Control of Prostate Growth and Tumor Progression

控制前列腺生长和肿瘤进展

• 批准号: 6931491
• 负责人: ROBERT J. MATUSIK
• 金额: $ 30.2万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931491
• 关键词: SCID mouse; androgens; developmental genetics; gene expression; hormone regulation /control mechanism; matrix assisted laser desorption ionization; neoplastic process; prostate; prostate neoplasms; protein structure function; reproductive development; transcription factor

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.

描述（由申请人提供）： 我们已经鉴定出 HNF3alpha 是 HNF3 叉头家族的成员，与共有 DNA 序列结合，作为一种新的 AR 共激活剂，参与雄激素调节和前列腺特异性表达的 probasin (PB)。 HNF3α 在正常啮齿动物前列腺、发生癌前病变的转基因小鼠模型、腺癌以及所有检查的人类前列腺癌中表达。密切相关的 HNF3（叉头蛋白）在正常啮齿动物前列腺中不表达，但在不依赖雄激素的小鼠神经内分泌 (NE) 前列腺癌模型和人类前列腺癌的子集中表达。细胞培养物中 HNF3α 的表达会增加雄激素依赖性 AR 激活最重要的是，HNF3beta 基因与 PSA 启动子报告基因在细胞培养物中的共表达将激活 PSA 启动子。我们的假设是 HNF3α 是正常前列腺发育的关键，并且 HNF3β 的表达会将雄激素调节基因转变为“雄激素独立”方式，我们的三个具体目标如下： 目标 1：表征小鼠 UGS 和前列腺中的 HNF3 表达；目标 2：测试 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 在肿瘤发生和进展中的作用。该资助的总体目标是确定 HNF3α 在前列腺正常发育和雄激素依赖性肿瘤生长中的重要性，以及 HNF3β 在前列腺肿瘤进展至雄激素非依赖性中的作用。