1. Radiation clastogenesis and cell cycle checkpoint function as functional markers of breast cancer risk.
- Author
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Kaufmann WK, Filatov L, Oglesbee SE, Simpson DA, Lotano MA, McKeen HD, Sawyer LR, Moore DT, Millikan RC, Cordeiro-Stone M, and Carey LA
- Subjects
- Ataxia Telangiectasia Mutated Proteins, Breast Neoplasms genetics, Cell Cycle Proteins genetics, DNA-Binding Proteins genetics, Female, Genes, BRCA1, Genes, BRCA2, Genes, p53, Humans, Middle Aged, Protein Serine-Threonine Kinases genetics, Racial Groups, Risk Factors, Smoking, Tumor Suppressor Proteins genetics, Breast Neoplasms epidemiology, Cell Cycle genetics, Cell Cycle radiation effects, Mutation
- Abstract
Background: Familial breast cancer is associated with mutations in several genes (BRCA1, BRCA2, p53, ATM) whose protein products protect against radiation-induced genotoxicity. This study tested whether sporadic breast cancer was associated with constitutive radiation hypersensitivity., Methods: Blood lymphocytes and EBV-transformed lymphoblasts from patients with newly diagnosed breast cancer and controls without cancer were evaluated for ionizing radiation (IR)-induced chromosomal aberrations and cell cycle delays. Lymphoblasts from patients with ataxia telangiectasia (AT) and heterozygous AT carriers were tested as positive controls for radiation hypersensitivity., Results: Lymphoblasts from AT patients and AT carriers displayed G2-irradiation, chromosomal hypersensitivity (GICH). Irradiated G2 phase lymphocytes from breast cancer cases and controls displayed 3-fold inter-individual variation in frequencies of chromatid damage. However, the percentage of breast cancer cases with damage frequencies in excess of 2 SD of the control mean (8/102 or 8%) was not significantly elevated compared to controls (2/48 or 4%, P=0.5). Lymphoblasts sampled 24 h after 3 Gy of IR also varied in the ratios of cells with 4N and 2N DNA content (4N/2N ratio), as a measure of cell cycle checkpoint function. 4N/2N ratios in irradiated lymphoblasts were strongly correlated with the fractions of S phase cells in un-irradiated control cultures (Pearson's correlation coefficient, r=0.87). After normalization to S fraction, the radiation-induced increment in the 4N/2N ratio was significantly elevated in AT lymphoblasts but not in lymphoblasts from AT carriers. The fraction of breast cancer cases with reduced checkpoint function (2/45 or 4%) was equal to the control fraction (2/45 or 4%). For breast cancer cases and controls, GICH in primary lymphocytes was not associated with reduced cell cycle checkpoint function in lymphoblasts., Conclusion: Constitutive radiation hypersensitivity in blood lymphocytes and lymphoblasts was not a useful biomarker for identifying women at increased risk of breast cancer.
- Published
- 2006
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