Endocrine Abstracts

Recent statistics indicate that prostate cancer (PC) is the most frequent cancer in men worldwide and is the leading cause of cancer death in men above 50 years of age. The Androgen receptor (AR), a member of the superfamily of nuclear hormone receptors, plays a well-established role in the development and progression of the disease. PC localized to the prostate is commonly treated with surgical removal of the gland and is often associated with a favorable outcome. However, metastatic PC requires more aggressive treatment modalities often consisting of gonadotropin releasing hormone (GnRH) agonists and/or an AR antagonist (ex: bicalutamide). Although initially successful in alleviating symptoms, the disease progresses to a castrate resistant state, where drugs targeting the AR axis have limited clinical utility. Several mechanisms were suggested to explain resistance to antiandrogen treatment including AR mutations, AR amplification and/or local production of androgens. Additionally, some studies also suggest that deregulation of AR cofactor expression may permit weak androgens or even antiandrogens to function as full AR agonists and fuel tumor growth, a mechanism that contributes to the castrate resistance phenotype. This puts into context our observation that RAD52, a protein involved in DNA repair machinery also functions as an AR cofactor whose deregulation affects PC response to antiandrogens. Herein, using PC cell models, we found that knockdown of RAD52 increases AR protein levels and enhances AR transcriptional activity in the presence of low levels of androgens. More importantly, we found that RAD52 knockdown converts the AR antagonist bicalutamide into a full agonist in cell reporter assays and on AR target genes; an activity associated with enhanced recruitment of AR to target gene promoters. Taken together, our results suggest that deregulation of RAD52 expression may mediate PC resistance to antiandrogen therapy.