Date on Master's Thesis/Doctoral Dissertation
Pharmacology and Toxicology
Pharmacology and Toxicology, PhD
Hein, David W.
Committee Co-Chair (if applicable)
States, J. Christopher
States, J. Christopher
Samuelson, David J.
Jenson, Alfred B.
arylamine N-acetyltransferase 1; tumorigenesis; breast cancer
Human arylamine N-acetyltransferase 1 (NAT1) is a well-known phase II metabolic enzyme that has been associated with carcinogenesis. Its role in the biotransformation of aromatic and heterocyclic amine carcinogens has been investigated for many years, but more recent investigations focus on a possible endogenous role of human NAT1 in cancer initiation and progression. To further explore and understand possible endogenous roles for NAT1, we conducted in vitro enzymatic reactions, in vivo studies using homozygous high (rapid) or low (slow) NAT2 activity congenic F344.WKY rats, and genetically modified human breast cancer cell lines. Human NAT1 and rodent NAT2 hydrolyzed acetyl-coenzyme A (AcCoA) in a folate-dependent manner. The rat Nat2 gene is a functional ortholog for the human NAT1 because it has similar sequence and substrate specificity to human NAT1. Rapid acetylator NAT2 congenic rats developed more mammary tumors than the slow acetylator NAT2 congenic rats following administration of the mammary carcinogens methylnitrosourea and 7,12-dimethylbenzanthracene, neither of which is metabolized by rat NAT2. Investigations of partial NAT1 knockdown and complete NAT1 knockout were completed in MDA-MB-231 and MCF7 human breast cancer cell lines. Both partial and complete NAT1 knockout reduced ability for colony formation in soft agar compared to parental cell lines. Endogenous AcCoA levels in congenic rat embryonic fibroblasts and in human breast cancer cell lines with partial and complete NAT1 knockout showed increased AcCoA when the level of NAT1 was reduced within the cells. In summary, the findings compliment but do not fully replicate previous reports regarding the effect of reducing NAT1 activity on cancer cell properties. Use of this model system further suggests that human NAT1 could serve as a target for the prevention and/or treatment of breast cancer.
Stepp, Marcus William, "Role of human arylamine n-acetyltransferase 1 in tumorigenesis and cancer biology." (2017). Electronic Theses and Dissertations. Paper 2862.