Progressive senescence programs induce intrinsic vulnerability to aging-related female breast cancer

Huiru Bai, Xiaoqin Liu, Meizhen Lin, Yuan Meng, Ruolan Tang, Yajing Guo, Nan Li, Michael F. Clarke and Shang Cai ()
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Huiru Bai: Westlake Laboratory of Life Sciences and Biomedicine
Xiaoqin Liu: Westlake Laboratory of Life Sciences and Biomedicine
Meizhen Lin: Westlake Laboratory of Life Sciences and Biomedicine
Yuan Meng: Westlake Laboratory of Life Sciences and Biomedicine
Ruolan Tang: Westlake Laboratory of Life Sciences and Biomedicine
Yajing Guo: Westlake Laboratory of Life Sciences and Biomedicine
Nan Li: Westlake University
Michael F. Clarke: Stanford University
Shang Cai: Westlake Laboratory of Life Sciences and Biomedicine

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Cancer incidence escalates exponentially with advancing age; however, the underlying mechanism remains unclear. In this study, we build a chronological molecular clock at single-cell transcription level with a mammary stem cell-enriched population to depict physiological aging dynamics in female mice. We find that the mammary aging process is asynchronous and progressive, initiated by an early senescence program, succeeded by an entropic late senescence program with elevated cancer associated pathways, vulnerable to cancer predisposition. The transition towards senescence program is governed by a stem cell factor Bcl11b, loss of which accelerates mammary ageing with enhanced DMBA-induced tumor formation. We have identified a drug TPCA-1 that can rejuvenate mammary cells and significantly reduce aging-related cancer incidence. Our findings establish a molecular portrait of progressive mammary cell aging and elucidate the transcriptional regulatory network bridging mammary aging and cancer predisposition, which has potential implications for the management of cancer prevalence in the aged.

Date: 2024
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DOI: 10.1038/s41467-024-49106-2

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