Progressive Senescence Programs Induce Intrinsic Vulnerability to Aging-related Breast Cancer

Abstract

SUMMARYCancer incidence escalates exponentially with advancing age; however, the underlying mechanism remains unclear. In this study, we built a chronological molecular clock at the single-cell transcription level with a mammary stem cell-enriched population to depict physiological aging dynamics in mice. We found that the mammary aging process was asynchronous and progressive, initiated by an early senescence program with elevated NF-kB and P53 signaling, succeeded by an entropic late senescence program with reduced NF-kB and P53 signaling and enhanced PI3K-Akt-mTOR, Wnt, Notch and pluripotent activity, vulnerable to cancer predisposition. The transition towards senescence program was governed by the master stem cell factorBcl11b, loss of which accelerated mammary ageing with enhanced DMBA-induced tumor formation. We identified a drug TPCA-1 that can elevateBcl11b, rejuvenate mammary cells and significantly reduce aging-related cancer incidence. Our findings established a molecular portrait of progressive mammary cell aging and elucidated the transcriptional regulatory network bridging mammary aging and cancer predisposition, which can be modulated to control cancer initiation; therefore, this study has potential implications for the management of cancer prevalence in the aged.