Friend or foe? Deciphering androgen receptor action to improve bipolar androgen therapy for prostate cancer

Abstract

Inhibiting the activity of the androgen receptor (AR) is the cornerstone treatment for advanced prostate cancer. AR-targeted therapies are highly effective in slowing disease progression but are not curative and the resultant disease state, termed castration-resistant prostate cancer, is associated with significant patient morbidity and mortality. In most cases, resistance to these therapies arises due to alterations that reactivate the AR signalling axis. Interestingly, it has long been recognised that potent activation of AR with supraphysiological levels of androgens can suppress prostate cancer growth in both preclinical models and patients. This intriguing paradox – where both inhibition and activation of AR have anti-cancer effects – is now being harnessed clinically in the form of bipolar androgen therapy (BAT). This review describes mechanisms underlying the tumour-suppressive functions of AR in the context of potent androgenic stimulation and discusses how our maturing understanding of these mechanisms is influencing the clinical deployment of BAT.