The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer
Date
2021
Authors
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.
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Journal article
Citation
Nature Medicine, 2021; 27(2):310-320
Statement of Responsibility
Theresa E. Hickey, Luke A. Selth, Kee Ming Chia, Geraldine Laven-Law, Heloisa H. Milioli, Daniel Roden ... et al.
Conference Name
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.
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© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.