The growth and differentiation of prostatic epithelial cells is initiated and mediated through androgen regulation of prostatic stromal cells. Upon stimulation by androgen, signals from stromal cells direct ductal morphogenesis and cytodifferentiation of epithelial cells to form glandular acini. Little is known about the molecular mechanisms of androgen action in prostatic stromal cells. Prostate cancer is an androgen dependent disease. Alterations i the axis of stromal-epithelial interactions are likely in prostatic carcinoma. It is our hypothesis that prostate stromaspecific molecular pathways are fundamental in the endocrine and paracrine regulation of prostatic epithelial cell proliferation and differentiation, and that such pathways are central to androgen regulated prostate cancer initiation and progression. To address this hypothesis and identify key molecular mechanisms, the specific aims of this proposal are centered on the role of prostate stroma gene expression in several aspects of prostate cancer. Specifically, we want to study the role of stromal and androgen dependent genes, such as COUP-TFs, in the initiation and progression of prostate tumors and to define the promoters of these genes for future gene targeting specifically expressed in prostate stroma cells. We will use transgenic mice, gene specific knockout (homologous recombination) and in vitro mouse prostate reconstitution system (MPR) to achieve these goals. We expect results obtained from these studies will help us understanding the role of stroma in prostate carcinogenesis. In addition, we hope to identify gene probe for prostate tumor and eventually devise as method for genetic therapy.
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