Mammary Stem Cells and Tumor-Initiating Cells Are More Resistant to Apoptosis and Exhibit Increased DNA Repair Activity in Response to DNA Damage

Stem Cell Reports. 2015 Sep 8;5(3):378-91. doi: 10.1016/j.stemcr.2015.07.009. Epub 2015 Aug 20.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • DNA Damage*
  • DNA Repair*
  • Female
  • Mammary Glands, Animal / metabolism*
  • Mammary Glands, Animal / pathology
  • Mammary Neoplasms, Animal / metabolism*
  • Mammary Neoplasms, Animal / pathology
  • Mice
  • Mice, Inbred BALB C
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology