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.