Prostatic adenocarcinomas are treated based on their androgen dependence. The goal of standard therapy for this tumor type is ablation of androgen receptor (AR) function, either through direct AR inhibition or through inhibition of androgen synthesis. Although these lines of treatment are initially effective, recurrent tumors ultimately arise which are refractory to androgen/AR ablation. Clinical evidence suggests that the AR is inappropriately activated in these recurrent tumors, through largely undefined mechanisms. Given the importance of AR activity in prostate cancer growth, considerable effort is being undertaken to delineate the function and regulation of AR modulatory proteins. Cyclin D1 is an integral component of the cell cycle machinery that is induced by androgen in prostatic adenocarcinoma cells. However, we and others have shown that Cyclin D1 has a second role in regulation of androgen dependent proliferation, manifested through its ability to modulate AR activity. We have shown that Cyclin D1 binds the AR directly and through interaction with the N-terminus inhibits AR transactivation potential. Interaction between AR and Cyclin D1 has been shown with endogenous proteins. The repressor function of Cyclin D1 occurs independently of its role in the cell cycle, is dominant to the effects of known AR co-activators, and attenuates the rate of androgen dependent proliferation. Our data put forth the hypothesis that Cyclin D1 is a critical mediator of AR activity that could be exploited to inhibit androgen-mediated proliferation. Initially, we will delineate the precise mechanism of Cyclin D1 action (Aim 1). Subsequent analyses are designed to test the specificity of Cyclin D1 regulation, with a specific emphasis on multiple AR targets and alternate mechanisms through which AR is inappropriately activated in tumorigenesis (Aim 2). Lastly, we will evaluate the impact of the Cyclin D1-AR interaction on androgen dependent tumor proliferation, using a well-defined model system (Aim 3). Collectively, these studies will define the action of a potent AR regulator in the context of prostate cancer. Given the importance of AR activity in the prostate tumor formation and progression, it is our belief that a better understanding of AR regulation is critical for the design of novel, effective therapeutics.
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