ROLE OF BRCA1 AS A HUMAN PROSTATE SUPPRESSOR GENE

乳腺癌和卵巢癌易感基因-1（BRCA 1）的遗传突变使男性先证者患前列腺癌的风险显著增加;但目前尚不清楚BRCA 1是否以及如何调节前列腺癌细胞的功能。 我们的初步研究表明，野生型和突变型BRCA 1转基因差异调节人前列腺癌细胞系DU-145的多种表型特征，包括细胞增殖，体内肿瘤生长，细胞凋亡的易感性，DNA修复活性和雌激素受体活性。 BRCA 1诱导的一些表型改变可能部分是由于关键调控蛋白表达的改变，包括p300、Bcl-2、BRCA 2、p21 WAF 1/CIP 1和Mdm-2。 我们假设BRCA 1作为前列腺肿瘤抑制基因，通过抑制细胞增殖，增强细胞对凋亡的敏感性，降低细胞对雄激素的敏感性。 在本申请中，我们建议进一步研究BRCA 1诱导的几种不同前列腺癌细胞系细胞改变的机制。 我们将确定BRCA 1分子的关键区域参与前列腺癌细胞增殖，DNA损伤反应，重要的细胞调节蛋白的表达和雄激素受体活性的调制。 这些研究的知识将有助于：1）阐明遗传性和散发性人类前列腺癌发生的共同机制; 2）使用BRCA 1基因治疗相关方法，通过增强前列腺癌对细胞毒性药物的敏感性，为靶向前列腺癌提供实验基础。

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.