Date on Master's Thesis/Doctoral Dissertation

8-2014

Document Type

Master's Thesis

Degree Name

M.S.

Department

Pharmacology and Toxicology

Committee Chair

Hein, David W.

Committee Co-Chair (if applicable)

States, J. Christopher

Committee Member

States, J. Christopher

Committee Member

Samuelson, David J.

Committee Member

Barve, Shirish S.

Committee Member

Jenson, Alfred B.

Subject

Cancer--Genetic aspects

Abstract

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. We conducted in vivo studies using homozygous Fischer 344 rats, congenic at the rat Nat2 locus for high (rapid) and low (slow) activity. Wistar Kyoto inbred rats were used to breed in the slow activity rat Nat2 locus into the Fischer 344 inbred rat, which contains the rapid activity rat Nat2 locus. The rat Nat2 gene is a functional ortholog for the human NAT1 because it has similar sequence and substrate specificity to human NAT1. Chemically induced breast tumors are produced in the rat following administration of methyl-nitrosourea (MNU). In this thesis, rapid and slow acetylator female congenic rats were administrated a single dose of MNU (50 mg/kg) by intraperitoneal injection at three weeks of age. Weekly measurements of weights and palpable breast tumors were recorded. Palpable breast tumors showed a significantly shorter latency in rapid compared to slow acetylator congenic rats (p=0.040). At 23 weeks post MNUadministration, rats were euthanized, and tumor and adjacent non-tumor tissue were collected. Tumors were found in 78% of the rapid acetylator congenic rats with an average ± SEM of 1.78 ± 0.7 tumors per rat. In contrast, tumors were found in only 30% of slow acetylator congenic rats with an average of 0.5 ± 0.3 tumors per rat. Both tumor multiplicity and incidence approached significance (p=0.073 and 0.069, respectively) in this initial pilot experiment. Histopathology of the tumors classified the majority of the tumors as intraductal papillomas that were estrogen receptor positive by immunohistochemistry. The miRNA 574-3p was under expressed in intraductal papilloma breast tumors compared to normal tissues. These results suggest an important role for rat Nat2 in MNU-induced carcinogenesis and possibly carcinogenesis in general. Additional studies are proposed to confirm and understand the mechanism of rat Nat2’s involvement in carcinogenesis.

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