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Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey SM2 5NG, United Kingdom
Breast cancer is the major cause of cancer death in women worldwide. High penetrance genes account for only 5% of cases, whereas polymorphic low penetrance genes acting in concert with lifestyle/environmental risk factors are likely to account for a much higher proportion. Genotoxic compounds implicated in human breast carcinogenesis include endogenous compounds, estrogens, and dietary or environmental xenobiotics–heterocyclic amines, aromatic amines, polycyclic aromatic hydrocarbons, and nitropolycyclic aromatic hydrocarbons. Here we review evidence for a role of mammary-expressed enzymes that metabolically activate and/or detoxify potential genotoxic breast carcinogens: cytochrome P-450s, catechol-O-methyltransferase, epoxide hydrolase, peroxidases, glutathione S-transferases, N-acetyltransferases, sulfotransferases, and other enzymes catalyzing conjugation reactions. This information is particularly relevant in the light of evidence for the presence of genotoxic agents that require metabolic activation in mammary lipid, in nipple aspirates and in breast milk, and for the presence of DNA adducts in human mammary epithelial cells (from which most breast carcinomas originate). The effect of polymorphisms in the genes encoding these enzymes on breast cancer risk are also considered. The evidence for the role of genotoxic carcinogens in the etiology of breast cancer is compelling, but mammary-specific enzyme expression should be taken into account when considering the contribution of polymorphisms to risk.
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