Physiological DNA Damage Promotes Functional Polyploidization of Mammary Gland Alveolar Cells During Lactation

Lactation insufficiency affects many women worldwide. During lactation, a large portion of mammary alveolar cells become polyploid, but how these cells couple the hyperproliferation occurring during normal lactogenesis with terminal differentiation is unknown. Here, we find DNA damage accumulates due to replication stress during pregnancy, activating the ATR-DNA damage response pathway. Modulation of DNA damage levels in vivo by intraductal injections of nucleosides or DNA damaging agents demonstrates that the degree of DNA damage accumulated during pregnancy governs endoreplication and milk production. We identify a mechanism involving early mitotic arrest through CDK1 inactivation, resulting in a heterogeneous alveolar population with regards to ploidy and nuclei number. The inactivation of CDK1 is mediated by the DNA damage response kinase WEE1 with heterozygous loss of Wee1 resulting in decreased endoreplication and milk production. Thus, we propose the DNA damage response to replication stress couples proliferation and endoreplication during mammary gland alveologenesis. Our study sheds light on mechanisms governing lactogenesis and provides non-hormonal means for increasing milk production.