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

Theresa E. Hickey, Luke A. Selth, Kee Ming Chia, Geraldine Laven-Law, Heloisa H. Milioli, Daniel Roden, Shalini Jindal, Mun Hui, Jessica Finlay-Schultz, Esmaeil Ebrahimie, Stephen N. Birrell, Suzan Stelloo, Richard Iggo, Sarah Alexandrou, C. Elizabeth Caldon, Tarek M. Abdel-Fatah, Ian O. Ellis, Wilbert Zwart, Carlo Palmieri, Carol A. SartoriusAlex Swarbrick, Elgene Lim, Jason S. Carroll, Wayne D. Tilley

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)310-320
Number of pages11
JournalNATURE MEDICINE
Volume27
Issue number2
DOIs
Publication statusPublished - Feb 2021
Externally publishedYes

Keywords

  • Breast cancer
  • Preclinical research

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