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

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/EBPa. Using ChIP-seq, we identify around 1,000 sites where C/EBPa binding precedes and helps binding of Progesterone Receptor (PR) in response to hormone. These regions exhibit epigenetic marks of active enhancers and C/EBPa maintains an open chromatin conformation that facilitates loading of ligand activated PR. Prior to hormone exposure, C/EBPa 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/EBPa disrupts enhancer-promoter contacts and decreases the presence of these architectural proteins, highlighting its key role in 3D chromatin looping. Thus, C/EBPa fulfills a previously unknown function as a potential growth modulator in hormone-dependent breast cancer. Overall design: Examination of progesterone receptor, Topo2a and C/EBPa binding in T47D breast cancer cell line. Effect of Topo2a inhibition in hormone-dependent gene regulation.