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

The EMBO Journal
A Silvina NachtGuillermo P Vicent

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.

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Citations

May 21, 2020·Breast Cancer Research : BCR·Henri-Philippe KonanMuriel Le Romancer
Aug 17, 2020·International Journal of Molecular Sciences·Charu KothariFrancine Durocher
Jan 17, 2021·Protein & Cell·Yuliang FengSiim Pauklin
May 13, 2021·Genome Biology·Chia-Chi Flora HuangNathan A Lack

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