Exposure to estrogens has been associated with an increased risk of developing breast cancer. Breast biopsy tissues from 49 women without breast cancer (controls) and 28 with breast carcinoma (cases) were analyzed by HPLC with electrochemical detection for 31 estrogen metabolites and catechol estrogen quinone–glutathione conjugates. The levels of estrone and estradiol were higher in cases. More 2-catechol estrogen (CE) than 4-CE was observed in controls, but the 4-CE were three times higher than 2-CE in cases. In addition, the 4-CE were nearly four times higher in cases than in controls. Less O -methylation was observed for the CE in cases. The level of catechol estrogen quinone conjugates in cases was three times that in controls, suggesting in the cases a higher probability for the quinones to react with DNA and generate mutations that may initiate cancer. The levels of 4-CE and quinone conjugates were highly significant predictors of breast cancer. These results suggest that some catechol estrogen metabolites and conjugates could serve as biomarkers to predict risk of breast cancer.

Estrogens can initiate cancer by reacting with DNA. Specific metabolites of endogenous estrogens, the catechol estrogen‐3,4‐quinones, react with DNA to form depurinating estrogen‐DNA adducts. Loss of these adducts leaves apurinic sites in the DNA, generating mutations that can lead to the initiation of cancer. A variety of endogenous and exogenous factors can disrupt estrogen homeostasis, which is the normal balance between estrogen activating and protective enzymes. In fact, if estrogen metabolism becomes unbalanced and generates excessive catechol estrogen 3,4‐quinones, formation of depurinating estrogen‐DNA adducts increases and the risk of initiating cancer is greater. The levels of depurinating estrogen‐DNA adducts are high in women diagnosed with breast cancer and those at high risk for the disease. High levels of depurinating estrogen‐DNA adducts before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Women with thyroid or ovarian cancer also have high levels of estrogen‐DNA adducts, as do men with prostate cancer or non‐Hodgkin lymphoma. Depurinating estrogen‐DNA adducts are initiators of many prevalent types of human cancer. These findings and other discoveries led to the recognition that reducing the levels of estrogen‐DNA adducts could prevent the initiation of human cancer. The dietary supplementsN‐acetylcysteine and resveratrol inhibit formation of estrogen‐DNA adducts in cultured human breast cells and in women. These results suggest that the two supplements offer an approach to reducing the risk of developing various prevalent types of human cancer.

Exposure to estrogens is a risk factor for breast cancer. Specific estrogen metabolites may initiate breast cancer and other cancers. Genotoxicity may be caused by cytochrome P450 (CYP)–mediated oxidation of catechol estrogens to quinones that react with DNA to form depurinating estrogen-DNA adducts. CYP1B1 favors quinone formation by catalyzing estrogen 4-hydroxylation, whereas NAD(P)H quinone oxidoreductase 1 (NQO1) catalyzes the protective reduction of quinones to catechols. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1B1 expression through the aryl hydrocarbon receptor (AhR). Resveratrol has anticancer effects in diverse in vitro and in vivo systems and is an AhR antagonist that decreases CYP expression but induces NQO1 expression. The chemopreventive effect of resveratrol on breast cancer initiation was investigated in MCF-10F cells. Its effects on estrogen metabolism and formation of estrogen-DNA adducts were analyzed in culture medium by high-performance liquid chromatography, whereas its effects on CYP1B1 and NQO1 were determined by immunoblotting and immunostaining. The antitransformation effects of resveratrol were also examined. TCDD induced expression of CYP1B1 and its redistribution in the nucleus and cytoplasm. Concomitant treatment with resveratrol dose-dependently suppressed TCDD-induced expression of CYP1B1, mainly in the cytoplasm. Resveratrol dose- and time-dependently induced expression of NQO1. NQO1 is mainly in the perinuclear membrane of control cells, but resveratrol induced NQO1 and its intracellular redistribution, which involves nuclear translocation of nuclear factor erythroid 2–related factor 2. Resveratrol decreased estrogen metabolism and blocked formation of DNA adducts in cells treated with TCDD and/or estradiol. Resveratrol also suppressed TCDD and/or estradiol-induced cell transformation. Thus, resveratrol can prevent breast cancer initiation by blocking multiple sites in the estrogen genotoxicity pathway.