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

Nat Med. 2021 Feb;27(2):310-320. doi: 10.1038/s41591-020-01168-7. Epub 2021 Jan 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / pharmacology*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 6 / genetics
  • Estrogen Receptor alpha / genetics*
  • Female
  • Humans
  • MCF-7 Cells
  • Nuclear Receptor Coactivator 3 / genetics
  • Receptors, Androgen / drug effects
  • Receptors, Androgen / genetics*
  • Signal Transduction / drug effects

Substances

  • AR protein, human
  • Androgens
  • Estrogen Receptor alpha
  • Receptors, Androgen
  • NCOA3 protein, human
  • Nuclear Receptor Coactivator 3
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6