Genetic susceptibility to breast cancer is determined by an interaction of genes and environment but remains poorly understood. In this revised competing renewal of our investigation into the role of pharmacogenetic polymorphisms in carcinogen metabolism on genetic predisposition to cancer, we hypothesize that aromatic amine carcinogens such as 4-aminobiphenyl (ABP) present in tobacco smoke and heterocyclic amine carcinogens such as 2-amino-3-methylimidazo [4,5-f]pyridine (IQ) present in deep-fried, well-done meats are more likely to initiate breast cancer in those individuals with rapid and/or slow acetylator N-acetyltransferase- 1 (NAT1) and - 2 (NAT2) acetylator genotypes. We hypothesize that breast cancer frequency will be higher in tobacco smokers with very slow NAT2 acetylator / rapid NAT1 acetylator genotypes, and in individuals who eat deep-fried, well-done meats and are rapid for both NAT1 and NAT2 acetylator genotypes. To test this hypothesis, we propose to determine the effect of single nucleotide polymorphisms (SNPs) in human NAT1 and NAT2 on ABP and IQ genotoxicity through stable transfection of human NAT1 or NAT2 variant alleles into Chinese hamster ovary cells transfected with human CYP1A1 or CYP1B1; determine the relative level of NAT1 and NAT2 expression in normal human mammary tissue as a function of genotype; construct and characterize rapid and slow acetylator rat strains congenic at the NAT2 locus to determine the frequency of breast tumors in female rapid and slow acetylator congenic rats administered ABP or IQ; determine quantity, stability and regulatory effects of ABP or IQ on NAT1- and NAT2-specific mRNA, protein and catalytic activity; and determine the metabolism and genotoxicity of ABP and IQ in primary mammary cell cultures derived from rapid and slow acetylator congenic rats. We also will assess the effect of NAT1 and NAT2 genotypes in breast cancer risk through participation in ongoing molecular epidemiology investigations of breast cancer in Shanghai China and in Nashville, Tennessee.
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