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

• Published in: The EMBO journal Vol. 38; no. 18; pp. e101426 - n/a
• Main 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
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 16.09.2019; John Wiley and Sons Inc
• Subjects: Animals; Binding; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; C/EBPα; CCAAT-Enhancer-Binding Proteins - genetics; CCAAT-Enhancer-Binding Proteins - metabolism; Cell cycle; Cell Cycle Proteins - metabolism; Cell growth; Cell Line, Tumor; Cell proliferation; Chromatin; Cohesin; Conformation; Crosstalk; DNA-Binding Proteins - metabolism; Enhancer Elements, Genetic; Enhancers; Epigenesis, Genetic; Estrogens; Female; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Gene regulation; Genes; Genomes; Hormones; hormone‐dependent gene regulation; Humans; Ligands; MCF-7 Cells; Menopause; Mice; Neoplasm Transplantation; Progesterone; progesterone receptor; Progestin; Progestins - pharmacology; Promoter Regions, Genetic; Proteins; Receptors; Receptors, Progesterone - metabolism; Steroid hormones; Steroids; Tumorigenesis; Xenograft Model Antitumor Assays; YY1 Transcription Factor - metabolism; C/EBPα; breast cancer; hormone-dependent gene regulation; cell proliferation; progesterone receptor
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.2018101426

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. 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.