Since the introduction of androgen deprivation therapy (ADT) by Huggins and colleagues some 80 years ago, it has become the mainstay strategy for treatment of prostate cancer. ADT specifically targets the androgen receptor (AR). Since the cloning of the human AR in the late 1980’s extensive evidence has accumulated for its oncogenic role in prostate cancer, leading to potent new hormone therapies to target the AR. Unfortunately, ADT remains a blunt clinical weapon as AR activity influences the health and function of most body tissues. Side effects associated with ADT adversely affect quality of life in patients and can contribute to drug non-compliance. Moreover, while new hormone therapies developed over the past decade for the treatment of metastatic hormone sensitive prostate cancer prolong life, resistance to these agents is inevitable as tumours evolve to reactivate AR and regulate expression of genes that promote tumour growth and survival. Smarter therapeutic strategies are needed to achieve more durable responses and improve quality of life for patients actively on ADT. More recently, we and others have investigated reprograming of AR from an oncogenic to a more normal, pro-differentiating factor rather than abolishing its activity altogether, thus driving AR toward better outcomes in prostate cancer.
Resistance to estrogen receptor alpha (ER) target therapies is the major cause of breast cancer death. Therapeutic engagement of steroid receptors that impinge on, but do not ablate, ER signalling is an emerging new treatment strategy. The AR is expressed in the majority of breast tumours and represents an exceptional therapeutic target, especially as a range of drugs including AR agonists, antagonists and selective AR modulators (SARMs) are available. Interest in targeting AR for treatment of breast cancer has escalated over the past decade. Despite clinical correlations and preclinical studies supporting a protective role for AR in breast cancer, especially in ER-positive disease, enthusiasm was largely directed toward antagonizing AR with anti-androgenic drugs used to treat men with prostate cancer, a disease definitively driven by oncogenic AR activity. While some pre-clinical studies supported use of an AR antagonist for ER-positive breast cancer, this strategy has had minimal success in clinical trials. Our most recent preclinical studies using a diverse range of in vivo breast cancer models (Hickey et al, Nature Medicine 2021) provides compelling evidence for (i) AR being a tumour suppressor in ER+ breast cancer, and (ii) an AR agonist, not an antagonist, treatment strategy being the optimal therapeutic approach.