Pregnancy Reprograms the Epigenome of Mammary Epithelial Cells and Blocks the Development of Premalignant Lesions

Feigman, M.J., Moss, M.A., Chen, C., Cyrill, S.L., Cicone, M.F., Trousdell, M.C., Yang, S.-T., Frey, W.D., Wilkinson, J.E., Dos Santos, C. O. (May 2020) Pregnancy Reprograms the Epigenome of Mammary Epithelial Cells and Blocks the Development of Premalignant Lesions. Nat Commun, 11 (1). p. 2649. ISSN 2041-1723

[img] PDF
s41467-020-16479-z.pdf - Published Version

Download (4MB)
URL: https://pubmed.ncbi.nlm.nih.gov/32461571/
DOI: 10.1038/s41467-020-16479-z

Abstract

Pregnancy causes a series of cellular and molecular changes in mammary epithelial cells (MECs) of female adults. In addition, pregnancy can also modify the predisposition of rodent and human MECs to initiate oncogenesis. Here, we investigate how pregnancy reprograms enhancer chromatin in the mammary epithelium of mice and influences the transcriptional output of the oncogenic transcription factor cMYC. We find that pregnancy induces an expansion of the active cis-regulatory landscape of MECs, which influences the activation of pregnancy-related programs during re-exposure to pregnancy hormones in vivo and in vitro. Using inducible cMYC overexpression, we demonstrate that post-pregnancy MECs are resistant to the downstream molecular programs induced by cMYC, a response that blunts carcinoma initiation, but does not perturb the normal pregnancy-induced epigenomic landscape. cMYC overexpression drives post-pregnancy MECs into a senescence-like state, and perturbations of this state increase malignant phenotypic changes. Taken together, our findings provide further insight into the cell-autonomous signals in post-pregnancy MECs that underpin the regulation of gene expression, cellular activation, and resistance to malignant development.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > Myc
diseases & disorders > cancer > cancer types > breast cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > cis-regulatory elements
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cells
organs, tissues, organelles, cell types and functions > tissues types and functions > epithelium
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation
CSHL Authors:
Communities: CSHL labs > Dos Santos lab
CSHL Cancer Center Program > Cellular Communication in Cancer Program
Depositing User: Adrian Gomez
Date: 27 May 2020
Date Deposited: 01 Jun 2020 14:12
Last Modified: 26 Oct 2020 16:50
PMCID: PMC7253414
Related URLs:
URI: https://repository.cshl.edu/id/eprint/39485

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving