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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)-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.

Type Journal
ISBN 1546-170X (Electronic) 1078-8956 (Linking)
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.; 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.; Swarbrick, A.; Lim, E.; Carroll, J. S.; Tilley, W. D.
Responsible Garvan Author Prof Elgene Lim
Publisher Name NATURE MEDICINE
Published Date 2021-02-28
Published Volume 27
Published Issue 2
Published Pages 310-320
Status Published in-print
DOI 10.1038/s41591-020-01168-7
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/33462444