title: Topoisomerase IIα levels and G2 radiosensitivity in T-lymphocytes of women presenting with breast cancer.
abstract: Previous studies from our laboratory have identified a link between intracellular topoisomerase IIα (topo IIα) levels and chromosomal radiosensitivity, as measured by the frequencies of chromatid breaks in the so-called G2-assay. Lower topo IIα levels were associated with reduced chromosomal radiosensitivity in cultured human cells. These findings supported a model, in which it is proposed that such chromatid breaks are the result of radiation-induced errors made by topoisomerase IIα during decatenation of chromatids. Studies from our and other laboratories, using the G2-assay, have shown that phytohaemagglutinin (PHA)-stimulated peripheral blood T-lymphocytes from 40% of female breast cancer cases show elevated chromatid break frequencies when exposed to a small standard dose of ionizing radiation, i.e. elevated above the 90th percentile of a group of female control samples. In the present study we have used a modified G2-assay to test whether elevated frequency of chromatid breaks in breast cancer cases is linked with elevated intracellular topo IIα level in PHA-stimulated T-lymphocytes, and also whether there is a general correlation between chromosomal radiosensitivity and topo IIα level. Our results confirm previous studies that 40% of breast cancer cases show elevated radiosensitivity as compared with controls. Also, the mean chromatid break frequency in breast cancer cases was significantly higher than in controls (P = 0.0001). We found that the mean topo IIα level in the cohort of breast cancer cases studied was significantly raised, as compared with controls (P = 0.0016), which could indicate a genetic propensity towards a raised intracellular production of topo IIα in these individuals. There was no direct correlation between chromosomal radiosensitivity and topo IIα level for individual samples either in the breast cancer cohort or in controls. However, a comparison between control and breast cancer samples shows a higher mean topo IIα level in breast cancer samples that correlates with the elevated mean chromatid break frequency seen in these patient samples. We found no meaningful correlations between either chromatid break frequency or topo IIα level and either tumour grade or hormone status. We conclude that elevated intracellular topo IIα level is likely to be a significant factor in determining the chromosomal response of stimulated T-lymphocytes from certain breast cancer cases.
authors.affiliation: School of Medicine, University of St Andrews North Haugh, St Andrews KY16 9TF, UK. peb@st-and.ac.uk
authors.forename: Peter E
authors.initials: PE
authors.lastname: Bryant
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Riches
authors.forename: Olga
authors.initials: O
authors.lastname: Shovman
authors.forename: John A
authors.initials: JA
authors.lastname: Dewar
authors.forename: Douglas J A
authors.initials: DJ
authors.lastname: Adamson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000032:analysis*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002842:Chromatids / Q000235:genetics; D002877:Chromosomes, Human; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000032:analysis*; D004268:DNA-Binding Proteins / Q000032:analysis*; D005260:Female; D006801:Humans; D008875:Middle Aged; D011836:Radiation Tolerance / Q000235:genetics*; D011839:Radiation, Ionizing; D013601:T-Lymphocytes / Q000378:metabolism / Q000528:radiation effects*
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D004250:DNA Topoisomerases, Type II