Mammary expression of xenobiotic metabolizing enzymes and their potential role in breast cancer

Breast cancer is the major cause of cancer death in women worldwide. High p enetrance genes account for only 5% of cases, whereas polymorphic low penet rance genes acting in concert with lifestyle/environmental risk factors are likely to account for a much higher proportion. Genotoxic compounds implic ated in human breast carcinogenesis include endogenous compounds, estrogens , and dietary or environmental xenobiotics-heterocyclic amines, aromatic am ines, polycyclic aromatic hydrocarbons, and nitropolycyclic aromatic hydroc arbons. Here we review evidence for a role of mammary-expressed enzymes tha t metabolically activate and/or detoxify potential genotoxic breast carcino gens: cytochrome P-450s, catechol-O-methyltransferase, epoxide hydrolase, p eroxidases, glutathione S-transferases, N-acetyltransferases, sulfotransfer ases, and other enzymes catalyzing conjugation reactions. This information is particularly relevant in the light of evidence for the presence of genot oxic agents that require metabolic activation in mammary lipid, in nipple a spirates and in breast milk, and for the presence of DNA adducts in human m ammary epithelial cells (from which most breast carcinomas originate). The effect of polymorphisms in the genes encoding these enzymes on breast cance r risk are also considered. The evidence for the role of genotoxic carcinog ens in the etiology of breast cancer is compelling, but mammary-specific en zyme expression should be taken into account when considering the contribut ion of polymorphisms to risk.