Progestins (P) are major mitogens in the adult human breast and contribute significantly to breast cancer risk. Since P are widely used in oral contraceptives and in postmenopausal hormone replacement therapy it is critically important that their mechanims of action be understood. It is the goal of the proposed research to delineate the mechanisms of P-dependent proliferation in the normal mammary gland. In the current grant period, using the mouse mammary gland model, we have developed a minimally-supplemented, serum-free collagen gel primary culture system in which mammary epithelial organoids, made up from both luminal epithelial and myoepithelial cells, proliferate and undergo alveolar morphogenesis in response to P. In addition to P, these responses require mammary stroma derived-hepatocyte growth factor (HGF). Treatment with HGF alone induces proliferation and tubulo-ductal morphogenesis, whereas P alone does not induce proliferation but induces lumen formation that is associated with increased apoptosis. HGF+P increase proliferation above HGF alone and cause a change from ductal to alveolar morphology. This is a novel in vitro demonstration of a mitogenic and morphological response to P that recapitulates the proliferative and alveologenesis response to P in vivo. In addition a pro-apoptotic response to P in normal mammary cells has been identified. In this proposal we will determine whether and how P acts in the cytoplasm, possibly through an SH3 binding domain on the progesterone receptor (PR), to affect HGF/Met-activated pathways associated with mammary-specific tublogenesis (FAK, SHIP-1, PI3-K) and proliferation (ERK, Src/Myc) to inhibit tubulogenesis, promote proliferation and cause alveologenesis. We will also determine the effect of PR action in the nucleus, via its transcriptional activation function, on the expression of P-responsive target genes relevant to alveologenesis (Wnt-4) and proliferation (Met, cyclin D1, Myc). In addition will also identify the specific cells types (luminal epithelial, myoepithelial cells) in which these effects of P occur. Using cultures derived from PRA null or PRB null mice we will also determine the role of the two PR isoforms (A and B) in proliferation and alveologenesis. The long-term goal of this proposal is the delineation of the mechanisms of P-dependent growth regulation in the adult normal mammary gland that may lead to novel strategies for the prevention and treatment of breast cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Metabolic Pathology Study Section (MEP)
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Jhappan, Chamelli
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Michigan State University
Schools of Medicine
East Lansing
United States
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Meyer, Gabriele; Leipprandt, Jeffrey; Xie, Jianwei et al. (2012) A potential role of progestin-induced laminin-5/?6-integrin signaling in the formation of side branches in the mammary gland. Endocrinology 153:4990-5001
Haslam, Sandra Z; Drolet, Alexis; Smith, Kyle et al. (2008) Progestin-regulated luminal cell and myoepithelial cell-specific responses in mammary organoid culture. Endocrinology 149:2098-107
Haslam, Sandra Z; Woodward, Terry L (2003) Host microenvironment in breast cancer development: epithelial-cell-stromal-cell interactions and steroid hormone action in normal and cancerous mammary gland. Breast Cancer Res 5:208-15
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Sunil, N; Bennett, Jessica M; Haslam, Sandra Z (2002) Hepatocyte growth factor is required for progestin-induced epithelial cell proliferation and alveolar-like morphogenesis in serum-free culture of normal mammary epithelial cells. Endocrinology 143:2953-60
Haslam, S Z; Woodward, T L (2001) Reciprocal regulation of extracellular matrix proteins and ovarian steroid activity in the mammary gland. Breast Cancer Res 3:365-72
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Woodward, T L; Lu, H; Haslam, S Z (2000) Laminin inhibits estrogen action in human breast cancer cells. Endocrinology 141:2814-21
Heppner, G H; Wolman, S R; Rosen, J et al. (1999) Research potential of a unique xenograft model of human proliferative breast disease. Breast Cancer Res Treat 58:183-6
Woodward, T L; Xie, J W; Haslam, S Z (1998) The role of mammary stroma in modulating the proliferative response to ovarian hormones in the normal mammary gland. J Mammary Gland Biol Neoplasia 3:117-31

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