Journal Article

Progesterone receptor modulates ERα action in breast cancer

Mohammed, Hisham, Tilley, Wayne D., Russell, I. Alasdair, Stark, Rory, Silva, Grace, Launchbury, Rosalind, Menon, Suraj, Brown, Gordon D., Birrell, Stephen N., Bruna, Alejandra, Rueda, Oscar M., Raj, Ganesh V., D’Santos, Clive, Robinson, Jessica L. L., Serandour, Aurelien A., Hickey, Theresa E., Carroll, Jason S., Pugh, Michelle, Tarulli, Gerard A., Perou, Charles M., Saadi, Amel, Stingl, John, Caldas, Carlos, Hadfield, James

2015

Overview

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. Progesterones, oestrogens and their receptors (PR, ERα and ERβ) are essential in normal breast development and homeostasis, as well as in breast cancer; here it is shown that PR controls ERα function by redirecting where ERα binds to the chromatin, acting as a proliferative brake in ERα + breast tumours. Steroid receptor crosstalk in breast cancer Progesterones and their receptor (PR) and oestrogens and their receptors (ERα and ERβ) play crucial roles in normal breast development and homeostasis, as well as in breast cancer, where the presence of these receptors has been used as a prognostic marker of whether breast cancers will respond to ER receptor antagonists. The relationship between their functions has not been entirely clear, and now Jason Carroll and colleagues reveal a key piece of the puzzle by showing that the PR controls ERα function. By re-directing where ERα binds to chromatin, it acts as a proliferative brake in ERα + breast tumours. Accordingly, loss of the PGR gene, which encodes the PR, is associated with poorer outcome in breast cancer patients.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 38/39 / 45/15 / 631/67/1347 / 82/80 / Analysis / 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 / Disease Progression / DNA Copy Number Variations - genetics / Estrogen Receptor alpha - antagonists & inhibitors / Estrogen Receptor alpha - metabolism / Estrogens - metabolism / Estrogens - pharmacology / Female / Gene Expression Regulation, Neoplastic - drug effects / Humanities and Social Sciences / Humans / Ligands / Mice / multidisciplinary / Progesterone - metabolism / Progesterone - pharmacology / Protein Binding - drug effects / Receptors, Progesterone - genetics / Receptors, Progesterone - metabolism / Science / Transcription, Genetic - drug effects / Xenograft Model Antitumor Assays