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Pregnancy reprograms the epigenome of mammary epithelial cells and blocks the development of premalignant lesions.

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.

SUBMITTER: Feigman MJ

PROVIDER: S-EPMC7253414 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Pregnancy reprograms the epigenome of mammary epithelial cells and blocks the development of premalignant lesions.

Feigman Mary J MJ Moss Matthew A MA Chen Chen C Cyrill Samantha L SL Ciccone Michael F MF Trousdell Marygrace C MC Yang Shih-Ting ST Frey Wesley D WD Wilkinson John E JE Dos Santos Camila O CO

Nature communications 20200527 1

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, wh ...[more]

PMID: 32461571

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Dataset Information

Pregnancy reprograms the epigenome of mammary epithelial cells and blocks the development of premalignant lesions.

Publications

Pregnancy reprograms the epigenome of mammary epithelial cells and blocks the development of premalignant lesions.

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