A senescent-immune reserve niche hypothesis for incomplete lobular involution in the aging breast

Abstract

Breast cancer incidence rises with age and peaks across the menopausal transition, yet why some postmenopausal lobules persist, and why that persistence predicts cancer risk, remains unresolved. Incomplete age-related lobular involution is one of the strongest tissue-level predictors of subsequent breast cancer, but it is still commonly viewed as passive failure of hormonally driven regression. This Review proposes a different framework: persistent lobules are maintained by an active reserve niche that outlasts its reproductive function. Recent human tissue studies show that persistent postmenopausal lobules retain a proliferation-competent epithelial state and that immune cells accumulate at the lobular boundary without being positioned to engage p16INK4a-positive epithelial foci; in a separate longitudinal cohort, senescence-linked programs reverse their association with involution pace across menopause. We integrate these findings with breast epidemiology and mammary stromal biology, and draw on reserve systems in skeletal muscle, hematopoiesis, and postmenopausal endometrium as sources of candidate mechanisms and testable predictions rather than as evidence for the breast. We argue that menopause is a biological control point at which tissue fate diverges, and that what distinguishes persistence from resolution is not the amount of inflammation present but whether immune effectors are spatially positioned to execute clearance. This shifts attention from epithelial quantity to microenvironmental state and identifies the perimenopausal window as a promising interval for biomarker-guided risk stratification and prevention.

Revised version following eLife peer review (eLife-RP-RV-2026-111667)