In the previous grant period we have delineated the ontogeny of responsiveness of the normal mouse mammary gland to growth regulation by estrogen (E) and progesterone (P) in relation to the ontogeny of estrogen (ER) and progesterone receptor (PR) cellular distribution. We discovered that there is a sequential acquisition of responsiveness, such that E-inducible proliferation is observed first at 3 weeks of age, whereas E-inducible PR and P-inducible proliferation are detected later, at 7 weeks. However, ER are detected as early as 3 days of age in both epithelial and stromal cells and the lack of a proliferative response at this age indicates that non-steroidal growth factors are likely to be biologically relevant mitogens and regulators of mammary gland growth and function in vivo. In this regard, we find that epidermal growth factor (EGF) can mediate the proliferative effective of E at early ages in vivo. In addition, in vitro in organ culture, treatment with EGF+E causes the precocious acquisition of E-inducible PR. Furthermore, our studies demonstrate that adult mammary stroma also can cause the precocious acquisition of E-inducible PR in immature 3 week old epithelium. Thus the insights obtained by us in the previous grant period put us in a strong position to now determine the molecular mechanisms mediating epithelial-stromal cell interactions and the acquisition of hormonal responsiveness in the normal mouse gland. We hypothesize that 1) changes in specific growth factor (EGF, TGF-alpha, bFGF, IGF-I, II) or growth inhibitor (TGF-beta) levels in epithelial and/or stromal cells and/or 2) changes in specific extracellular matrix (ECM) components (collagen I, IV, laminin, fibronectin, tenascin) are correlated with the acquisition of responsiveness to E and P in vivo. Each of these growth factors/inhibitors and ECM components have been implicated to affect mammary gland growth and function. Our goal will be to then test the biological relevance of these changes using in vivo and in vitro approaches. Detailed analysis of the molecular mechanisms underlying the epithelial-stromal cell interactions which result in the transition from a hormonally non-responsive to a responsive state may lead to new therapeutic strategies for the treatment of breast cancer.
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