Androgen Receptor Associated Proteins in Prostate Cancer

描述(申请人提供)：像大多数癌症一样，前列腺癌的发生涉及从癌前细胞到细胞的多步骤进展，这些细胞在局部以不受调控的方式增殖，然后转移。雄激素消融治疗前列腺癌的观察表明，雄激素信号通路对前列腺癌的生长和发展具有重要作用。雄激素的促生长作用主要是通过雄激素受体(AR)介导的。AR是核激素受体家族的一员，通过调节配体依赖的转录，在正常前列腺的发育和前列腺癌的发生中发挥核心作用。因此，了解AR调节基因表达的机制应该有助于洞察可能导致前列腺癌发展的异常，并为未来的治疗提供可能的靶点。在过去的四年里，我们和其他人已经证明了AR的功能受其他转录激活因子、抑制因子和调节因子的调节。特别是，我们最近发现了三个重要的、但不同的AR相互作用蛋白，其中包括转录激活因子β-连环蛋白、转录抑制因子TGIF和新的转录因子TAC10。最近的研究表明，β-连环素和TGIF分别通过Wnt和TGF-β信号通路在正常发育和肿瘤发生中发挥关键作用。TAC10是一种通过改良的酵母单杂交系统鉴定的蛋白质。它选择性地在前列腺细胞中表达，并含有一个有效的反式激活结构域。基于这一证据，我们假设这三个因子是前列腺细胞中雄激素信号的关键中介，它们的调节或失调在前列腺癌的发病机制中起着重要作用。因此，我们提出了几种方法来研究这些辅助因子调节AR作用的机制，并确定这些相互作用在前列腺癌发生和发展中的生物学意义。其具体目的如下：(1)检测前列腺癌细胞中AR和β-连环蛋白之间的相互作用；(2)确定TGIF如何调节前列腺癌细胞中AR的活性；(3)研究TAC10在调节AR介导的转录中的生物学作用。

DESCRIPTION (provided by applicant): Like most cancers, prostate carcinogenesis involves a multistep progression from precancerous cells to cells that proliferate locally in an unregulated fashion and then metastasize. Observations from androgen ablation treatment of prostate cancer have shown that the androgen-signaling pathway is important for the growth and progression of prostate cancer. The growth-promoting effects of androgen are mediated mostly through the androgen receptor (AR). AR is a member of the nuclear hormone receptor family and plays a central role in the development of the normal prostate and in prostate cancer through the regulation of ligand dependent transcription. Understanding the mechanisms by which the AR regulates gene expression should, therefore, provide insight into abnormalities that may contribute to the development of prostate cancer and provide possible targets for future treatment. In the past four years, we and others have demonstrated that the function of AR is regulated by other transcriptional activators, repressors, and modulators. In particular, we recently identified three important, but distinct, AR-interacting proteins, which include a transcriptional activator, beta-catenin; a transcriptional repressor, TGIF; and a novel transcription factor, TAC10. Recent studies have shown that both beta-catenin and TGIF play critical roles in normal development and tumorigenesis through the Wnt and TGF-beta signaling pathways, respectively. TAC10 is a protein that was identified by a modified yeast one-hybrid system. It is selectively expressed in prostate cells and contains a potent transactivation domain. Based on this evidence, we hypothesize that these three factors are critical mediators in androgen signaling in prostate cells, and that their regulation or dysregulation are important in the pathogenesis of prostate cancer. Therefore, we propose several approaches to study the mechanisms by which these cofactors regulate AR action and to define the biological significance of these interactions in the development and progression of prostate cancer. The Specific Aims are as follows: (1) Examine the interaction between AR and beta-catenin in prostate cancer cells; (2) Determine how TGIF regulates AR activity in prostate cancer cells; (3) Study the biological roles of TAC 10 in modulating AR-mediated transcription.