The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer.

Abstract:: The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a diverse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses. Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators (p300, SRC-3), resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. A gene signature of AR activity positively predicted disease survival in multiple clinical ER-positive breast cancer cohorts. These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity.

Authors:: TE Hickey, LA Selth, KM Chia, G Laven-Law, HH Milioli, D Roden, S Jindal, M Hui, J Finlay-Schultz, E Ebrahimie, SN Birrell, S Stelloo, R Iggo, S Alexandrou, CE Caldon, TM Abdel-Fatah, IO Ellis, W Zwart, C Palmieri, CA Sartorius, A Swarbrick, E Lim, JS Carroll, WD Tilley

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