SENSITIVITY TO 4-HYDROXYESTRADIOL AND DNA REPAIR EFFICIENCY IN PERIPHERAL BLOOD LYMPHOCYTES OF ENDOMETRIAL CANCER PATIENTS

Abstract

The development of hormone-dependent cancers, including endometrial carcinomas, in great part may be mediated by the genotoxic effects of estrogen metabolites, among which 4-hydroxyestradiol (4OHE2) is characterized by the most prominent DNA-damaging properties. It is assumed that the individual sensitivity to the 4OHE2may determine the predisposition to endometrial cancer (EС). To analyze the sensitivity of peripheral blood lymphocytes (PBLs) of EC patients to the 4OHE2and to evaluate the repair efficiency of 4OHE2-induced DNA damage. The study was performed on the PBLs of 53EC patients and 20healthy women. The level of DNA damage was measured using the comet assay and was expressed as% tail DNA. The DNA repair efficiency (%) was evaluated by determining the ratio between the amount of repaired DNA damage and the level of 4OHE2-induced damage that appeared after incubation of PBLs with 4OHE2. In PBLs of EC patients, a higher level of 4OHE2-induced DNA damage (32.0 ± 2.2% tail DNA) and lower DNA repair efficiency (34.0 ± 4.5%) was observed compared to PBLs of healthy women (22.3 ± 2.3% tail DNA and 48.8 ± 4.5%, respectively). PBLs of EC patients with deep tumor invasion of myometrium were characterized by more prominent decrease of DNA repair than those with less invasive tumor (<½of myometrium) (20.9 ± 7.8 and 43.7 ± 6.7%, respectively). Furthermore, lower DNA repair efficiency was detected in the PBLs of EC patients with a family history of cancer compared to this parameter in patients with sporadic tumors (20.9±7.8and 47.1 ± 5.5%, respectively). The PBLs of EC patients are characterized by increased sensitivity to the genotoxic effect of 4OHE2and reduced repair efficiency regarding 4OHE2-induced DNA damage. A lower level of DNA repair is observed in EC patients with deep tumor myometrial invasion and a family history of cancer.