The unifying mechanism in the initiation and prevention of breast and other human cancers

Exposure to estrogens is a risk factor for human breast cancer. Experiments on estrogen metabolism, formation of DNA adducts, carcinogenicity, mutagenicity and cell transformation led to and support the hypothesis that reaction of specific estrogen metabolites, catechol estrogen-3,4-quinones, with DNA can generate the critical mutations to initiate breast, prostate and other human cancers. The major initiating pathway is illustrated in Figure 1. Estrone (E1) and estradiol (E2) can be metabolically converted to 4-OHE1(E2) by cytochrome P450 (CYP)1B1. Oxidation of these catechol estrogens leads to the corresponding catechol estrogen-3,4-quinones, which can react with DNA to form very small amounts of stable adducts, which remain in DNA unless removed by repair, and predominant amounts (99%) of depurinating adducts, which detach from DNA, leaving behind apurinic sites. Errors in the repair of these sites can lead to the critical mutations that can initiate breast, prostate and other human cancers.