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

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. Failure of these therapies results in a disease state termed castration-resistant prostate cancer, which is associated with significant patient morbidity and mortality. In most cases, resistance to AR-targeted 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 preclinicalmodels and patients. This intriguing paradox, where both inhibition and activation of AR have anti-cancer effects, is nowbeing harnessed clinically in the formof bipolar androgen therapy (BAT). This review describes mechanisms underlying the tumour-suppressive functions of AR in the context of potent androgenic stimulation and discusses howourmaturing understanding of these processes is influencing the clinical deployment of BAT.