期刊
STEM CELL REPORTS
卷 5, 期 3, 页码 378-391出版社
CELL PRESS
DOI: 10.1016/j.stemcr.2015.07.009
关键词
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资金
- NIH/NCI [CA148761, CA142898]
- NIH [P30 AI036211, P30 CA125123, S10 RR024574]
- Cancer Prevention and Research Institute of Texas Proteomics and Metabolomics Core Facility Support Award [RP120092]
- NCI Cancer Center Support Grant [P30CA125123]
Adult stem cells and tumor-initiating cells (TICs) often employ different mechanisms of DNA damage response (DDR) as compared to other tissue cell types. However, little is known about how mammary stem cells (MaSCs) and mammary TICs respond to DNA damage. Using the mouse mammary gland and syngeneic p53-null tumors as models, we investigated the molecular and physiological consequences of DNA damage in wild-type MaSCs, p53-null MaSCs, and p53-null TICs. We showed that wild-type MaSCs and basal cells are more resistant to apoptosis and exhibit increased non-homologous end joining (NHEJ) activity. Loss of p53 in mammary epithelium affected both cell-cycle regulation and DNA repair efficiency. In p53-null tumors, we showed that TICs are more resistant to ionizing radiation (IR) due to decreased apoptosis, elevated NHEJ activity, and more-rapid DNA repair. These results have important implications for understanding DDR mechanisms involved in both tumorigenesis and therapy resistance.
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