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

Pregnancy 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.