cancer Inference), a versatile, modular, and customizable pipeline to extract ensemble-level progression models from cross-sectional sequenced cancer genomes. The pipeline has many translational implications because it combines state-of-the-art techniques for sample stratification, driver selection, identification of fitness-equivalent exclusive alterations, and progression model inference. We demonstrate PiCnIc’s ability to reproduce much of the current knowledge on colorectal cancer progression as well as to suggest novel experimentally verifiable hypotheses. PMID:27357673

  5. Integrated Proteomic and Metabolic Analysis of Breast Cancer Progression

    PubMed Central

    Shaw, Patrick G.; Chaerkady, Raghothama; Wang, Tao; Vasilatos, Shauna; Huang, Yi; Van Houten, Bennett; Pandey, Akhilesh; Davidson, Nancy E.

    2013-01-01

    One of the most persistent hallmarks of cancer biology is the preference of tumor cells to derive energy through glycolysis as opposed to the more efficient process of oxidative phosphorylation (OXPHOS). However, little is known about the molecular cascades by which oncogenic pathways bring about this metabolic switch. We carried out a quantitative proteomic and metabolic analysis of the MCF10A derived cell line model of breast cancer progression that includes parental cells and derivatives representing three different tumor grades of Ras-driven cancer with a common genetic background. A SILAC (Stable Isotope Labeling by Amino acids in Cell culture) labeling strategy was used to quantify protein expression in conjunction with subcellular fractionation to measure dynamic subcellular localization in the nucleus, cytosol and mitochondria. Protein expression and localization across cell lines were compared to cellular metabolic rates as a measure of oxidative phosphorylation (OXPHOS), glycolysis and cellular ATP. Investigation of the metabolic capacity of the four cell lines revealed that cellular OXPHOS decreased with breast cancer progression independently of mitochondrial copy number or electron transport chain protein expression. Furthermore, glycolytic lactate secretion did not increase in accordance with cancer progression and decreasing OXPHOS capacity. However, the relative expression and subcellular enrichment of enzymes critical to lactate and pyruvate metabolism supported the observed extracellular acidification profiles. This analysis of metabolic dysfunction in cancer progression integrated with global protein expression and subcellular localization is a novel and useful technique for determining organelle-specific roles of proteins in disease. PMID:24086712

  6. Effect of Age at Exposure on the Incidence of Lung and Mammary Cancer after Thoracic X-Ray Irradiation in Wistar Rats.

    PubMed

    Yamada, Yutaka; Iwata, Ken-Ichi; Blyth, Benjamin J; Doi, Kazutaka; Morioka, Takamitsu; Daino, Kazuhiro; Nishimura, Mayumi; Kakinuma, Shizuko; Shimada, Yoshiya

    2017-02-01

    Epidemiology studies have shown that children are at greater overall risk of radiation-induced cancer, but the modifying effect of age at exposure in different tissues is heterogeneous. Early epidemiology findings of increased lung cancer risk with increasing age at the time of exposure have been dismissed, with suggestions that the trend is an artefact from a failure to adequately correct for the effects of tobacco smoking. Yet, differing models used in subsequent analyses have shown that the increased susceptibility with age, counter to the overall solid tumor trend, can either be confirmed or discounted depending on the model parameters used. In this study, we analyzed the induction of tumors in female Wistar rats exposed to increasing thoracic doses of X-ray as neonates, juveniles or young adults, to allow the effect of age at exposure in this early period to be observed in the absence of any interactions with smoking. Histology was used to compare tumor subtypes among groups, and genomic DNA copy number alterations in a number of tumors arising after irradiation at different ages were examined. Induction of lung cancers increased with radiation dose, with the frequency of early occurring lung adenomas greater in rats irradiated at older ages. At the highest dose, the rats irradiated at 5 or 15 weeks of age showed increased age-specific rates of lung adenocarcinomas in later life compared to those irradiated at 1 week of age. However, thoracic mammary gland tumors induced by the highest dose at the later ages significantly decreased the lifespan in these groups, reducing the number of rats at risk of radiation-induced lung adenocarcinoma. There was no induction of mammary tumors outside of the irradiated field. Lung adenocarcinomas showed widespread DNA copy number aberrations at the chromosome level, but the only recurrent lesions were intragenic Fhit deletions and losses on chromosome 4. The results presented here suggest that the risk of radiation

