Congenic rats with higher arylamine N-acetyltransferase 2 activity exhibit greater carcinogen-induced mammary tumor susceptibility independent of carcinogen metabolism

Marcus W Stepp,Mark A Doll,Mary Ann G Sanders,David J Samuelson,David W Hein,J Christopher States

doi:10.1186/s12885-017-3221-9

Marcus W Stepp, Mark A Doll + Show 4 more

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https://doi.org/10.1186/s12885-017-3221-9

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Abstract

BackgroundRecent investigations suggest role(s) of human arylamine N-acetyltransferase 1 (NAT1) in breast cancer. Rat NAT2 is orthologous to human NAT1 and the gene products are functional homologs. We conducted in vivo studies using F344.WKY-Nat2rapid/slow rats, congenic at rat Nat2 for high (rapid) and low (slow) arylamine N-acetyltransferase activity, to assess a possible role for rat NAT2 in mammary tumor susceptibility.MethodsMammary carcinogens, methylnitrosourea (MNU) and 7,12-dimethylbenzanthracene (DMBA) neither of which is metabolized by N-acetyltransferase, were administered to assess mammary tumors. MNU was administered at 3 or 8 weeks of age. DMBA was administered at 8 weeks of age. NAT2 enzymatic activity and endogenous acetyl-coenzyme A (AcCoA) levels were measured in tissue samples and embryonic fibroblasts isolated from the congenic rats.ResultsTumor latency was shorter in rapid NAT2 rats compared to slow NAT2 rats, with statistical significance for MNU administered at 3 and 8 weeks of age (p = 0.009 and 0.050, respectively). Tumor multiplicity and incidence were higher in rapid NAT2 rats compared to slow NAT2 rats administered MNU or DMBA at 8 weeks of age (MNU, p = 0.050 and 0.035; DMBA, p = 0.004 and 0.027, respectively). Recombinant rat rapid-NAT2, as well as tissue samples and embryonic fibroblasts derived from rapid NAT2 rats, catalyzed p-aminobenzoic acid N-acetyl transfer and folate-dependent acetyl-coenzyme A (AcCoA) hydrolysis at higher rates than those derived from rat slow-NAT2. Embryonic fibroblasts isolated from rapid NAT2 rats displayed lower levels of cellular AcCoA than slow NAT2 rats (p < 0.01).ConclusionsA novel role for rat NAT2 in mammary cancer was discovered unrelated to carcinogen metabolism, suggesting a role for human NAT1 in breast cancer.

Highlights

Recent investigations suggest role(s) of human arylamine N-acetyltransferase 1 (NAT1) in breast cancer
Rapid and slow acetylator rats congenic at the Nat2 locus Rapid and slow acetylator Nat2 congenic Fischer 344 (F344.Wistar Kyoto (WKY)) rats were housed in the University of Louisville animal facility and the experiments were reviewed and approved by the University’s Institutional Animal Care and Use Committee
The results reported in the current study suggest that the human NAT1 phenotype and prepubescent carcinogen exposure should be studied as additional factors in human breast cancer susceptibility

Summary

Introduction

Recent investigations suggest role(s) of human arylamine N-acetyltransferase 1 (NAT1) in breast cancer. One role for NAT1 in carcinogenesis is its ability to biotransform arylamine procarcinogens to active carcinogens [4]. Recent findings in vitro suggest that NAT1 activity level may influence cancer cell proliferation and survival [5,6,7,8]. NAT1*10, the most common haplotype, is associated with increased NAT1 activity in human bladder [15], colon [16], and liver [17]. NAT1*10 has been associated with higher risk of developing cancers of the breast [18], colon/rectum [19, 20], lung [21], pancreas [22], and urinary bladder [23]. Other studies have reported no association between NAT1*10 and cancer risk [24, 25]

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