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 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. PerouJohn Stingl, Carlos Caldas, Wayne D. Tilley, Jason S. Carroll

Research output: Contribution to journalArticle

260 Scopus citations

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<sup>+</sup> cell line xenografts and primary ERα<sup>+</sup> 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<sup>+</sup> 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.

Original languageEnglish (US)
Pages (from-to)313-317
Number of pages5
JournalNature
Volume523
Issue number7560
DOIs
StatePublished - Jul 16 2015

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    Mohammed, H., Russell, I. A., Stark, R., Rueda, O. M., Hickey, T. E., Tarulli, G. A., Serandour, A. A. A., Birrell, S. N., Bruna, A., Saadi, A., Menon, S., Hadfield, J., Pugh, M., Raj, G. V., Brown, G. D., D'Santos, C., Robinson, J. L. L., Silva, G., Launchbury, R., ... Carroll, J. S. (2015). Progesterone receptor modulates ERα action in breast cancer. Nature, 523(7560), 313-317. https://doi.org/10.1038/nature14583