Validation of the cell cycle G₂ delay assay in assessing ionizing radiation sensitivity and breast cancer risk

Original Research

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Authors: Jeff W Hill, Kristina Tansavatdi, Kristin L Lockett, Glenn O Allen, et al.

Published Date April 2009 Volume 2009:1 Pages 39 - 48

DOI: http://dx.doi.org/10.2147/CMAR.S4548

Jeff W Hill¹, Kristina Tansavatdi⁴, Kristin L Lockett⁴, Glenn O Allen¹, Cristiane Takita², Alan Pollack², Jennifer J Hu^1,3

¹Sylvester Comprehensive Cancer Center, ²Department of Radiation Oncology, ³Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, FL, USA; ⁴Department of Cancer Biology, Wake Forest University Health Sciences, Winston-Salem, NC, USA

Abstract: Genetic variations in cell cycle checkpoints and DNA repair genes are associated with prolonged cell cycle G₂ delay following ionizing radiation (IR) treatment and breast cancer risk. However, different studies reported conflicting results examining the association between post-IR cell cycle delay and breast cancer risk utilizing four different parameters: cell cycle G₂ delay index, %G₂–M, G₂/G₀–G₁, and (G₂/G₀–G₁)/S. Therefore, we evaluated whether different parameters may influence study results using a data set from 118 breast cancer cases and 225 controls as well as lymphoblastoid and breast cancer cell lines with different genetic defects. Our results suggest that cell cycle G₂ delay index may serve as the best parameter in assessing breast cancer risk, genetic regulation of IR-sensitivity, and mutations of ataxia telangiectasia mutated (ATM) and TP53. Cell cycle delay in 21 lymphoblastoid cell lines derived from BRCA1 mutation carriers was not different from that in controls. We also showed that IR-induced DNA-damage signaling, as measured by phosphorylation of H2AX on serine 139 (γ-H2AX) was inversely associated with cell cycle G2 delay index. In summary, the cellular responses to IR are extremely complex; mutations or genetic variations in DNA damage signaling, cell cycle checkpoints, and DNA repair contribute to cell cycle G₂ delay and breast cancer risk. The cell cycle G₂ delay assay characterized in this study may help identify subpopulations with elevated risk of breast cancer or susceptibility to adverse effects in normal tissue following radiotherapy.

Keywords: breast cancer, ionizing radiation sensitivity, cell cycle, G₂ delay, radiotherapy

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