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.

C/EBPα mediates the growth inhibitory effect of progestins on breast cancer cells / Nacht, A. S.; Ferrari, Roberto; Zaurin, R.; Scabia, V.; Carbonell-Caballero, J.; Le Dily, F.; Quilez, J.; Leopoldi, A.; Brisken, C.; Beato, M.; Vicent, G. P.. - In: EMBO JOURNAL. - ISSN 0261-4189. - 38:18(2019), p. e101426. [10.15252/embj.2018101426]

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

Ferrari Roberto;
2019

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.
C/EBPα mediates the growth inhibitory effect of progestins on breast cancer cells / Nacht, A. S.; Ferrari, Roberto; Zaurin, R.; Scabia, V.; Carbonell-Caballero, J.; Le Dily, F.; Quilez, J.; Leopoldi, A.; Brisken, C.; Beato, M.; Vicent, G. P.. - In: EMBO JOURNAL. - ISSN 0261-4189. - 38:18(2019), p. e101426. [10.15252/embj.2018101426]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2874934
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