Inhibition of depurinating estrogen-DNA adduct formation in the prevention of breast and other cancers

One problem in the efforts to prevent breast cancer has been the lack of recognition that estrogens can initiate cancer by acting as chemical carcinogens and 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. If estrogen metabolism becomes unbalanced and generates excessive catechol estrogen-3,4-quinones, formation of depurinating estrogen-DNA adducts and the risk of initiating cancer increase. Inhibiting formation of depurinating estrogen-DNA adducts can, therefore, prevent cancer. Levels of the estrogen-DNA adducts are high in women diagnosed with breast cancer and those at high risk for the disease. The finding that high levels of depurinating estrogen-DNA adducts precede the presence of breast cancer indicates that formation of these adducts 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. The findings summarized above and other discoveries led to the recognition that reducing the levels of estrogen-DNA adducts would prevent the initiation of breast and other types of human cancer. We have found that the dietary supplements N-acetylcysteine and resveratrol inhibit estrogen-DNA adduct formation in both cultured human breast cells and in women. These results suggest that these two supplements offer an approach to reduce risk of developing breast and other types of human cancer.