Progesterone Receptor Determines ERα Function

Expression of the progesterone receptor (PR, encoded by the PGR gene) is associated with response to endocrine therapy, decreased metastasis, and improved prognosis in patients with estrogen receptor α–positive (ERα⁺) breast cancer. Although PR is frequently used as a marker of active ERα signaling and both receptors have been shown to interact, whether there is functional cross-talk between PR and ERα is unknown. Mohammed and colleagues found that, in the presence of estrogen, progesterone stimulation triggered recruitment of PR to chromatin and interaction of PR with ERα and its cofactors in ERα⁺PR⁺ breast cancer cell lines. This progesterone-induced interaction resulted in a rapid and global redistribution of ERα chromatin binding to a distinct set of genes marked by binding of the coactivator p300 and harboring progesterone-responsive elements, suggesting that PR mediates this change in ERα binding and modifies ERα transcriptional activity. Indeed, ERα reprogramming in response to dual treatment with estrogen and progesterone resulted in an altered gene expression profile enriched in genes associated with cell death, apoptosis, and differentiation. Consistent with this finding, progesterone treatment decreased estrogen-induced proliferation and inhibited estrogen-driven ERα⁺ tumor growth in xenograft models and primary human ERα⁺PR⁺ breast tumor explants. Furthermore, dual treatment with the ERα antagonist tamoxifen and progesterone more effectively suppressed estrogen-stimulated tumor growth. Copy-number loss of the PGR locus was found to be a common event in ERα⁺ breast cancer, with heterozygous or homozygous PGR deletion occurring in 21% of patients, and was associated with poor clinical outcome in one third of patients with luminal B tumors and in a subset of patients with luminal A tumors. These results demonstrate a functional interplay between the ERα and PR steroid receptors and suggest that PR modulates ERα transcriptional activity under estrogenic conditions to block ERα⁺ breast cancer proliferation and tumorigenicity.

Mohammed H, Russell IA, Stark R, Rueda OM, Hickey TE, Tarulli GA, et al. Progesterone receptor modulates ERα action in breast cancer. Nature 2015;523:313–7.

Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.