Role of Nuclear Receptor Coactivators in Recurrent Prostate Cancer

摘要

The purpose of our studies supported by this DOD award has been to characterize the signaling pathways and interacting proteins that contribute to increased androgen receptor (AR) mediated gene activation in recurrent prostate cancer. We have followed up our previous studies on the AR by focusing on the EGF and heregulin-induced signaling pathways. We have used traditional yeast two hybrid screening methods to identify two key regulatory proteins that interact with AR. In collaborative studies with Dr. James Mohler, the levels of several androgen metabolites were determined in prostate cancer tissue specimens. In collaboration with Robert Gampe at GlaxoSmithKline, we determined the structural basis for FXXLF and LXXLL motif binding to AR AF2 in the ligand binding domain. In collaboration with Dr. Shelly Earp, we determined the presence of HER2 and HER3 receptors in the CWR-R1 prostate cancer cell line derived from the CWR22 recurrent human xenograft propagated in nude mice. We established the functional basis for an AR mutation in prostate cancer that involves increased AR recruitment of the SRC/p160 coactivators. Previously we reported increased levels of SRC1 and TIF2 in prostate cancer specimens obtained after recurrent growth following androgen ablation therapy. As outlined below, our studies have led to several important conclusions regarding AR function in prostate cancer cells. Importantly, the work has set the stage for our continued experiments designed to understand AR functional activity in prostate cancer.