Control of Prostate Growth and Tumor Progression

描述(由申请人提供)： 我们已经确定HNF3pha是HNF3叉头家族的成员，它与一个共同的DNA序列结合，是一种新的AR辅助激活因子，参与雄激素调节和前列腺特异性表达(PB)。HNF3α在正常的啮齿动物前列腺、我们的发生癌前病变的转基因小鼠模型和腺癌中表达，在所有被检测的人类前列腺癌中都有表达。密切相关的HNF3(叉头蛋白)在正常啮齿动物的前列腺中不表达，但在雄激素非依赖性小鼠神经内分泌(NE)前列腺癌模型和人类前列腺癌的亚组中表达。在细胞培养中表达HNF3α将增加PB和人前列腺特异性抗原(PSA)启动子的雄激素依赖性AR激活。最重要的是，HNF3β基因与PSA启动子-报告基因在细胞培养中的共表达将以雄激素非依赖性的方式激活PSA启动子。我们的假设是，HNF3α是正常前列腺发育的关键，HNF3β的表达将切换雄激素调节基因的行为，使其表现为“雄激素非依赖”的方式。我们的三个具体目标如下：目标1：研究HNF3在小鼠前列腺和UGS中的表达；目标2：检测HNF3蛋白在前列腺发育中的功能作用；以及目标3：确定HNF3α和HNF3β在肿瘤发生发展中的作用。这项赠款的总体目标是确定HNF3α在前列腺正常发育和雄激素依赖型肿瘤生长中的重要性，以及HNF3β在前列腺癌向雄激素非依赖性发展过程中的作用。

DESCRIPTION (provided by applicant): We have identified HNF3alpha , a member of the HNF3 forkhead family that bind to a consensus DNA sequence, as a new AR co-activator that is involved in androgen regulation and prostate-specific expression of the probasin (PB). HNF3alpha is expressed in the normal rodent prostate, our transgenic mouse models that develop preneoplastic lesions and in adenocarcinoma, and in all human prostate cancers examined. The closely related HNF3( forkhead protein was not expressed in the normal rodent prostate but was expressed in an androgen independent mouse neuroendocrine (NE) prostate cancer model and a subset of human prostate cancers. Expression of HNF3alpha in cell culture will increased androgen dependent AR activation of the PB and human Prostate Specific Antigen (PSA) promoters. Most importantly, co-expression of the HNF3beta gene with the PSA promoter-reporter in cell culture will activate the PSA promoter in an androgen-independent manner. Our Hypothesis is that HNF3alpha is key to normal prostate development and the expression of HNF3beta will switch androgen regulated genes to behave in an "androgen independent" manner. Our three Specific Aims are as follows: Aim 1: To characterize the HNF3 expression in the mouse UGS and prostate; Aim 2: To test the functional role of HNF3 proteins in prostate development; and Aim 3: To determine the role of HNF3alpha and HNF3beta in tumor development and progression. The overall goals of this grant are to establish the importance of the HNF3alpha in the normal development of the prostate and in androgen dependent tumor growth and the role of HNF3beta in rostate tumor progression to androgen-independence.