  7. Automatic segmentation of histological structures in mammary gland tissue sections

    SciTech Connect

    Fernandez-Gonzalez, Rodrigo; Deschamps, Thomas; Idica, Adam K.; Malladi, Ravikanth; Ortiz de Solorzano, Carlos

    2004-02-17

    Real-time three-dimensional (3D) reconstruction of epithelial structures in human mammary gland tissue blocks mapped with selected markers would be an extremely helpful tool for breast cancer diagnosis and treatment planning. Besides its clear clinical application, this tool could also shed a great deal of light on the molecular basis of breast cancer initiation and progression. In this paper we present a framework for real-time segmentation of epithelial structures in two-dimensional (2D) images of sections of normal and neoplastic mammary gland tissue blocks. Complete 3D rendering of the tissue can then be done by surface rendering of the structures detected in consecutive sections of the blocks. Paraffin embedded or frozen tissue blocks are first sliced, and sections are stained with Hematoxylin and Eosin. The sections are then imaged using conventional bright field microscopy and their background is corrected using a phantom image. We then use the Fast-Marching algorithm to roughly extract the contours of the different morphological structures in the images. The result is then refined with the Level-Set method which converges to an accurate (sub-pixel) solution for the segmentation problem. Finally, our system stacks together the 2D results obtained in order to reconstruct a 3D representation of the entire tissue block under study. Our method is illustrated with results from the segmentation of human and mouse mammary gland tissue samples.

  8. Abnormal Mammary Adipose Tissue Environment of Brca1 Mutant Mice Show a Persistent Deposition of Highly Vascularized Multilocular Adipocytes.

    PubMed

    Jones, Laundette P; Buelto, Destiney; Tago, Elaine; Owusu-Boaitey, Kwadwo E

    2011-12-08

    A major challenge to breast cancer research is the identification of alterations in the architecture and composition of the breast that are associated with breast cancer progression. The aim of the present investigation was to characterize the mammary adipose phenotype from Brca1 mutant mice in the expectation that this would shed light on the role of the mammary tissue environment in the early stages of breast tumorigenesis. We observed that histological sections of mammary tissue from adult Brca1 mutant mice abnormally display small, multilocular adipocytes that are reminiscent of brown adipose tissue (BAT) as compared to wildtype mice. Using a marker for BAT, the uncoupling protein 1 (UCP1), we demonstrated that these multilocular adipose regions in Brca1 mutant mice stain positive for UCP1. Transcriptionally, UCP1 mRNA levels in the Brca1 mutant mice were elevated greater than 50-fold compared to age-matched mammary glands from wildtype mice. Indeed, BAT has characteristics that are favorable for tumor growth, including high vascularity. Therefore, we also demonstrated that the multilocular brown adipose phenotype in the mammary fat pad of Brca1 mutant mice displayed regions of increased vascularity as evidenced by a significant increase in the protein expression of CD31, a marker for angiogenesis. This Brca1 mutant mouse model should provide a physiologically relevant context to determine whether brown adipose tissue can play a role in breast cancer development.

