Date of Award

12-22-1999

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

David W. Hein

Abstract

Aromatic and heterocyclic amine carcinogens found in cigarette smoke and well done meat require host-mediated metabolic activation before initiating tumors in target organs. The N-acetyltransferase isozymes, NAT1 and NAT2, catalyze the activation (O-acetylation) of aromatic and heterocyclic amines and also the deactivation (N-acetylation) of aromatic amines. Both NAT1 and NAT2 are subject to genetic polymorphisms. Using molecular epidemiological studies, in vitro studies in human mammary tissues, and a genetically defined rapid and slow acetylator congenic hamster model, we tested our hypothesis that rapid NAT1 and/or NAT2 acetylators are at an increased risk of breast cancer, especially those women exposed to heterocyclic amine carcinogens through cigarette smoke or well-done meat. Individuals possessing a single NAT1*10 (n = 3) or NAT1*11 (n = 2) allele did not exhibit higher mammary NAT I activities in our study, and mammary NAT2 activity was below the limit of detection of our assay. However, NAT1 and NAT2 were expressed in mammary cytosols of Syrian hamsters congenic at the NAT2 locus, and rapid acetylator congenic hamsters had significantly higher rates of mammary tissue N-acetyltransferase activity than did slow acetylators. Neither NAT1 nor NAT2 catalyzed the N-acetylation of PhIP, suggesting that O-acetylation may be the preferred metabolic route for this heterocyclic amine. In molecular epidemiological studies, we found that post-menopausal women with at least one NAT1*11 allele had nearly a 4-fold elevated risk (95% CI = 1.5–10.5) of breast cancer. This association was more evident among smokers (OR = 13.2, 95% CI = 1.5–116.0), those who consumed a high level of red meat (OR = 6.1, 95% CI = 1.1–33.2), and those who consumed well-done meat (OR = 5.6, 95% CI = 0.5–62.7). The association of the NAT1*10 allele with breast cancer was confined to former smokers (OR = 3.3, 95% CI = 1.2–9.5). Deduced NAT2 phenotype was not associated with breast cancer risk. However, we observed a dose-dependent elevated risk (p = 0.01) among rapid/intermediate NAT2 acetylators who consumed well-done meat. Cigarette smoking increased breast cancer risk only among women with the rapid/intermediate NAT2 phenotype who were former smokers (OR = 3.2, 95% CI = 1.3–7.8).

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