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

Cellular senescence is an evolutionarily conserved stress response ¹ , yet its roles during physiological processes remain underexplored ^2,3 . Senescent cells are known to promote tissue repair ^4,5 and suppress tumorigenesis ⁶ , but their accumulation contributes to various pathological and physiological processes, including cancer and ageing ^7–9 . However, it is currently unknown whether physiological senescence can be co-opted by oncogenic events to promote tumorigenesis. Postpartum mammary gland involution is a major tissue remodelling event in adulthood ^10,11 , resembling the wound healing process, and is closely linked to postpartum breast cancer (PPBC) ¹² providing a compelling context to investigate this question. Here, we show that senescence is induced in alveolar luminal cells during involution in a p16-dependent manner. Reducing senescent cells hinders tissue remodeling and delays involution, underscoring their physiological importance. However, using a PPBC mouse model where the oncogenic event coincides with involution, we demonstrate that eliminating involution-associated senescent cells markedly extended the cancer latency. Mechanistically, we reveal that senescent cells enhance tumor-initiating cell plasticity in a paracrine manner, promoting tumor invasion and metastasis. Collectively, our findings uncover a dual role of senescence in mediating postpartum tissue remodeling and promoting tumorigenesis, highlighting a scenario where physiological senescence is hijacked to drive cancer progression. This work underscores that senescence might be a unifying mechanism linking tissue repair to tumorigenesis.