  9. PEG-3, a nontransforming cancer progression gene, is a positive regulator of cancer aggressiveness and angiogenesis.

    PubMed

    Su, Z Z; Goldstein, N I; Jiang, H; Wang, M N; Duigou, G J; Young, C S; Fisher, P B

    1999-12-21

    Cancer is a progressive disease culminating in acquisition of metastatic potential by a subset of evolving tumor cells. Generation of an adequate blood supply in tumors by production of new blood vessels, angiogenesis, is a defining element in this process. Although extensively investigated, the precise molecular events underlying tumor development, cancer progression, and angiogenesis remain unclear. Subtraction hybridization identified a genetic element, progression elevated gene-3 (PEG-3), whose expression directly correlates with cancer progression and acquisition of oncogenic potential by transformed rodent cells. We presently demonstrate that forced expression of PEG-3 in tumorigenic rodent cells, and in human cancer cells, increases their oncogenic potential in nude mice as reflected by a shorter tumor latency time and the production of larger tumors with increased vascularization. Moreover, inhibiting endogenous PEG-3 expression in progressed rodent cancer cells by stable expression of an antisense expression vector extinguishes the progressed cancer phenotype. Cancer aggressiveness of PEG-3 expressing rodent cells correlates directly with increased RNA transcription, elevated mRNA levels, and augmented secretion of vascular endothelial growth factor (VEGF). Furthermore, transient ectopic expression of PEG-3 transcriptionally activates VEGF in transformed rodent and human cancer cells. Taken together these data demonstrate that PEG-3 is a positive regulator of cancer aggressiveness, a process regulated by augmented VEGF production. These studies also support an association between expression of a single nontransforming cancer progression-inducing gene, PEG-3, and the processes of cancer aggressiveness and angiogenesis. In these contexts, PEG-3 may represent an important target molecule for developing cancer therapeutics and inhibitors of angiogenesis.

  10. Cancer stem cells as the engine of unstable tumor progression.

    PubMed

    Solé, Ricard V; Rodríguez-Caso, Carlos; Deisboeck, Thomas S; Saldaña, Joan

    2008-08-21

    Genomic instability is considered by many authors the key engine of tumorigenesis. However, mounting evidence indicates that a small population of drug resistant cancer cells can also be a key component of tumor progression. Such cancer stem cells would define a compartment effectively acting as the source of most tumor cells. Here we study the interplay between these two conflicting components of cancer dynamics using two types of tissue architecture. Both mean field and multicompartment models are studied. It is shown that tissue architecture affects the pattern of cancer dynamics and that unstable cancers spontaneously organize into a heterogeneous population of highly unstable cells. This dominant population is in fact separated from the low-mutation compartment by an instability gap, where almost no cancer cells are observed. The possible implications of this prediction are discussed.

  11. The role of gelatinases in colorectal cancer progression and metastasis.

    PubMed

    Mook, Olaf R F; Frederiks, Wilma M; Van Noorden, Cornelis J F

    2004-12-17

    Various proteases are involved in cancer progression and metastasis. In particular, gelatinases, matrix metalloproteinase-2 (MMP-2) and MMP-9, have been implicated to play a role in colon cancer progression and metastasis in animal models and patients. In the present review, the clinical relevance and the prognostic value of messenger ribonucleic acid (mRNA) and protein expression and proenzyme activation of MMP-2 and MMP-9 are evaluated in relation to colorectal cancer. Expression of tissue inhibitors of MMPs (TIMPs) in relation with MMP expression in cancer tissues and the relevance of detection of plasma or serum levels of MMP-2 and/or MMP-9 and TIMPs for prognosis are also discussed. Furthermore, involvement of MMP-2 and MMP-9 in experimental models of colorectal cancer is reviewed. In vitro studies have suggested that gelatinase is expressed in cancer cells but animal models indicated that gelatinase expression in non-cancer cells in tumors contributes to cancer progression. In fact, interactions between cancer cells and host tissues have been shown to modulate gelatinase expression in host cells. Inhibition of gelatinases by synthetic MMP inhibitors has been considered to be an attractive approach to block cancer progression. However, despite promising results in animal models, clinical trials with MMP inhibitors have been disappointing so far. To obtain more insight in the (patho)physiological functions of gelatinases, regulation of MMP-2 and MMP-9 expression is discussed. Mitogen activated protein kinase (MAPK) signalling has been shown to be involved in regulation of gelatinase expression in both cancer cells and non-cancer cells. Expression can be triggered by a variety of stimuli including growth factors, cytokines and extracellular matrix (ECM) components. On the other hand, MMP-2 and MMP-9 activity regulates bioavailability and activity of growth factors and cytokines, affects the immune response and is involved in angiogenesis. Because of the

  12. Multiscale Models of Breast Cancer Progression

    PubMed Central

    Chakrabarti, Anirikh; Verbridge, Scott; Stroock, Abraham D.; Fischbach, Claudia; Varner, Jeffrey D.

