Androgen Receptor Coregulatory Proteins as Potential Therapeutic Targets in the Treatment of Prostate Cancer

Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer death in western men, and as such constitutes a significant health problem. The male sex steroids, androgens, have long been recognized as major contributors to the progression of PCa. Still today, standard therapy for PCa is aimed at removing androgens and/or blocking the action of androgens. Although most PCas initially regress following anti-androgen therapy, a majority of these tumors eventually start to regrow, leaving the patient very little hope of curative treatment. Interestingly, in androgen-refractory PCas the androgen receptor (AR), the transcription factor mediating the effects of androgens, continues to be expressed, and AR signaling remains functional. Moreover, disruption of the activity or the expression of the AR inhibits proliferation of androgen-refractory PCa cells, emphasizing that, in the androgen-independent state of the disease, ARmediated signaling is crucial to the survival of PCa cells. Several potential mechanisms, most likely not mutually exclusive, have been described to account for activation of the AR in androgen-refractory PCa cells. Recent reports of aberrant expression of coregulators that are required for the formation of productive AR transcriptional complexes in androgen-refractory PCa and its correlation with PCa disease progression, have enhanced interest into this mechanism and have led to the proposition of AR coregulator protein complexes as potential novel targets for PCa therapy. This review seeks to critically analyze the current knowledge on AR coregulator expression in PCa tissues and to evaluate how this information could translate into novel therapeutic targets for PCa.