Control of Prostate Growth and Tumor Progression

控制前列腺生长和肿瘤进展

• 批准号: 6684011
• 负责人: ROBERT J. MATUSIK
• 金额: $ 26.43万
• 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/6684011
• 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）： 我们已经确定了HNF 3 α，HNF 3叉头家族的成员，结合到一个共识的DNA序列，作为一个新的AR共激活剂，参与雄激素调节和前列腺特异性表达的probasin（PB）。HNF 3 α在正常的啮齿类动物前列腺、我们的转基因小鼠模型（发生癌前病变和腺癌）以及所有检查的人类前列腺癌中表达。密切相关的HNF 3（叉头蛋白）在正常啮齿动物前列腺中不表达，但在雄激素非依赖性小鼠神经内分泌（NE）前列腺癌模型和人前列腺癌的子集中表达。HNF 3 α在细胞培养物中的表达将增加PB和人前列腺特异性抗原（PSA）启动子的雄激素依赖性AR活化。最重要的是，HNF 3 β基因与PSA启动子-报告基因在细胞培养物中的共表达将以雄激素非依赖性方式激活PSA启动子。我们的假设是，HNF 3 α是正常前列腺发育的关键，HNF 3 β的表达将转换雄激素调节基因，以“雄激素非依赖性”的方式发挥作用。我们的三个具体目的如下：目的1：表征HNF 3在小鼠UGS和前列腺中的表达;目的2：测试HNF 3蛋白在前列腺发育中的功能作用;目的3：确定HNF 3 α和HNF 3 β在肿瘤发展和进展中的作用。这项资助的总体目标是确定HNF 3 α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HNF 3 β在前列腺肿瘤进展为雄激素非依赖性中的作用。