Progesterone receptor modulates ER[alpha] action in breast cancer.

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From: Nature(Vol. 523, Issue 7560)
Publisher: Nature Publishing Group
Document Type: Report
Length: 10,104 words
Lexile Measure: 1630L

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Abstract :

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].sup.+ cell line xenografts and primary ER[alpha].sup.+ 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].sup.+ 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. Progesterones, oestrogens and their receptors (PR, ER[alpha] and ER[beta]) are essential in normal breast development and homeostasis, as well as in breast cancer; here it is shown that PR controls ER[alpha] function by redirecting where ER[alpha] binds to the chromatin, acting as a proliferative brake in ER[alpha].sup.+ breast tumours. Steroid receptor crosstalk in breast cancer Progesterones and their receptor (PR) and oestrogens and their receptors (ER[alpha] and ER[beta]) 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 ER[alpha] function. By re-directing where ER[alpha] binds to chromatin, it acts as a proliferative brake in ER[alpha].sup.+ breast tumours. Accordingly, loss of the PGR gene, which encodes the PR, is associated with poorer outcome in breast cancer patients.

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Gale Document Number: GALE|A669908664