Roles of the androgen receptor and its co-regulators in prostate tumorigenesis

描述（由申请人提供）：像大多数其他癌症一样，前列腺癌的发生涉及从癌前细胞到细胞的多步骤进展，这些细胞以不受调节的方式局部增殖，然后转移。多种证据表明，雄激素的作用主要通过雄激素受体（AR）介导，对前列腺癌细胞的生长和存活很重要。因此，雄激素消融治疗已被广泛应用于大多数晚期前列腺癌患者。然而，大多数患者在开始治疗后的两到三年内发展为雄激素不敏感前列腺癌，目前尚无有效的治疗方法。尽管已经投入了大量的努力来了解前列腺癌细胞从雄激素敏感到不敏感状态的调节过程，但控制这种转换的精确分子机制仍然很大程度上不清楚。在过去的几年里，我们的实验室和其他研究人员已经证明了AR在前列腺癌的发生和发展中的重要作用。特别是，使用特异性小发夹RNA构建物敲低AR表达，我们发现AR在调节雄激素不敏感（AI）前列腺癌细胞的转录和细胞生长中继续发挥关键作用，这意味着AR仍然是该疾病的可行治疗靶点。此外，我们还证明，hZimp7、hZimp10和2-catenin可以通过特异性蛋白-蛋白相互作用增强ar介导的转录和细胞生长。这些共激活剂可以补偿雄激素水平下降时的AR活性，这可能在前列腺癌的进展中起作用。此外，我们最近的数据显示，AR抑制sp1诱导的c-Met转录，这表明AR在转录中具有双重调节作用。由于c-Met的上调与前列腺癌的进展有关，可以想象，通过雄激素消融抑制AR活性可能会增加c-Met的表达，这可能直接导致雄激素不敏感和前列腺癌更具侵袭性的表型。基于我们之前的工作和文献，我们假设AR作为一种转录因子，通过与多种协同调节因子的相互作用来调节前列腺细胞的生长和分化，而这一过程的失调可以改变AR的活性，并可能直接导致前列腺癌的发生和进展。本文提出了三个不同但相关的具体目标，以进一步解决AR的关键作用以及AR及其协同调节因子在前列腺癌肿瘤发生中的调节机制。它们是：1)评估AR在前列腺癌肿瘤发生中的主要作用；2)研究AR在前列腺癌进展中对c-Met表达的抑制作用；3)确定Zimp7和Zimp10在雄激素信号通路中的作用和调控。我们认为，这些研究的成功完成所产生的数据将为前列腺癌肿瘤发生机制提供新的见解，并可能有助于开发前列腺癌治疗的新靶点。公共卫生相关性：我们在这篇修订后的竞争性更新中提出了一系列实验，以进一步研究雄激素受体（AR）及其协同调节剂调节前列腺癌细胞生长和存活的分子机制。特别是，我们将使用AR转基因、ETV1转基因、Zimp10条件敲除和其他动物模型来评估AR及其协同调节因子和下游靶点在前列腺肿瘤发生中的生物学作用。该提案产生的数据将进一步扩展我们目前在前列腺癌生物学领域的知识，并可能产生重要的信息，这将导致我们制定新的治疗前列腺癌患者的策略。

DESCRIPTION (provided by applicant): Like most other cancers, prostate carcinogenesis involves a multi-step progression from precancerous cells to cells that proliferate locally in an unregulated fashion and then metastasize. Multiple lines of evidence have shown that the effects of androgens, which are mediated mostly through the androgen receptor (AR), are important for the growth and survival of prostate cancer cells. Therefore, androgen ablation therapy has been frequently used for the majority of advanced prostate cancer patients. However, most patients develop androgen-insensitive prostate cancer within two to three years following initiation of therapy, for which there is no effective treatment currently. Although substantial effort has been devoted toward understanding the regulatory process by which prostate cancer cells progress from androgen sensitive to insensitive status, the precise molecular mechanisms that control this conversion still remain largely unclear. In the past years, our lab and other investigators have demonstrated the important role of AR in prostate cancer development and progression. Particularly, using specific small hairpin RNA constructs to knockdown AR expression, we showed that the AR continues to play a critical role in regulating the transcription and cell growth of androgen-insensitive (AI) prostate cancer cells, implying that the AR remains a viable therapeutic target in this disease. Moreover, we also demonstrated that AR-mediated transcription and cell growth can be enhanced by hZimp7, hZimp10, and 2-catenin through specific protein-protein interactions. These co- activators can compensate for AR activity in decreased androgen levels, which may play a role in prostate cancer progression. Furthermore, our recent data showing that the AR represses Sp1-induced c-Met transcription suggest a dual regulatory role for AR in transcription. Since the up-regulation of c-Met is linked to the progression of prostate cancer, it is conceivable that inhibition of AR activity through androgen ablation may increase the expression of c-Met, which might directly contribute to androgen-insensitivity and more aggressive phenotypes of prostate cancer. Based on our previous works and the literature, we hypothesize that AR, acting as a transcriptional factor, regulates prostate cell growth and differentiation through interactions with a variety of co-regulators, and dys-regulation of this process can change AR activity and may directly contribute to prostate cancer development and progression. Three different but related specific aims are proposed in this revised competing renewal to further address the critical role of AR and the regulatory mechanisms for AR and its co-regulators in prostate cancer tumorigenesis. They are: 1) assessing the primary role of AR in prostate cancer tumorigenesis, 2) studying the inhibitory role of AR on c-Met expression in prostate cancer progression, and 3) determining the roles and regulation of Zimp7 and Zimp10 in androgen- signaling pathway. We feel that the data generated by the successful completion of the proposed studies will provide fresh insight into the mechanisms for prostate cancer tumorigenesis, and may contribute to the development of new targets for the treatment of prostate cancer. PUBLIC HEALTH RELEVANCE: We proposed a series of experiments in this revised competing renewal to further investigate the molecular mechanisms by which the androgen receptor (AR) and its co- regulators modulate the growth and survival of prostate cancer cells. Particularly, we will use the AR transgenics, ETV1 transgenics, Zimp10 conditional knockouts, and other animal models to assess the biological roles of AR and its co-regulators, and downstream targets in prostate tumorigenesis. The data generated from this proposal should further extend our current knowledge in the field of prostate cancer biology, and may generate important information that will lead us to develop new therapeutic strategies for prostate cancer patients.