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.

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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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cancer Etiology Study Section (CE)
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Sathyamoorthy, Neeraja
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Stanford University
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