Skip to main content

Advertisement

Log in

NAT2 polymorphisms combining with smoking associated with breast cancer susceptibility: a meta-analysis

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

To derive a more precise estimation of the relationship between the slow or rapid acetylation resulting from N-acetyltransferase 2 (NAT2) polymorphisms and breast cancer risk, a meta-analysis was performed. PubMed, Medline, Embase, and Web of Science were searched. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess strength of association. The pooled ORs were performed for slow versus rapid acetylation genotypes. A total of 26 studies including 9,215 cases and 10,443 controls were included in the meta-analysis. Overall, no significantly elevated breast cancer risk was associated with NAT2 slow genotypes when all studies were pooled into the meta-analysis (OR = 1.026, 95% CI = 0.968–1.087). In the subgroup analysis by ethnicity, increased risks were not found for either Caucasians (OR = 1.001, 95% CI = 0.938–1.068) or Asians (OR = 1.155, 95% CI = 0.886–1.506). When stratified by study design, statistically significantly elevated risk associated with NAT2 slow genotypes was only found among hospital-based studies (OR = 1.178, 95% CI = 1.037–1.339). In the subgroup analysis by menopausal status, no statistically significantly increased risk was found in either premenopausal (OR = 1.053, 95% CI = 0.886–1.252) or postmenopausal women (OR = 0.965, 95% CI = 0.844–1.104). When stratified by cumulative smoking exposure, in the subgroup of smokers with high pack-years, NAT2 slow genotypes were significantly associated with increased breast cancer risk (OR = 1.400, 95% CI = 1.099–1.784). In conclusion, this meta-analysis suggested that there is overall lack of association between NAT2 genotypes and breast cancer risk, however, NAT2 polymorphisms when combining with heavy smoking history may contribute to breast cancer susceptibility.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249

    Article  PubMed  Google Scholar 

  2. Dumitrescu RG, Cotarla I (2005) Understanding breast cancer risk—where do we stand in 2005? J Cell Mol Med 9:208–221

    Article  CAS  PubMed  Google Scholar 

  3. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K (2000) Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343:78–85

    Article  CAS  PubMed  Google Scholar 

  4. Smith CA, Smith G, Wolf CR (1994) Genetic polymorphisms in xenobiotic metabolism. Eur J Cancer 30A:1921–1935

    Article  CAS  PubMed  Google Scholar 

  5. Hein DW (1988) Acetylator genotype and arylamine-induced carcinogenesis. Biochim Biophys Acta 948:37–66

    CAS  PubMed  Google Scholar 

  6. Hein DW (2002) Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis. Mutat Res 506–507:65–77

    PubMed  Google Scholar 

  7. http://www.louisville.edu/medschool/pharmacology/NAT.html

  8. Agundez JA, Ladero JM, Olivera M, Abildua R, Roman JM, Benitez J (1995) Genetic analysis of the arylamine N-acetyltransferase polymorphism in breast cancer patients. Oncology 52:7–11

    Article  CAS  PubMed  Google Scholar 

  9. Ambrosone CB, Freudenheim JL, Graham S, Marshall JR, Vena JE, Brasure JR, Michalek AM, Laughlin R, Nemoto T, Gillenwater KA, Shields PG (1996) Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk. JAMA 276:1494–1501

    Article  CAS  PubMed  Google Scholar 

  10. Hunter DJ, Hankinson SE, Hough H, Gertig DM, Garcia-Closas M, Spiegelman D, Manson JE, Colditz GA, Willett WC, Speizer FE, Kelsey K (1997) A prospective study of NAT2 acetylation genotype, cigarette smoking, and risk of breast cancer. Carcinogenesis 18:2127–2132

    Article  CAS  PubMed  Google Scholar 

  11. Millikan RC, Pittman GS, Newman B, Tse CK, Selmin O, Rockhill B, Savitz D, Moorman PG, Bell DA (1998) Cigarette smoking, N-acetyltransferases 1 and 2, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 7:371–378

    CAS  PubMed  Google Scholar 

  12. Huang CS, Chern HD, Shen CY, Hsu SM, Chang KJ (1999) Association between N-acetyltransferase 2 (NAT2) genetic polymorphism and development of breast cancer in post-menopausal Chinese women in Taiwan, an area of great increase in breast cancer incidence. Int J Cancer 82:175–179

    Article  CAS  PubMed  Google Scholar 

  13. Morabia A, Bernstein MS, Bouchardy I, Kurtz J, Morris MA (2000) Breast cancer and active and passive smoking: the role of the N-acetyltransferase 2 genotype. Am J Epidemiol 152:226–232

    Article  CAS  PubMed  Google Scholar 

  14. Delfino RJ, Smith C, West JG, Lin HJ, White E, Liao SY, Gim JS, Ma HL, Butler J, Anton-Culver H (2000) Breast cancer, passive and active cigarette smoking and N-acetyltransferase 2 genotype. Pharmacogenetics 10:461–469

