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

Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE

Original Publication: [London] : Nature Pub. Group

Cellular Senescence* ; Aging* ; Breast Neoplasms*/pathology ; Breast Neoplasms*/metabolism ; Breast Neoplasms*/genetics; Female ; Animals ; Mice ; Humans ; Mammary Glands, Animal/pathology ; Mammary Glands, Animal/metabolism ; Stem Cells/metabolism

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.
(© 2024. The Author(s).)

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32170803 National Natural Science Foundation of China (National Science Foundation of China); 81872405 National Natural Science Foundation of China (National Science Foundation of China)

Date Created: 20240617 Date Completed: 20240617 Latest Revision: 20240620

20240620

PMC11183265

10.1038/s41467-024-49106-2

38886378