SWI/SNF Family Interactions in Refratory Prostate Cancer

Mayo Clinic Coll Of Medicine, Rochester, Rochester MN

Investigators

Abstract

DESCRIPTION (provided by applicant): Prostatic adenocarcinoma (PCa) is the second leading cause of cancer death and the most common type of cancer, excluding skin cancer, in adult men in the United States. Currently, androgen deprivation therapies are the most effective treatments for advanced prostate cancer. Regression of the cancer is seen early in the treatment. However, a majority of patients lapse and develop hormone refractory prostate cancer (HRPCa), and androgen-independent disease. Even in the absence of androgens these HRPCa cell continue to express androgen receptor (AR), which is transcriptionally active as is evidenced by the expression of AR mediated gene expression, i.e. continued PSA expression. Data generated by our laboratory suggests that the continued function of AR is through a ligand-independent mechanism of activation. One way in which AR could be activated in a ligand-independent manner is through its interaction with co-regulatory molecules such as CBP and RB. These co-regulatory proteins, which interact with AR, also interact with the SWI/SNF family of chromatin remodeling proteins. The SWI/SNF family of proteins plays an important role allowing transcription factors and nuclear receptors access to DNA. Therefore, by interacting with AR, either directly or indirectly through co-regulatory molecules, the SWI/SNF family members may facilitate the activity of AR by enhancing access to AR mediated genes. Our preliminary data suggests that the SWl/SNF family may be upregulated in HRPCa. In this study, it is hypothesized that SWI/SNF associates with the AR and facilitates AR transactivation in an androgen-independent manner. To test this hypothesis the following specific aims are proposed: (1) Characterization of the SWI/SNF expression profile of androgen refractory prostate cancer cell lines, (2) Examination of AR complex formation with specific members of the SWI/SNF family, and (3) Determination of the functional affects of SWI/SNF on AR transcriptional activation.