Journal
NATURE
Volume 523, Issue 7560, Pages 313-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/nature14583
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Funding
- University of Cambridge
- Cancer Research UK
- Hutchison Whampoa Limited
- National Cancer Institute of National Institutes of Health [5P30CA142543]
- Department of Defense [W81XWH-12-1-0288-03]
- National Health and Medical Research Council of Australia [1008349, 1084416]
- Cancer Australia [627229]
- US Department of Defense Breast Cancer Research Program (BCRP) [W81XWH-11-1-0592]
- Royal Adelaide Hospital Research Foundation
- ERC
- EMBO Young investigator award
- Cancer Research UK [20411, 16942, 22310] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10154] Funding Source: researchfish
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Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-alpha (ER alpha) function and breast cancer prognosis. Here we show that PR is not merely an ER alpha-induced gene target, but is also an ER alpha-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ER alpha to direct ER alpha 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 ER alpha(+) cell line xenografts and primary ER alpha(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ER alpha antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ER alpha(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ER alpha chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.
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