Progesterone receptor modulates ERα action in breast cancer

Hisham Mohammed, I. Alasdair Russell, Rory Stark, Oscar M. Rueda, Theresa E. Hickey, Gerard A. Tarulli, Aurelien A. Serandour, Stephen N. Birrell, Alejandra Bruna, Amel Saadi, Suraj Menon, James Hadfield, Michelle Pugh, Ganesh V. Raj, Gordon D. Brown, Clive D’Santos, Jessica L. L. Robinson, Grace Silva, Rosalind Launchbury, Charles M. Perou, John Stingl, Carlos Caldas, Wayne D. Tilley () and Jason S. Carroll ()
Additional contact information
Hisham Mohammed: Cancer Research UK Cambridge Institute, University of Cambridge
I. Alasdair Russell: Cancer Research UK Cambridge Institute, University of Cambridge
Rory Stark: Cancer Research UK Cambridge Institute, University of Cambridge
Oscar M. Rueda: Cancer Research UK Cambridge Institute, University of Cambridge
Theresa E. Hickey: Dame Roma Mitchell Cancer Research Laboratories and the Adelaide Prostate Cancer Research Centre, School of Medicine, Hanson Institute Building, University of Adelaide
Gerard A. Tarulli: Dame Roma Mitchell Cancer Research Laboratories and the Adelaide Prostate Cancer Research Centre, School of Medicine, Hanson Institute Building, University of Adelaide
Aurelien A. Serandour: Cancer Research UK Cambridge Institute, University of Cambridge
Stephen N. Birrell: Dame Roma Mitchell Cancer Research Laboratories and the Adelaide Prostate Cancer Research Centre, School of Medicine, Hanson Institute Building, University of Adelaide
Alejandra Bruna: Cancer Research UK Cambridge Institute, University of Cambridge
Amel Saadi: Cancer Research UK Cambridge Institute, University of Cambridge
Suraj Menon: Cancer Research UK Cambridge Institute, University of Cambridge
James Hadfield: Cancer Research UK Cambridge Institute, University of Cambridge
Michelle Pugh: Cancer Research UK Cambridge Institute, University of Cambridge
Ganesh V. Raj: University of Texas, Southwestern Medical Center at Dallas
Gordon D. Brown: Cancer Research UK Cambridge Institute, University of Cambridge
Clive D’Santos: Cancer Research UK Cambridge Institute, University of Cambridge
Jessica L. L. Robinson: Cancer Research UK Cambridge Institute, University of Cambridge
Grace Silva: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Rosalind Launchbury: Cancer Research UK Cambridge Institute, University of Cambridge
Charles M. Perou: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
John Stingl: Cancer Research UK Cambridge Institute, University of Cambridge
Carlos Caldas: Cancer Research UK Cambridge Institute, University of Cambridge
Wayne D. Tilley: Dame Roma Mitchell Cancer Research Laboratories and the Adelaide Prostate Cancer Research Centre, School of Medicine, Hanson Institute Building, University of Adelaide
Jason S. Carroll: Cancer Research UK Cambridge Institute, University of Cambridge

Nature, 2015, vol. 523, issue 7560, 313-317

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature14583

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