Role of Fanconi/BRCA DNA Repair Pathway in Epithelial Ovarian Carcinogenesis.

摘要

Our hypothesis is that reversible alterations in histones are a determining factor for low FANCD2 expression in ovarian surface epithelial (OSE) cells in women with a familial risk for ovarian cancer, and that cells with reduced FANCD2 levels are hypersensitive to the genotoxic effects of estrogen, therefore predisposing OSE to malignant transformation. During the study we have screened a large number of normal (no familial risk), high risk (with familial history of this disease), and ovarian cancer cell lines, and determined levels of FANCD2 protein and mRNA. In the first set of experiments, aimed at determining whether histone modifications (i.e. acetylation and/or methylation) affect FANCD2 levels, we established that Trichostatin A (TSA;10nM for 24 hours) corrects FANCD2 levels but not consistently. In the second set of experiments, aimed at establishing whether the estrogen metabolite 4-OHE2 is genotoxic for cells with low FANCD2 levels we: 1) identified the minimal concentration of 4- OHE2 that is associated with DNA damage in human and murine OSE, and; 2) found that OSE cultures with low FANCD2 exhibit significantly increased DNA damage after exposure to 50 uM 4-OHE2, in comparison with OSE cultures with normal levels of FANCD2 protein expression.