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Progesterone receptor modulates ERα action in breast cancer.


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Authors

Mohammed, Hisham 
Russell, I Alasdair 
Rueda, Oscar M 
Hickey, Theresa E 

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.

Description

Keywords

Animals, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Chromatin, DNA Copy Number Variations, Disease Progression, Estrogen Receptor alpha, Estrogens, Female, Gene Expression Regulation, Neoplastic, Humans, Ligands, Mice, Progesterone, Protein Binding, Receptors, Progesterone, Transcription, Genetic, Xenograft Model Antitumor Assays

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

523

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research Uk (None)
Cancer Research UK (CB4140)
Cancer Research UK (unknown)
Cancer Research UK (C507/A16278)
Cancer Research UK (unknown)
Cancer Research UK (60098573)
Cancer Research UK (unknown)
Department of Health (via National Institute for Health Research (NIHR)) (unknown)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Cancer Research Uk (None)
Cambridge University Hospitals NHS Foundation Trust (CUH) (RG51913)
Cancer Research UK (C14303/A17197)
European Research Council (242664)
We would like to acknowledge the support of the University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited. Research reported in this manuscript was supported by the National Cancer Institute of the National Institutes of Health under award number 5P30CA142543 (to UT Southwestern) and Department of Defense grants W81XWH-12-1-0288-03 (GVR). W.D.T. is supported by grants from the National Health and Medical Research Council of Australia (ID 1008349; ID 1084416) and Cancer Australia (ID 627229) T.E.H held a Fellowship Award from the US Department of Defense Breast Cancer Research Program (BCRP; #W81XWH-11-1-0592) and currently is supported by a Florey Fellowship from the Royal Adelaide Hospital Research Foundation. J.S.C is supported by an ERC starting grant and an EMBO Young investigator award.