Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer and is the third leading cause of cancer death in American men. As such it remains a major public health problem in the US despite improvements in diagnosis and treatment. The role of androgen receptor (AR) signaling in recurrent PCa cell growth is the subject of continuing research. It has been recognized for many years that androgen, by binding to and activating AR, promotes early stage PCa cell survival and growth. This has been the basis for androgen ablation therapy, which has served as a front-line therapy for metastatic PCa. Unfortunately, the effectiveness of androgen ablation therapy is short-lived as recurrent hormone-independent PCa cells usually emerge after one to three years of treatment. Our laboratory has also identified a repressive function of androgen in PCa cells when AR is expressed at high level. We hypothesize that this repression function of AR may be a remnant of AR action in normal healthy prostate epithelial cells and that restoring this repression function by over-expression may be effective therapy in many PCa patients. In the first aim we propose to test this hypothesis in preclinical """"""""proof of concept"""""""" experiments by generating adenoviral constructs expressing the AR gene and use them to infect a wide array of prostate tumor cells in vitro cell culture and in vivo as tumor xenografts in athymic mice. In the second aim, will explore the mechanistic basis for androgenic repression of growth and induction of apoptosis to provide a rationale for AR replacement therapy. In the third aim we will examine novel signaling pathways that may drive cell proliferation in androgen-independent cells. We recently uncovered three regulators in a screen for differentially expressed genes in androgen-dependent vs. androgen-independent PCa cells that we hypothesize cooperate to confer androgen-independent growth. In the fourth aim, we will examine liver X receptor (LXR) signaling and the regulation of cholesterol and lipid homeostasis in PCa cells as a novel means to control cell growth. We recently found that LXR agonists repress cell proliferation in both androgen-dependent and -independent PCa cells.
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