    Article  CAS  PubMed  Google Scholar 

  15. Deitz AC, Zheng W, Leff MA, Gross M, Wen WQ, Doll MA, Xiao GH, Folsom AR, Hein DW (2000) N-Acetyltransferase-2 genetic polymorphism, well-done meat intake, and breast cancer risk among postmenopausal women. Cancer Epidemiol Biomarkers Prev 9:905–910

    CAS  PubMed  Google Scholar 

  16. Krajinovic M, Ghadirian P, Richer C, Sinnett H, Gandini S, Perret C, Lacroix A, Labuda D, Sinnett D (2001) Genetic susceptibility to breast cancer in French-Canadians: role of carcinogen-metabolizing enzymes and gene-environment interactions. Int J Cancer 92:220–225

    Article  CAS  PubMed  Google Scholar 

  17. Wu FY, Lee YJ, Chen DR, Kuo HW (2002) Association of DNA-protein crosslinks and breast cancer. Mutat Res 501:69–78

    CAS  PubMed  Google Scholar 

  18. Chang-Claude J, Kropp S, Jager B, Bartsch H, Risch A (2002) Differential effect of NAT2 on the association between active and passive smoke exposure and breast cancer risk. Cancer Epidemiol Biomarkers Prev 11:698–704

    CAS  PubMed  Google Scholar 

  19. Matheson MC, Stevenson T, Akbarzadeh S, Propert DN (2002) GSTT1 null genotype increases risk of premenopausal breast cancer. Cancer Lett 181:73–79

    Article  CAS  PubMed  Google Scholar 

  20. Egan KM, Newcomb PA, Titus-Ernstoff L, Trentham-Dietz A, Mignone LI, Farin F, Hunter DJ (2003) Association of NAT2 and smoking in relation to breast cancer incidence in a population-based case–control study (United States). Cancer Causes Control 14:43–51

    Article  PubMed  Google Scholar 

  21. Lee KM, Park SK, Kim SU, Doll MA, Yoo KY, Ahn SH, Noh DY, Hirvonen A, Hein DW, Kang D (2003) N-Acetyltransferase (NAT1, NAT2) and glutathione S-transferase (GSTM1, GSTT1) polymorphisms in breast cancer. Cancer Lett 196:179–186

    Article  CAS  PubMed  Google Scholar 

  22. van der Hel OL, Peeters PH, Hein DW, Doll MA, Grobbee DE, Kromhout D, Bueno DMH (2003) NAT2 slow acetylation and GSTM1 null genotypes may increase postmenopausal breast cancer risk in long-term smoking women. Pharmacogenetics 13:399–407

    Article  PubMed  Google Scholar 

  23. Kocabas NA, Sardas S, Cholerton S, Daly AK, Karakaya AE (2004) N-Acetyltransferase (NAT2) polymorphism and breast cancer susceptibility: a lack of association in a case–control study of Turkish population. Int J Toxicol 23:25–31

    Article  CAS  PubMed  Google Scholar 

  24. Alberg AJ, Daudt A, Huang HY, Hoffman SC, Comstock GW, Helzlsouer KJ, Strickland PT, Bell DA (2004) N-acetyltransferase 2 (NAT2) genotypes, cigarette smoking, and the risk of breast cancer. Cancer Detect Prev 28:187–193

    Article  CAS  PubMed  Google Scholar 

  25. Sillanpaa P, Hirvonen A, Kataja V, Eskelinen M, Kosma VM, Uusitupa M, Vainio H, Mitrunen K (2005) NAT2 slow acetylator genotype as an important modifier of breast cancer risk. Int J Cancer 114:579–584

    Article  PubMed  Google Scholar 

  26. Lilla C, Risch A, Kropp S, Chang-Claude J (2005) SULT1A1 genotype, active and passive smoking, and breast cancer risk by age 50 years in a German case–control study. Breast Cancer Res 7:R229–R237

    Article  CAS  PubMed  Google Scholar 

  27. Lissowska J, Brinton LA, Zatonski W, Blair A, Bardin-Mikolajczak A, Peplonska B, Sherman ME, Szeszenia-Dabrowska N, Chanock S, Garcia-Closas M (2006) Tobacco smoking, NAT2 acetylation genotype and breast cancer risk. Int J Cancer 119:1961–1969

    Article  CAS  PubMed  Google Scholar 

  28. Chang TW, Wang SM, Guo YL, Tsai PC, Huang CJ, Huang W (2006) Glutathione S-transferase polymorphisms associated with risk of breast cancer in southern Taiwan. Breast 15:754–761

    Article  PubMed  Google Scholar 

  29. Sillanpaa P, Heikinheimo L, Kataja V, Eskelinen M, Kosma VM, Uusitupa M, Vainio H, Metsola K, Hirvonen A (2007) CYP1A1 and CYP1B1 genetic polymorphisms, smoking and breast cancer risk in a Finnish Caucasian population. Breast Cancer Res Treat 104:287–297

