C/EBPα mediates the growth inhibitory effect of progestins on breast cancer cells

Nacht, A. Silvina; Ferrari, Roberto; Zaurín Quer, Roser; Scabia, Valentina; Carbonell-Caballero, Jose; Le Dily, François; Quilez Oliete, Javier; Leopoldi, Alexandra; Brisken, Cathrin; Beato, Miguel; Vicent, Guillermo Pablo

doi:http://dx.doi.org/10.15252/embj.2018101426

C/EBPα mediates the growth inhibitory effect of progestins on breast cancer cells

Citation

Nacht, A S, Ferrari R, Zaurin R, Sacabia V, Carbonell-Caballero J, Le Dily F et al. C/EBPα mediates the growth inhibitory effect of progestins on breast cancer cells. EMBO J. 2019;38(18):e101426. DOI: 10.15252/embj.2018101426

Abstract

Steroid hormones are key gene regulators in breast cancer cells. While estrogens stimulate cell proliferation, progestins activate a single cell cycle followed by proliferation arrest. Here, we use biochemical and genome-wide approaches to show that progestins achieve this effect via a functional crosstalk with C/EBPα. Using ChIP-seq, we identify around 1,000 sites where C/EBPα binding precedes and helps binding of progesterone receptor (PR) in response to hormone. These regions exhibit epigenetic marks of active enhancers, and C/EBPα maintains an open chromatin conformation that facilitates loading of ligand-activated PR. Prior to hormone exposure, C/EBPα favors promoter-enhancer contacts that assure hormonal regulation of key genes involved in cell proliferation by facilitating binding of RAD21, YY1, and the Mediator complex. Knockdown of C/EBPα disrupts enhancer-promoter contacts and decreases the presence of these architectural proteins, highlighting its key role in 3D chromatin looping. Thus, C/EBPα fulfills a previously unknown function as a potential growth modulator in hormone-dependent breast cancer.