Pregnancy reprograms the enhancer landscape of mammary epithelial cells and alters the response to cMYC-driven oncogenesis

AbstractPregnancy leaves a series of cellular and molecular modifications on mammary epithelial cells (MECs). Pregnancy is also known for decreasing the predisposition of rodent and human MECs to oncogenesis. Here, in order to understand the molecular basis for this effect, we analyzed epigenetic changes in the enhancer landscape of murine post-pregnancy MECs, together with their effect on gene regulation, tissue development and oncogenesis. Using in vivo and in vitro analyses, we found that completion of a pregnancy cycle changed the dynamics of cellular proliferation and gene expression in response to a second pregnancy. Our results also demonstrated that post-pregnancy MECs are resistant to the initial molecular programs driven by cMYC overexpression, a response that blocked MEC proliferation but did not perturb the pregnancy-induced epigenomic landscape. Overall, our findings suggest that pregnancy-induced mammary cancer prevention involves the epigenomic changes in MECs brought about by pregnancy.

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A Dual Role for Oncostatin M Signaling in the Differentiation and Death of Mammary Epithelial Cells in Vivo

Molecular Endocrinology ◽

10.1210/me.2008-0097 ◽

2008 ◽

Vol 22 (12) ◽

pp. 2677-2688 ◽

Cited By ~ 45

Author(s):

Paul G. Tiffen ◽

Nader Omidvar ◽

Nuria Marquez-Almuina ◽

Dawn Croston ◽

Christine J. Watson ◽

...

Keyword(s):

Gene Expression ◽

Epithelial Cell ◽

Epithelial Cells ◽

Mammary Epithelial Cells ◽

Mammary Epithelial ◽

Oncostatin M ◽

Specific Gene ◽

Mammary Involution

Abstract Recent studies in breast cancer cell lines have shown that oncostatin M (OSM) not only inhibits proliferation but also promotes cell detachment and enhances cell motility. In this study, we have looked at the role of OSM signaling in nontransformed mouse mammary epithelial cells in vitro using the KIM-2 mammary epithelial cell line and in vivo using OSM receptor (OSMR)-deficient mice. OSM and its receptor were up-regulated approximately 2 d after the onset of postlactational mammary regression, in response to leukemia inhibitory factor (LIF)-induced signal transducer and activator of transcription-3 (STAT3). This resulted in sustained STAT3 activity, increased epithelial apoptosis, and enhanced clearance of epithelial structures during the remodeling phase of mammary involution. Concurrently, OSM signaling precipitated the dephosphorylation of STAT5 and repressed expression of the milk protein genes β-casein and whey acidic protein (WAP). Similarly, during pregnancy, OSM signaling suppressed β-casein and WAP gene expression. In vitro, OSM but not LIF persistently down-regulated phosphorylated (p)-STAT5, even in the continued presence of prolactin. OSM also promoted the expression of metalloproteinases MMP3, MMP12, and MMP14, which, in vitro, were responsible for OSM-specific apoptosis. Thus, the sequential activation of IL-6-related cytokines during mammary involution culminates in an OSM-dependent repression of epithelial-specific gene expression and the potentiation of epithelial cell extinction mediated, at least in part, by the reciprocal regulation of p-STAT5 and p-STAT3.

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