Role of N-acetyltransferase 1 (NAT1) and 2 (NAT2) polymorphisms in breast cancer risk with exposure to aromatic and heterocyclic amine carcinogens

• Main Author: Schlierf, Thomas Joseph
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2008
• Subjects: Pharmacology
• ISBN: 9780549859383; 0549859381

Breast cancer is one of the most common forms of cancer among women in the U.S. in which it ranks second in cancer deaths. Incidence of breast cancer varies among women in different ethnic groups within the Southwest. Smoking alone has been shown to increase the risk for various cancers. Cigarette smoke contains heterocyclic and aromatic amines which can undergo metabolic activation to form intermediates that initiate carcinogenesis. Heterocyclic amines are also found in meats when they are cooked well-done. N-acetyltransferase 1 (NAT1) and 2 (NAT2) catalyzes both O-acetylation and N-acetylation of these compounds. Polymorphisms in NAT are some of the most common in the human population with wide phenotypic (e.g. enzyme activity) and allelic variations. In addition to susceptibility to drug toxicity, NAT polymorphisms may contribute to differential susceptibilities in human cancers. We explored associations between breast cancer incidence rates and NAT1 and NAT2 genetic polymorphisms in a case-control study from the 4-Corner's Women's Health Study New Mexico site. Subjects were classified according to their NAT1 and NAT2 genotype. The NAT1 groups consisted of rapid, slow and NAT*1*10. NAT2 genotypes were translated into rapid, intermediate, slow, or very slow (NAT2*5/*5) acetylator phenotypes. Subjects were then classified as never or ever smokers and well-done or not well-done meat eaters. The role of NAT1 and NAT2 genotypes were investigated separately. Analyses for NAT2 using the rapid/intermediate phenotype as the referent group showed that subjects with a slow (OR 1.23; 95% Cl, 1.00-1.52) to very slow phenotype (significant, p-value = 0.009) had an increase in breast cancer risk. When analysis was stratified by smoking (ever vs. never), NAT2 slow acetylator phenotype increased breast cancer risk (marginally significant, p-value = 0.08) among smokers (OR = 1.32; 95% Cl 0.964-1.815) whereas, the NAT2 very slow phenotype showed a significant (p-value = 0.007) increase in breast cancer risk (OR = 1.91; 95% CI, 1.19-3.05). Breast cancer risk in the NAT2 very slow phenotype was more pronounced among postmenopausal women smokers (OR = 2.37; 95% Cl, 1.33-4.25; p-value = 0.004). NAT1 genotype did not increase risk when stratified by smoking and menopausal status. NAT1 rapid (OR = 1.27; 95% Cl 0.92-1.76) and NAT*1*10 (OR = 1.16; 95% Cl 0.84-1.61) individuals who consume well done meat did not show increased risk (non-significant, p-value > 0.05). Similarly no significant association between well-done meat and breast cancer was found among the NAT2 phenotypes. In conclusion, our results indicate that smoking increases breast cancer risk in postmenopausal women with a slow to very slow NAT2 phenotype.