ROLE OF BRCA1 AS A HUMAN PROSTATE SUPPRESSOR GENE

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Inherited mutations of the breast and ovary cancer susceptibility gene-1 (BRCA1) confer a significantly increased risk for prostate cancer in male probands; but it is not known if and how BRCA1 regulates the function of prostate cancer cells. Our preliminary studies indicate that wild-type and mutant BRCA1 transgenes differentially modulate multiple phenotypic characteristics of human prostate cancer cell line DU-145, including cell proliferation, in vivo tumor growth, susceptibility to apoptosis, DNA repair activity, and estrogen receptor activity. Some of the phenotypic alterations induced by BRCA1 may be due, in part, to alterations in the expression of key regulatory proteins, including p300, Bcl-2, BRCA2, p21WAF1/CIP1, and Mdm-2. We hypothesize that BRCA1 functions as a prostate tumor suppressor gene by inhibiting cell proliferation, enhancing cellular susceptibility to apoptosis, and reducing cell sensitivity to androgen. In this application, we propose to further investigate the mechanism(s) underlying BRCA1-induced cellular alterations in several different prostate cancer cell lines. We will identify key regions of the BRCA1 molecule involved in modulation of prostate cancer cell proliferation, DNA damage response, expression of important cellular regulatory proteins, and androgen receptor activity. The knowledge from these studies will help to: 1) elucidate mechanisms that may be common to hereditary and sporadic human prostate carcinogenesis; and 2) provide an experimental basis for targetting prostate cancers by enhancing their sensitivity to cytotoxic agents, using BRCA1 gene therapy-related approaches.