2,3,7,8-Tetrachlorodibenzo-p-dioxin modulates estradiol-induced aldehydic DNA lesions in human breast cancer cells through alteration of CYP1A1 and CYP1B1 expression

Abstract

Background Many genes responsible for the bioactivationof endogenous estrogen to reactive quinonoid metabolites,including cytochrome P450 (CYP) 1A1, 1A2, and 1B1, arewell-known target genes of the aryl hydrocarbon receptoragonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).Methods The purpose of this research was to investigatethe roles of TCDD-mediated altered gene expression in theinduction of aldehydic DNA lesions (ADLs) by 17bestradiol(E2) in human MDA-MB-231 and MCF-7 breastcancer cells.Results We demonstrated that increases in the number ofoxidant-mediated ADLs, including abasic sites and aldehydicbase/sugar lesions, were detected in MDA-MB-231cells exposed to E2. The DNA-damaging effects of E2 inMDA-MB-231 cells were prevented by pretreatment ofcells with TCDD. In contrast, we did not observe statisticallysignificant increases in the number of ADLs in MCF-7 cells exposed to E2. However, with TCDD pretreatment,an approximately twofold increase in the number of ADLswas detected in MCF-7 cells exposed to E2.Conclusions TCDD pretreatment induces disparity in thedisposition of E2 to reactive quinonoid metabolites and thesubsequent formation of oxidative DNA lesions throughalteration of CYP1A1 and CYP1B1 expression in humanbreast cancer cells