Pharmacological Targeting of Androgen Receptor Elicits Context-Specific Effects in Estrogen Receptor-Positive Breast Cancer

Androgen receptor (AR) is expressed in 80% to 90% of estrogen receptor a-positive (ER+) breast cancers. Accumulated evidence has shown that AR is a tumor suppressor and that its expression is associated with improved prognosis in ER+ breast cancer. However, both a selective AR agonist (RAD140) and an AR inhibitor (enza-lutamide, ENZ) have shown a therapeutic effect on ER+ breast cancer, so the potential for clinical application of AR-targeting therapy for ER+ breast cancer is still in dispute. In this study, we evaluated the efficacy of ENZ and RAD140 in vivo and in vitro in AR+/ER+ breast cancer models, characterizing the relationship of AR and ER levels to response to AR-targeting drugs and investi-gating the alterations of global gene expression and chromatin binding of AR and ERa after ENZ treatment. In the AR-low setting, ENZ directly functioned as an ERa antagonist. Cell growth inhi-bition by ENZ in breast cancer with low AR expression was independent of AR and instead dependent on ER. In AR-high breast cancer models, AR repressed ERa signaling and ENZ pro-moted ERa signaling by antagonizing AR. In contrast, RAD140 activated AR signaling and suppressed AR-high tumor growth by deregulating ERa expression and blocking ERa function. Overall, analysis of the dynamic efficacies and outcomes of AR agonist, and antagonist in the presence of different AR and ERa levels reveals regulators of response and supports the clinical investigation of ENZ in selected ER+ tumors with a low AR/ER ratio and AR agonists in tumors with a high AR/ER ratio.