    2013-01-01

    Breast cancer initiation, invasion and metastasis span multiple length and time scales. Molecular events at short length scales lead to an initial tumorigenic population, which left unchecked by immune action, acts at increasingly longer length scales until eventually the cancer cells escape from the primary tumor site. This series of events is highly complex, involving multiple cell types interacting with (and shaping) the microenvironment. Multiscale mathematical models have emerged as a powerful tool to quantitatively integrate the convective-diffusion-reaction processes occurring on the systemic scale, with the molecular signaling processes occurring on the cellular and subcellular scales. In this study, we reviewed the current state of the art in cancer modeling across multiple length scales, with an emphasis on the integration of intracellular signal transduction models with pro-tumorigenic chemical and mechanical microenvironmental cues. First, we reviewed the underlying biomolecular origin of breast cancer, with a special emphasis on angiogenesis. Then, we summarized the development of tissue engineering platforms which could provide highfidelity ex vivo experimental models to identify and validate multiscale simulations. Lastly, we reviewed top-down and bottom-up multiscale strategies that integrate subcellular networks with the microenvironment. We present models of a variety of cancers, in addition to breast cancer specific models. Taken together, we expect as the sophistication of the simulations increase, that multiscale modeling and bottom-up agent-based models in particular will become an increasingly important platform technology for basic scientific discovery, as well as the identification and validation of potentially novel therapeutic targets. PMID:23008097

  13. A role of ghrelin in canine mammary carcinoma cells proliferation, apoptosis and migration

    PubMed Central

    2012-01-01

    Background Ghrelin is a natural ligand of the growth hormone secretagogue receptor (GHS-R). They are often co-expressed in multiple human tumors and related cancer cell lines what can indicate that the ghrelin/GHS-R axis may have an important role in tumor growth and progression. However, a role of ghrelin in canine tumors remains unknown. Thus, the aim of our study was two-fold: (1) to assess expression of ghrelin and its receptor in canine mammary cancer and (2) to examine the effect of ghrelin on carcinoma cells proliferation, apoptosis, migration and invasion. The expression of ghrelin and its receptor in canine mammary cancer tissues and cell lines (isolated from primary tumors and their metastases) was examined using Real-time qPCR and immunohistochemistry. For apoptosis analysis the Annexin V and propidium iodide dual staining was applied whereas cell proliferation was evaluated by MTT assay and BrdU incorporation test. The influence of ghrelin on cancer cells migration and invasion was assessed using Boyden chamber assays and wound healing assay. Results The highest expression of ghrelin was observed in metastatic cancers whereas the lowest expression of ghrelin receptor was detected in tumors of the 3rd grade of malignancy. Higher expression of ghrelin and its receptor was detected in cancer cell lines isolated from metastases than in cell lines isolated from primary tumors. In vitro experiments demonstrated that exposure to low doses of ghrelin stimulates cellular proliferation, inhibits apoptosis and promotes motility and invasion of canine mammary cancer cells. Growth hormone secretagogue receptor inhibitor ([D-Lys3]-GHRP6) as well as RNA interference enhances early apoptosis. Conclusion The presence of ghrelin and GHS-R in all of the examined canine mammary tumors may indicate their biological role in cancer growth and development. Our experiments conducted in vitro confirmed that ghrelin promotes cancer development and metastasis. PMID:22999388

  14. Evaluation Frequency of Merkel Cell Polyoma, Epstein-Barr and Mouse Mammary Tumor Viruses in Patients with Breast Cancer in Kerman, Southeast of Iran.

