Regulation of mammary gland development at puberty and the cyclical changes that occur in the adult mammary gland during pregnancy and lactation are highly dependent upon estrogen (E) and progesterone (P). During normal development the mammary gland undergoes reversible changes from hormone responsive to hormone refractory states. It is the long- term goal of this proposal to determine how these changes in responsiveness to E and P occur. Mammary stroma plays a critical role in mediating and inducing the proliferative effects of E and P in the mammary epithelium in vivo. The hypothesis being tested in this proposal is that the mitogenic effects of E and P are mediated by stroma-derived growth factors and extracellular matrix (ECM) molecules. We have developed a novel primary co-culture system of mammary epithelial cells and mammary stromal cells in serum-free medium in which the epithelial cells exhibit a proliferative response to both e and P. Using this culture system we will: 1) Identify the respective roles of mammary adipocytes and fibroblasts and characterize the nature of their interactions with epithelial cells; 2) Determine the role of growth factors, EGF, IGF-I, HGF, IGF binding proteins and their respective receptors (EGF-R, IGF-R and c-met) in E and P responsiveness in vitro and in vivo; 3) Define the role of stroma-derived ECM proteins (collagen IV, fibronectin and laminin) and their integrins in mediating E and P responsiveness; 4) Determine if estrogen responsiveness is determined by receptor (ER) isoform (alpha or beta) expression in epithelial and stromal cells. In order to understand E action in the stroma vs. epithelium, the temporal and cellular distribution of ER isoforms will be analyzed in relation to E responsiveness, both in vivo and in vitro. Determining the mechanisms that mediate epithelial-stromal cell interactions in normal mammary gland development and epithelial cell proliferation may provide a conceptual basis for novel approaches that focus on mammary stromal as a potential target for human breast cancer prevention and treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Mohla, Suresh
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Michigan State University
Schools of Medicine
East Lansing
United States
Zip Code
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
Zhang, Hong-Zheng; Bennett, Jessica M; Smith, Kyle T et al. (2002) Estrogen mediates mammary epithelial cell proliferation in serum-free culture indirectly via mammary stroma-derived hepatocyte growth factor. Endocrinology 143:3427-34
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
Woodward, T L; Xie, J; Fendrick, J L et al. (2000) Proliferation of mouse mammary epithelial cells in vitro: interactions among epidermal growth factor, insulin-like growth factor I, ovarian hormones, and extracellular matrix proteins. Endocrinology 141:3578-86
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

Showing the most recent 10 out of 22 publications