Hickey, T.E.Selth, L.A.Chia, K.M.Laven-Law, G.Milioli, H.H.Roden, D.Jindal, S.Hui, M.Finlay-Schultz, J.Ebrahimie, E.Birrell, S.N.Stelloo, S.Iggo, R.Alexandrou, S.Caldon, C.E.Abdel-Fatah, T.M.Ellis, I.O.Zwart, W.Palmieri, C.Sartorius, C.A.et al.2021-06-222021-06-222021Nature Medicine, 2021; 27(2):310-3201078-89561546-170Xhttp://hdl.handle.net/2440/130850The 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.en© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.Cell Line, TumorHumansBreast NeoplasmsReceptors, AndrogenEstrogen Receptor alphaAndrogensSignal TransductionCell ProliferationFemaleCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Nuclear Receptor Coactivator 3MCF-7 CellsThe androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancerJournal article100003390610.1038/s41591-020-01168-70006086778000012-s2.0-85100216291563025Hickey, T.E. [0000-0002-2752-730X]Selth, L.A. [0000-0002-4686-1418]Laven-Law, G. [0000-0001-5326-1931]Birrell, S.N. [0000-0002-1023-413X]Tilley, W.D. [0000-0003-1893-2626]