    PubMed

    Reza, Malekpour Afshar; Reza, Mollaie Hamid; Mahdiyeh, Lashkarizadeh; Mehdi, Fazlalipour; Hamid, Zeinali Nejad

    2015-01-01

    Breast cancer is the most common cancer among women worldwide. Roles of the Epstein-Barr, Merkel cell polyoma and mouse mammary tumor viruses in breast carcinogenesis are still controversial although any relationship would clearly be important for breast cancer etiology, early detection and prevention. In the present study associations between EBV, MMTV and Merkel cell polyoma virus and breast cancer in 100 Iranian patients were evaluated using paraffin-embedded tissues. EBER RNA and expression of p53 and large T antigen were evaluated by real time PCR and CD34, p63, HER2, PR and ER markers were studied by immunohistochemistry. EBV was detected in 8/100 (8%), MMTV in 12/100 (12%), MPy in 3/100 (3%) and EBER RNA in 18/100 (18%) cases. None of the control samples demonstrated any of the viruses. p53 was suppressed in EBV, MPy and MMTV positive samples. The large T antigen rate was raised in MPy positive samples. Our results showed that EBV, MMTV and the Merkel cell polyoma virus are foundwith some proportion of breast cancers in our patients, suggesting that these viruses might have a significant role in breast cancer in Kerman, southeast of Iran.

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

    PubMed

    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.

  16. Sclerotium rolfsii lectin induces stronger inhibition of proliferation in human breast cancer cells than normal human mammary epithelial cells by induction of cell apoptosis.

    PubMed

    Savanur, Mohammed Azharuddin; Eligar, Sachin M; Pujari, Radha; Chen, Chen; Mahajan, Pravin; Borges, Anita; Shastry, Padma; Ingle, Arvind; Kalraiya, Rajiv D; Swamy, Bale M; Rhodes, Jonathan M; Yu, Lu-Gang; Inamdar, Shashikala R

    2014-01-01

    Sclerotium rolfsii lectin (SRL) isolated from the phytopathogenic fungus Sclerotium rolfsii has exquisite binding specificity towards O-linked, Thomsen-Freidenreich (Galβ1-3GalNAcα1-Ser/Thr, TF) associated glycans. This study investigated the influence of SRL on proliferation of human breast cancer cells (MCF-7 and ZR-75), non-tumorigenic breast epithelial cells (MCF-10A) and normal mammary epithelial cells (HMECs). SRL caused marked, dose-dependent, inhibition of proliferation of MCF-7 and ZR-75 cells but only weak inhibition of proliferation of non-tumorigenic MCF-10A and HMEC cells. The inhibitory effect of SRL on cancer cell proliferation was shown to be a consequence of SRL cell surface binding and subsequent induction of cellular apoptosis, an effect that was largely prevented by the presence of inhibitors against caspases -3, -8, or -9. Lectin histochemistry using biotin-labelled SRL showed little binding of SRL to normal human breast tissue but intense binding to cancerous tissues. In conclusion, SRL inhibits the growth of human breast cancer cells via induction of cell apoptosis but has substantially less effect on normal epithelial cells. As a lectin that binds specifically to a cancer-associated glycan, has potential to be developed as an anti-cancer agent.

  17. Marginal activity of progesterone receptor B (PR-B) in dogs but high incidence of mammary cancer.

    PubMed

    Gracanin, Ana; Voorwald, Fabiana A; van Wolferen, Monique; Timmermans-Sprang, Elpetra; Mol, Jan A

