Progesterone receptor modulates ERα action in breast cancer

Nature. 2015 Jul 16;523(7560):313-7. doi: 10.1038/nature14583. Epub 2015 Jul 8.

Abstract

Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited oestrogen-mediated growth of ERα(+) cell line xenografts and primary ERα(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ERα(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.

Publication types

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

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromatin / drug effects
  • Chromatin / genetics
  • Chromatin / metabolism
  • DNA Copy Number Variations / genetics
  • Disease Progression
  • Estrogen Receptor alpha / antagonists & inhibitors
  • Estrogen Receptor alpha / metabolism*
  • Estrogens / metabolism
  • Estrogens / pharmacology
  • Female
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Humans
  • Ligands
  • Mice
  • Progesterone / metabolism
  • Progesterone / pharmacology
  • Protein Binding / drug effects
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism*
  • Transcription, Genetic / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Chromatin
  • Estrogen Receptor alpha
  • Estrogens
  • Ligands
  • Receptors, Progesterone
  • estrogen receptor alpha, human
  • Progesterone

Associated data

  • GEO/GSE68359