C/EBPα mediates the growth inhibitory effect of progestins on breast cancer cells.
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Date
2019-09-16ICR Author
Author
Nacht, AS
Ferrari, R
Zaurin, R
Scabia, V
Carbonell-Caballero, J
Le Dily, F
Quilez, J
Leopoldi, A
Brisken, C
Beato, M
Vicent, GP
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Cell Line, Tumor
Animals
Humans
Mice
Breast Neoplasms
Cell Cycle Proteins
DNA-Binding Proteins
CCAAT-Enhancer-Binding Proteins
Receptors, Progesterone
Progestins
Xenograft Model Antitumor Assays
Neoplasm Transplantation
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Female
YY1 Transcription Factor
Enhancer Elements, Genetic
Promoter Regions, Genetic
Gene Knockdown Techniques
MCF-7 Cells
Research team
Endocrine control mechanisms
Language
eng
Date accepted
2019-06-24
License start date
2019-09
Citation
The EMBO journal, 2019, 38 (18), pp. e101426 - ?
Publisher
WILEY