    2014-10-01

    Progesterone plays an important role in the normal development and carcinogenesis of the mammary gland. In vitro studies have shown that the canine progesterone receptor B (cPR-B), which is essential for mammary development in the mouse, does not transactivate reporter constructs containing progesterone response elements. Therefore, the question was raised whether the cPR-B was completely devoid of transactivation potential of endogenous progesterone regulated genes. Canine mammary cell lines expressing doxycycline-inducible cPR-B, human PR-B or a chimera in which the canine B-upstream segment (BUS) was replaced by a human BUS were treated for 24h with doxycycline, progesterone or a combination of the two. The expression profiling was subsequently performed using a dog-specific microarray and miRNA primers. Incubation of stably transfected cell lines with doxycycline or progesterone alone, did not change expression of any endogenous gene. Expression of activated human PR-B or the chimera of human BUS with the canine PR resulted in differential expression of >500 genes whereas the activated cPR-B regulated only a subset of 40 genes and to a limited extent. The relevance of the marginal transactivation potential or the consequence of a lack of cPR-B function for the carcinogenesis of mammary gland tumors is discussed.

  18. Neutrophil extracellular traps in cancer progression.

    PubMed

    Cools-Lartigue, Jonathan; Spicer, Jonathan; Najmeh, Sara; Ferri, Lorenzo

    2014-11-01

    Neutrophils are being increasingly recognized as an important element in tumor progression. They have been shown to exert important effects at nearly every stage of tumor progression with a number of studies demonstrating that their presence is critical to tumor development. Novel aspects of neutrophil biology have recently been elucidated and its contribution to tumorigenesis is only beginning to be appreciated. Neutrophil extracellular traps (NETs) are neutrophil-derived structures composed of DNA decorated with antimicrobial peptides. They have been shown to trap and kill microorganisms, playing a critical role in host defense. However, their contribution to tumor development and metastasis has recently been demonstrated in a number of studies highlighting NETs as a potentially important therapeutic target. Here, studies implicating NETs as facilitators of tumor progression and metastasis are reviewed. In addition, potential mechanisms by which NETs may exert these effects are explored. Finally, the ability to target NETs therapeutically in human neoplastic disease is highlighted.

  19. Transcriptional network of androgen receptor in prostate cancer progression.

    PubMed

    Takayama, Ken-ichi; Inoue, Satoshi

    2013-08-01

    The androgen receptor belongs to the nuclear receptor superfamily and functions as a ligand-dependent transcription factor. It binds to the androgen responsive element and recruits coregulatory factors to modulate gene transcription. In addition, the androgen receptor interacts with other transcription factors, such as forkhead box A1, and other oncogenic signaling pathway molecules that bind deoxyribonucleic acid and regulate transcription. Androgen receptor signaling plays an important role in the development of prostate cancer. Prostate cancer cells proliferate in an androgen-dependent manner, and androgen receptor blockade is effective in prostate cancer therapy. However, patients often progress to castration-resistant prostate cancer with elevated androgen receptor expression and hypersensitivity to androgen. Recently, comprehensive analysis tools, such as complementary DNA microarray, chromatin immunoprecipitation-on-chip and chromatin immunoprecipitation-sequence, have described the androgen-mediated diverse transcriptional program and gene networks in prostate cancer. Furthermore, functional and clinical studies have shown that some of the androgen receptor-regulated genes could be prognostic markers and potential therapeutic targets for the treatment of prostate cancer, particularly castration-resistant prostate cancer. Thus, identifying androgen receptor downstream signaling events and investigating the regulation of androgen receptor activity is critical for understanding the mechanism of carcinogenesis and progression to castration-resistant prostate cancer.

  20. SUMOylation-mediated regulation of cell cycle progression and cancer

    PubMed Central

    Eifler, Karolin; Vertegaal, Alfred C.O.

    2016-01-01

    SUMOylation plays critical roles during cell cycle progression. Many important cell cycle regulators, including many oncogenes and tumor suppressors, are functionally regulated via SUMOylation. The dynamic SUMOylation pattern observed throughout the cell cycle is ensured via distinct spatial and temporal regulation of the SUMO machinery. Additionally, SUMOylation cooperates with other post-translational modifications to mediate cell cycle progression. Deregulation of these SUMOylation and deSUMOylation enzymes causes severe defects in cell proliferation and genome stability. Different types of cancers were recently shown to be dependent on a functioning SUMOylation system, a finding that could potentially be exploited in anti-cancer therapies. PMID:26601932