A woman's reproductive history is one of the principal determinants of her susceptibility to breast cancer. An early full-term pregnancy is protective and the length of time between menarche and the first full term- pregnancy appears to be critical for the initiation of breast cancer. This proposal is based upon the hypothesis that the protective effects of an early pregnancy and lactation result from estrogen and progesterone-induced differentiation and the resultant loss of cells susceptible to carcinogenesis. Furthermore, these effects of estrogens and progestins rave mediated by the induction of specific """"""""local mediators"""""""", i.e. growth factors that act via autocrine and paracrine mechanisms to influence end bud growth and differentiation. Comparative studies of human and rat mammary tumorigenesis suggest that the terminal end bud (TEB) in the rat is probably equivalent to the intralobular terminal duct (TD) in the human, and that these rapidly proliferating cells are the most susceptible to neoplastic transformation. Unfortunately, we do not have any molecular markers to identify and follow the fate of these susceptible cells. This information is required to understand the etiology of breast cancer, to develop effective diagnostic tools and to design preventive therapies. The following specific aims are proposed in our application: 1. To develop molecular markers for the cells of the TEB and TD, and to follow their fate during mammary development and carcinogenesis. 2. To identify the """"""""early response genes"""""""" to estrogen and progesterone-treatment in the end buds and surrounding stroma. 3. To characterize the changes in the expression patterns of several growth factor gene family members that are likely candidates for local mediators of estrogen and progesterone action on end bud growth and differentiation. These include members of the Wnt, EGF, FgF, Fgf and TG?beta gene families and IGF-I. 4. To characterize the regulatory sequences for TEB- and TD-specific genes. 5. To evaluate the functional importance of local mediators by perturbing their expression patterns in transgenic rat (germline) and transgenic mammary glands using the TEB- and TD-specific regulatory sequences. These studies will be performed using 50 day old inbred Wistar/Furth rats treated with E and P as a model system. The technique of mRNA differential display will be employed to identify cell type-specific and hormonally- regulated mRNAs. Those mRNAs with the appropriate specific temporal and spatial expression patterns will be sequenced, and used to isolate complete cDNA and genomic clones. The regulatory sequences from """"""""TEB-specific marker"""""""" genes will be characterized to determine their ability to target the expression of a reporter gene to the appropriate mammary cells type, and finally, to study the functional effects of targeted overexpression of steroid-responsive 'local mediators"""""""" and dominant-negative receptor mutants on mammary gland differentiation.
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