C/EBPα mediates the growth inhibitory effect of progestins on breast cancer cells. (2nd August 2019)

• Record Type: Journal Article
• Authors: Nacht, A Silvina; Ferrari, Roberto; Zaurin, Roser; Scabia, Valentina; Carbonell‐Caballero, José; Le Dily, Francois; Quilez, Javier; Leopoldi, Alexandra; Brisken, Cathrin; Beato, Miguel; Vicent, Guillermo P
• Is Part Of: EMBO journal. Volume 38:Number 18(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-08-02
• Subjects: breast cancer -- C/EBPα -- cell proliferation -- hormone‐dependent gene regulation -- progesterone receptor; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2018101426
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: Steroid hormones, such as progestins, control proliferation of breast cancer cells via their intracellular receptors. Here, the transcription factor C/EBPα is shown to facilitate open chromatin conformation and loading of ligand‐activated progesterone receptor (PR) at key cell cycle genes, revealing functional crosstalk between PR and C/EBPα in repression of hormone‐dependent cancer growth. Progestins increase C/EBPα expression in human breast cancer cells. C/EBPα enhances progesterone‐induced growth inhibition in vitro and delays tumorigenesis in vivo . C/EBPα occupies around 1, 000 active enhancer regions and maintains chromatin accessibility prior to PR binding. C/EBPα exerts this function by establishing chromatin loops with architectural proteins (such as YY1), mediator and the cohesin complex. Abstract : C/EBPα acts as a tumor suppressor in hormone‐dependent breast cancer by facilitating chromatin accessibility and progesterone receptor loading at key cell cycle genes.