University of Virginia Health System

Email Address: dgg3f@virginia.edu

When disseminated prostate cancer initially presents in the clinic, the tumor is dependent on androgen for growth and, therefore, responsive to androgen ablation therapy. However, there is a high rate of treatment failure due to the recurrence of androgen-independent metastases. Most androgen-independent prostate tumors continue to express the AR as well as androgen responsive genes, despite the near absence of circulating androgens in these patients. Late-stage prostate cancer is functionally androgen-independent; however, it is still dependent on the AR, as several studies have demonstrated that 1) inhibiting AR expression reduced the growth of androgen-independent prostate cancer, and 2) AR expression levels increase with prostate cancer progression to androgen independence. Our guiding hypothesis is that the AR is regulated not only by androgen, but also by cell signaling pathways that are upregulated as prostate cancer progresses to androgen-independence. Activation of these signaling pathways results in post-translational modifications of the AR that play a critical role in regulating AR function and consequently the acquisition and maintenance of androgen-independent disease. While much is known about which sites of the AR undergo post-translational modifications, little is known about how these post-translational modifications regulate AR function. In order to develop novel therapeutics combating advanced stage prostate cancer, we must understand the function of the AR phosphorylation sites and how AR post-translational modifications partner to choreograph AR function. Our goal is to characterize the regulation and functions of AR phosphorylations and determine the kinases and signaling pathways responsible for these modifications. This work will provide important insights into ways that the AR can serve as an integration node for steroid hormone and growth factor signaling, particularly in the context of prostate cancer progression.

We previously identified the major serine phosphorylation sites on the AR and observed regulation of AR phosphorylation by multiple agonists. Most recently we have determined that stress kinase signaling regulates S650 phosphorylation and that this phosphorylation is required for optimal nuclear export. Our research focuses on identifying the functional consequences and regulators of AR phosphorylation. Specifically, we are determining the role of specific AR phosphorylations in AR function, identifying AR kinases, and determining the relationship between AR phosphorylation and other AR posttranslational modifications (acetylation, SUMOlyation). Understanding the direct mechanism of signal transduction regulation of AR activity is critical to understanding prostate cancer progression and developing targeted therapies for androgen-independent prostate cancer.