C/EBPa crosstalks with progesterone receptor to control hormone-dependent cell growth in breast cancer cells

Trabajo presentado en la IX Jornada de Cromatina i Epigenètica, organizada por la Secció de Cromatina i Epigenètica de la Societat Catalana de Biologia (SCB) y celebrada en Barcelona el 22 de marzo de 2019.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/EBP¿. Using ChIP-seq, we identify around 1,000 sites where C/EBP¿ binding precedes and helps binding of Progesterone Receptor (PR) in response to hormone. These regions exhibit epigenetic marks of active enhancers and C/EBP¿ maintains an open chromatin conformation that facilitates loading of ligand activated PR. Prior to hormone exposure, C/EBP¿ 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/EBP¿ disrupts enhancer-promoter contacts and decreases the presence of these architectural proteins, highlighting its key role in 3D chromatin looping. Thus, C/EBP¿ fulfills a previously unknown function as a potential growth modulator in hormone-dependent breast cancer