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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA034627-21
Application #
7098042
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Poland, Alan P
Project Start
1989-09-01
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
21
Fiscal Year
2006
Total Cost
$977
Indirect Cost
Name
University of Louisville
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Hein, David W; Zhang, Xiaoyan; Doll, Mark A (2018) Role of N-acetyltransferase 2 acetylation polymorphism in 4, 4'-methylene bis (2-chloroaniline) biotransformation. Toxicol Lett 283:100-105
Zhang, Xiaoyan; Carlisle, Samantha M; Doll, Mark A et al. (2018) High N-Acetyltransferase 1 Expression Is Associated with Estrogen Receptor Expression in Breast Tumors, but Is not Under Direct Regulation by Estradiol, 5?-androstane-3?,17?-Diol, or Dihydrotestosterone in Breast Cancer Cells. J Pharmacol Exp Ther 365:84-93
Hein, David W; Doll, Mark A (2017) Catalytic properties and heat stabilities of novel recombinant human N-acetyltransferase 2 allozymes support existence of genetic heterogeneity within the slow acetylator phenotype. Arch Toxicol 91:2827-2835
Hein, David W; Doll, Mark A (2017) Rabbit N-acetyltransferase 2 genotyping method to investigate role of acetylation polymorphism on N- and O-acetylation of aromatic and heterocyclic amine carcinogens. Arch Toxicol 91:3185-3188
Stepp, Marcus W; Doll, Mark A; Samuelson, David J et al. (2017) Congenic rats with higher arylamine N-acetyltransferase 2 activity exhibit greater carcinogen-induced mammary tumor susceptibility independent of carcinogen metabolism. BMC Cancer 17:233
Middlebrooks, Candace D; Banday, A Rouf; Matsuda, Konichi et al. (2016) Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors. Nat Genet 48:1330-1338
Carlisle, Samantha M; Trainor, Patrick J; Yin, Xinmin et al. (2016) Untargeted polar metabolomics of transformed MDA-MB-231 breast cancer cells expressing varying levels of human arylamine N-acetyltransferase 1. Metabolomics 12:
Lavender, Nicole; Hein, David W; Brock, Guy et al. (2015) Evaluation of Oxidative Stress Response Related Genetic Variants, Pro-oxidants, Antioxidants and Prostate Cancer. AIMS Med Sci 2:271-294
Figueroa, Jonine D; Ye, Yuanqing; Siddiq, Afshan et al. (2014) Genome-wide association study identifies multiple loci associated with bladder cancer risk. Hum Mol Genet 23:1387-98
Figueroa, Jonine D; Han, Summer S; Garcia-Closas, Montserrat et al. (2014) Genome-wide interaction study of smoking and bladder cancer risk. Carcinogenesis 35:1737-44

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