Award Number : W 81 XWH - 11 - 1 - 0128 TITLE : Why are breast cancer stem cells resistant to radiation ?

There are contradictory observations about the different radiosensitivities of cancer stem cells and cancer non-stem cells. To resolve these contradictory observations, we studied radiosensitivities by employing breast cancer stem cell (CSC)-like MDAMB231 and MDA-MB453 cells as well as their corresponding non-stem cells. CSC-like cells proliferate without differentiating and have characteristics of tumor-initiating cells [1]. These cells were exposed to c-rays (1.25–8.75 Gy) and survival curves were determined by colony formation. A final slope, D0, of the survival curve for each cell line was determined to measure radiosensitivity. The D0 of CSC-like and non-stem MDA-MB-453 cells were 1.16 Gy and 1.55 Gy, respectively. Similar results were observed in MDA-MB-231 cells (0.94 Gy vs. 1.56 Gy). After determination of radiosensitivity, we investigated intrinsic cellular determinants which influence radiosensitivity including cell cycle distribution, free-radical scavengers and DNA repair. We observed that even though cell cycle status and antioxidant content may contribute to differential radiosensitivity, differential DNA repair capacity may be a greater determinant of radiosensitivity. Unlike non-stem cells, CSC-like cells have little/no sublethal damage repair, a low intracellular level of ataxia telangiectasia mutated (ATM) and delay of c-H2AX foci removal (DNA strand break repair). These results suggest that low DNA repair capacity is responsible for the high radiosensitivity of these CSC-like cells. Citation: Kim S-Y, Rhee JG, Song X, Prochownik EV, Spitz DR, et al. (2012) Breast Cancer Stem Cell-Like Cells Are More Sensitive to Ionizing Radiation than NonStem Cells: Role of ATM. PLoS ONE 7(11): e50423. doi:10.1371/journal.pone.0050423 Editor: Brendan D. Price, Dana-Farber/Harvard Cancer Institute, United States of America Received June 28, 2012; Accepted October 23, 2012; Published November 21, 2012 Copyright: 2012 Kim et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the following grants: United States National Institutes of Health (NIH) R01 CA140554 (YJL), DOD Breast Cancer Program BC103217 (YJL & EVP), NIH P30 CA086862 (DRS) and NIH R01CA133114 (DRS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected]