Hormones and reproductive factors are associated with human breast cancer pathogenesis, but there is a paucity of information regarding the basic biology of normal human breast development. Our proposal is directly aimed at gaining insight into the endocrine control of normal human breast cell proliferation and estrogen/progesterone/epidermal growth factor receptor status. Perhaps the only definitive way to study normal human breast cells consists of sampling the patients breast in response to various hormonal manipulation and following the clinical course. Such a longitudinal study, of course, cannot be done, and the analyses of the endocrine stimulated breast epithelia in vivo in a patient can never be followed. The availability of a model system which could propagate and maintain normal human breast cells similar to those seen in vivo would greatly enhance our understanding of the endocrine control of human breast cell proliferation. In essence, in our model system, the breast cells from a single patient can be propagated into multiple reconstituted human breasts in an experimentally manipulatable animal system. This model system thus provides an unique opportunity to study normal human breast cell proliferation, as well as the influence of various hormonal environment. Specifically, we propose to provide answers to three questions: (1) whether an estrogen alone, or estrogen plus progesterone combined is more growth promoting in vivo, (2) whether an environment similar to human pregnancy can be mimicked, (3) which, among the many growth factors, most stimulatory in vivo for proliferation of normal human breast epithelial cells. We will then attempt to duplicate the in vivo findings in the primary cell culture system in which the cells are embedded inside the collagen gels and can be stimulated to proliferate into 3-dimensional outgrowth with in vivo- like features. Collectively, these results using a physiologically relevant in vivo and in vitro model systems will not only provide a better understanding of normal human breast cell proliferation but may have far-reaching implications in both the prevention and intervention of human breast cancer.
