Recent 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-Nat2 rapid/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.
Mammary 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.
Tumor 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).
A novel role for rat NAT2 in mammary cancer was discovered unrelated to carcinogen metabolism, suggesting a role for human NAT1 in breast cancer.
Hein DW, Doll MA, Fretland AJ, Leff MA, Webb SJ, Xiao GH, Devanoboyina US, Nangju NA, Feng Y. Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Cancer Epidemiol Biomark Prev. 2000;9(1):29–42.
Adam PJ, Berry J, Loader JA, Tyson KL, Craggs G, Smith P, De Belin J, Steers G, Pezzella F, Sachsenmeir KF, et al. Arylamine N-Acetyltransferase-1 is highly expressed in breast cancers and conveys enhanced growth and resistance to etoposide in vitro. Mol Cancer Res. 2003;1(11):826–35. PubMed
Wakefield L, Robinson J, Long H, Ibbitt JC, Cooke S, Hurst HC, Sim E. Arylamine N-acetyltransferase I expression in breast cancer cell lines: a potential marker in estrogen receptor-positive tumors. Gene Chromosomes Cancer. 2008;47(2):118–26. CrossRef
Kim SJ, Kang HS, Chang HL, Jung YC, Sim HB, Lee KS, Ro J, Lee ES. Promoter hypomethylation of the N-acetyltransferase 1 gene in breast cancer. Oncol Rep. 2008;19(3):663–8. PubMed
Butcher NJ, Ilett KF, Minchin RF. Substrate-dependent regulation of human arylamine N-acetyltransferase-1 in cultured cells. Mol Pharmacol. 2000;57(3):468–73. PubMed
Badawi AF, Hirvonen A, Bell DA, Lang NP, Kadlubar FF. Role of aromatic amine acetyltransferases, NAT1 and NAT2, in carcinogen-DNA adduct formation in the human urinary-bladder. Cancer Res. 1995;55(22):5230–7. PubMed
Bell DA, Badawi AF, Lang NP, Ilett KF, Kadlubar FF, Hirvonen A. Polymorphism in the N-acetyltransferase 1 (NAT1) polyadenylation signal: association of NAT1*10 allele with higher N-acetylation activity in bladder and colon tissue. Cancer Res. 1995;55(22):5226–9. PubMed
Millikan RC, Pittman GS, Newman B, Tse CKJ, Selmin O, Rockhill B, Savitz D, Moorman PG, Bell DA. Cigarette smoking, N-acetyltransferases 1 and 2, and breast cancer risk. Cancer Epidemiol Biomark Prev. 1998;7(5):371–8.
Lilla C, Verla-Tebit E, Risch A, Jager B, Hoffmeister M, Brenner H, Chang-Claude J. Effect of NAT1 and NAT2 genetic polymorphisms on colorectal cancer risk associated with exposure to tobacco smoke and meat consumption. Cancer Epidemiol Biomark Prev. 2006;15(1):99–107. CrossRef
Bell DA, Stephens EA, Castranio T, Umbach DM, Watson M, Deakin M, Elder J, Hendrickse C, Duncan H, Strange RC. Polyadenylation polymorphism in the acetyltransferase-1 gene (NAT1) increases risk of colorectal-cancer. Cancer Res. 1995;55(16):3537–42. PubMed
Taylor JA, Umbach DM, Stephens E, Castranio T, Paulson D, Robertson C, Mohler JL, Bell DA. The role of N-acetylation polymorphisms in smoking-associated bladder cancer: evidence of a gene-gene-exposure three-way interaction. Cancer Res. 1998;58(16):3603–10. PubMed
Gu J, Liang D, Wang YF, Lu C, Wu XF. Effects of N-acetyl transferase 1 and 2 polymorphisms on bladder cancer risk in Caucasians. Mutat Res-Genet Toxicol Environ Mutag. 2005;581(1-2):97–104. CrossRef
Hein DW, Rustan TD, Bucher KD, Furman EJ, Martin WJ. Extrahepatic expression of the N-acetylation polymorphism toward arylamine carcinogens in tumor target organs of an inbred rat model. J Pharmacol Exp Ther. 1991;258(1):232–6. PubMed
Hein DW, Rustan TD, Bucher KD, Martin WJ, Furman EJ. Acetylator phenotype-dependent and -independent expression of arylamine N-acetyltransferase isozymes in rapid and slow acetylator inbred rat liver. Drug Metab Dispos. 1991;19(5):933–7. PubMed
Pegg AE. Methylation of the O6position of guanine in DNA is the most likely initiating event in carcinogenesis by methylating agents. Cancer Investig. 2009;2(3):223–31. CrossRef
Budan F, Varjas T, Nowrasteh G, Prantner I, Varga Z, Ember A, Cseh J, Gombos K, Pazsit E, Gobel G, et al. Early modification of c-myc, ha-ras and p53 expressions by chemical carcinogens (DMBA, MNU). In vivo. 2009;23(4):591–8. PubMed
Samuelson DJ, Hesselson SE, Aperavich BA, Zan YH, Haag JD, Trentham-Dietz A, Hampton JM, Mau B, Chen KS, Baynes C, et al. Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk. Proc Natl Acad Sci U S A. 2007;104(15):6299–304. CrossRefPubMedPubMedCentral
Bieche I, Girault I, Urbain E, Tozlu S, Lidereau R. Relationship between intratumoral expression of genes coding for xenobiotic-metabolizing enzymes and benefit from adjuvant tamoxifen in estrogen receptor alpha-positive postmenopausal breast carcinoma. Breast Cancer Res. 2004;6(3):R252–63. CrossRefPubMedPubMedCentral
NTP (National Toxicology Program). Report on Carcinogens, Fourteenth Edition.; Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service. 2016. http://ntp.niehs.nih.gov/go/roc14/.
Laurieri N, Dairou J, Egleton JE, Stanley LA, Russell AJ, Dupret JM, Sim E, Rodrigues-Lima F. From arylamine N-acetyltransferase to folate-dependent acetyl CoA hydrolase: impact of folic acid on the activity of (HUMAN)NAT1 and its homologue (MOUSE)NAT2. PLoS One. 2014;9(5):e96370. CrossRefPubMedPubMedCentral
Siudeja K, Srinivasan B, Xu LJ, Rana A, de Jong J, Nollen EAA, Jackowski S, Sanford L, Hayflick S, Sibon OCM. Impaired coenzyme a metabolism affects histone and tubulin acetylation in drosophila and human cell models of pantothenate kinase associated neurodegeneration. EMBO Mol Med. 2011;3(12):755–66. CrossRefPubMedPubMedCentral
- 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
David J. Samuelson
Mary Ann G. Sanders
J. Christopher States
David W. Hein
- BioMed Central
Neu im Fachgebiet Onkologie
Mail Icon II