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During the lifetime of females, mammary epithelial cells undergo cyclical expansion and proliferation depending on the cyclical activation of mammary gland stem/progenitor cells (MaSCs) in response to the change of hormone level. The structural shrink of mammary duct tree and the functional loss of mammary gland occur along with inactivation of MaSCs in old females, even leading to breast cancer occasionally. However, the gene expression signature in MaSCs across the lifespan remains unclear. Herein, we tested the tissue regeneration ability of CD24 + CD49f high  MaSCs over six time points from neonatal (4-day-old) to aged mice (360-day-old). Further RNA-seq analyses identified four clusters of gene signatures based on the gene expression patterns. A subset of stemness-related genes was identified, showing the highest level at day 4 of the neonatal age, and the lowest level at the old age. We also identified an aging-related gene signature showing significant change in the old mice, in which an association between aging process and stemness loss was indicated. The aging-related gene signature showed regulation of cancer signaling pathways, as well as aging-related diseases including Huntington disease, Parkinson disease, and Alzheimer disease. Moreover, 425, 1056, 418, and 1107 gene variants were identified at D20, D40, D90, and D180, respectively, which were mostly reported to associated with tumorigenesis and metastasis in cancer. In summary, the current study is the first to demonstrate the gene expression shift in MaSCs from neonatal to aging, which leads to stemness loss, aging, aging-related diseases, and even breast cancer in old mice.

Evolution of gene expression signature in mammary gland stem cells from neonatal to old mice