    Article  PubMed  Google Scholar 

  30. Khedhaier A, Hassen E, Bouaouina N, Gabbouj S, Ahmed SB, Chouchane L (2008) Implication of xenobiotic metabolizing enzyme gene (CYP2E1, CYP2C19, CYP2D6, mEH and NAT2) polymorphisms in breast carcinoma. BMC Cancer 8:109

    Article  PubMed  Google Scholar 

  31. Egeberg R, Olsen A, Autrup H, Christensen J, Stripp C, Tetens I, Overvad K, Tjonneland A (2008) Meat consumption, N-acetyl transferase 1 and 2 polymorphism and risk of breast cancer in Danish postmenopausal women. Eur J Cancer Prev 17:39–47

    Article  CAS  PubMed  Google Scholar 

  32. Baumgartner KB, Schlierf TJ, Yang D, Doll MA, Hein DW (2009) N-acetyltransferase 2 genotype modification of active cigarette smoking on breast cancer risk among hispanic and non-hispanic white women. Toxicol Sci 112:211–220

    Article  CAS  PubMed  Google Scholar 

  33. Rabstein S, Bruning T, Harth V, Fischer HP, Haas S, Weiss T, Spickenheuer A, Pierl C, Justenhoven C, Illig T, Vollmert C, Baisch C, Ko YD, Hamann U, Brauch H, Pesch B (2010) N-acetyltransferase 2, exposure to aromatic and heterocyclic amines, and receptor-defined breast cancer. Eur J Cancer Prev 19:100–109

    Article  CAS  PubMed  Google Scholar 

  34. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560

    Article  PubMed  Google Scholar 

  35. Tobias A (1999) Assessing the influence of a single study in the meta-analysis estimate. Stata Tech Bull 8:15–17

    Google Scholar 

  36. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    CAS  PubMed  Google Scholar 

  37. Hoffmann D, Hoffmann I, El-Bayoumy K (2001) The less harmful cigarette: a controversial issue. A tribute to Ernst L. Wynder. Chem Res Toxicol 14:767–790

    Article  CAS  PubMed  Google Scholar 

  38. Faraglia B, Chen SY, Gammon MD, Zhang Y, Teitelbaum SL, Neugut AI, Ahsan H, Garbowski GC, Hibshoosh H, Lin D, Kadlubar FF, Santella RM (2003) Evaluation of 4-aminobiphenyl-DNA adducts in human breast cancer: the influence of tobacco smoke. Carcinogenesis 24:719–725

    Article  CAS  PubMed  Google Scholar 

  39. Naito S, Tanaka K, Koga H, Kotoh S, Hirohata T, Kumazawa J (1995) Cancer occurrence among dyestuff workers exposed to aromatic amines. A long term follow-up study. Cancer 76:1445–1452

    Article  CAS  PubMed  Google Scholar 

  40. Hoffmann D, Hoffmann I (1997) The changing cigarette, 1950–1995. J Toxicol Environ Health 50:307–364

    Article  CAS  PubMed  Google Scholar 

  41. Talaska G (2003) Aromatic amines and human urinary bladder cancer: exposure sources and epidemiology. J Environ Sci Health C 21:29–43

    Article  Google Scholar 

  42. Swaminathan S, Frederickson SM, Hatcher JF (1994) Metabolic activation of N-hydroxy-4-acetylaminobiphenyl by cultured human breast epithelial cell line MCF 10A. Carcinogenesis 15:611–617

    Article  CAS  PubMed  Google Scholar 

  43. Vineis P, Bartsch H, Caporaso N, Harrington AM, Kadlubar FF, Landi MT, Malaveille C, Shields PG, Skipper P, Talaska G, Et A (1994) Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens. Nature 369:154–156

    Article  CAS  PubMed  Google Scholar 

  44. Firozi PF, Bondy ML, Sahin AA, Chang P, Lukmanji F, Singletary ES, Hassan MM, Li D (2002) Aromatic DNA adducts and polymorphisms of CYP1A1, NAT2, and GSTM1 in breast cancer. Carcinogenesis 23:301–306

    Article  CAS  PubMed  Google Scholar 

  45. Michnovicz JJ, Naganuma H, Hershcopf RJ, Bradlow HL, Fishman J (1988) Increased urinary catechol estrogen excretion in female smokers. Steroids 52:69–83

    Article  CAS  PubMed  Google Scholar 

  46. Bartsch H, Malaveille C, Friesen M, Kadlubar FF, Vineis P (1993) Black (air-cured) and blond (flue-cured) tobacco cancer risk. IV: Molecular dosimetry studies implicate aromatic amines as bladder carcinogens. Eur J Cancer 29A:1199–1207

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xi-Chun Hu.

Additional information

Jian Zhang and Li-Xin Qiu equally contributed to this work and should be considered as co-first authors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, J., Qiu, LX., Wang, ZH. et al. NAT2 polymorphisms combining with smoking associated with breast cancer susceptibility: a meta-analysis. Breast Cancer Res Treat 123, 877–883 (2010). https://doi.org/10.1007/s10549-010-0807-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-010-0807-1

Keywords

Navigation