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The role of the androgen receptor (AR) in estrogen receptor (ER)-[alpha]-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. Functional interplay of sex hormones in estrogen receptor-positive breast cancer unveils the therapeutic potential of androgen receptor agonists., Author(s): Theresa E. Hickey [sup.1] , Luke A. Selth [sup.1] [sup.2] [sup.3] , Kee Ming Chia [sup.4] , Geraldine Laven-Law [sup.1] , Heloisa H. Milioli [sup.4] , Daniel Roden [sup.4] [...]