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

Cancer 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 factor Bcl11b, loss of which accelerated mammary ageing with enhanced DMBA-induced tumor formation. We identified a drug TPCA-1 that can elevate Bcl11b, 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.