Induction of Senescence During Postpartum Mammary Gland Involution supports tissue remodeling and promotes postpartum tumorigenesis

Cellular senescence is an evolutionarily conserved stress response which contributes to tissue repair and tumor suppression, yet its accumulation is also linked to aging and disease. Whether physiological senescence can be exploited by oncogenic events to promote tumorigenesis is unknown. Postpartum mammary gland involution is a major adult tissue-remodeling event, resembling wound healing, and is closely associated with postpartum breast cancer (PPBC). Here, we show that during mammary gland involution in mice, a p16-dependent senescence response is induced in alveolar luminal cells. Eliminating senescent cells disrupts tissue remodeling and delays involution, demonstrating their physiological importance. However, in a PPBC model where oncogenic activation coincides with involution, removing involution-associated senescent cells extended tumor latency. Mechanistically, senescent cells enhance tumor cell plasticity via the senescence-associated secretory phenotype (SASP), fostering metastasis. Our findings reveal that senescence, while required for postpartum tissue remodelling, can be hijacked to facilitate tumorigenesis, defining senescence as a unifying mechanism linking tissue repair to tumorigenesis. Overall design: Bulk RNAseq data include mammary gland from wild type females at different involution timepoints (Inv0, Inv1, Inv3, Inv7)