Skip to main content

Advertisement

Log in

A prospective study of genetic polymorphism in MPO, antioxidant status, and breast cancer risk

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

Abstract

Oxidative stress may be involved in breast carcinogenesis. Myeloperoxidase (MPO) is an endogenous oxidant enzyme that generates reactive oxygen species (ROS). A single nucleotide polymorphism (SNP) G-463A in the promoter region has been associated with a decrease in risk of breast cancer. We assessed the association between this polymorphism and breast cancer risk in a nested case-control study within the Nurses’ Health Study (1,269 incident breast cancer cases and 1,761 matched controls). We further investigated potential gene-gene and gene-environment interactions. There were no significant associations between MPO or COMT genotypes and risk of breast cancer. However, the combination of a priori hypothesized low-risk genotypes in MPO and COMT genes was associated with a marginally significant decrease in breast cancer risk (OR, 0.28; 95% CI, 0.08–1.00). Dietary intake and plasma antioxidant levels may modify the association between the MPO polymorphism and breast cancer risk. Although the test for departure from multiplicative interaction was not significant, inverse associations with MPO genotype were more pronounced among women who consumed higher amounts of total fruits and vegetables (OR, 0.58; 95% CI, 0.30–1.12); this association was not found among the low-consumption group (OR, 1.11; 95% CI, 0.63–1.96). The relative risk associated with the MPO homozygous variant genotype was 0.44 (95% CI, 0.18–1.09) for women who had the highest level of plasma carotenoids. Results from this study suggest that exogenous and endogenous modulators of oxidative stress may modify the association between the MPO polymorphism and breast cancer risk. Further research is needed to confirm these possible associations.

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.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ambrosone CB (2000) Oxidants and antioxidants in breast cancer. Antioxid Redox Signal 2:903–917

    Article  PubMed  CAS  Google Scholar 

  2. Feig DI, Reid TM, Loeb LA (1994) Reactive oxygen species in tumorigenesis. Cancer Res 54:1890s–1894s

    PubMed  CAS  Google Scholar 

  3. Cooke MS, Evans MD, Dizdaroglu M et al (2003) Oxidative DNA damage: mechanisms, mutation, and disease. Faseb J 17:1195–1214

    Article  PubMed  CAS  Google Scholar 

  4. de Zwart LL, Meerman JH, Commandeur JN et al (1999) Biomarkers of free radical damage applications in experimental animals and in humans. Free Radic Biol Med 26:202–226

    Article  PubMed  Google Scholar 

  5. Lancaster JR Jr, Xie K (2006) Tumors face NO problems? Cancer Res 66:6459–6462

    Article  PubMed  CAS  Google Scholar 

  6. Arnhold J (2004) Properties, functions, and secretion of human myeloperoxidase. Biochemistry (Mosc) 69:4–9

    Article  CAS  Google Scholar 

  7. Gilbert DL CC (1999) Reactive oxygen species in biological systems: an interdisciplinary approach. Kluwer Academic/Plenum Publishers, New York

    Google Scholar 

  8. Klebanoff SJ (2005) Myeloperoxidase: friend and foe. J Leukoc Biol 77:598–625

    Article  PubMed  CAS  Google Scholar 

  9. Kiyohara C, Yoshimasu K, Takayama K et al (2005) NQO1, MPO, and the risk of lung cancer: a HuGE review. Genet Med 7:463–478

    Article  PubMed  CAS  Google Scholar 

  10. Hansson M, Olsson I, Nauseef WM (2006) Biosynthesis, processing, and sorting of human myeloperoxidase. Arch Biochem Biophys 445:214–224

    Article  PubMed  CAS  Google Scholar 

  11. Feyler A, Voho A, Bouchardy C et al (2002) Point: myeloperoxidase -463G→ a polymorphism and lung cancer risk. Cancer Epidemiol Biomarkers Prev 11:1550–1554

    PubMed  CAS  Google Scholar 

  12. Schabath MB, Spitz MR, Hong WK et al (2002) A myeloperoxidase polymorphism associated with reduced risk of lung cancer. Lung Cancer 37:35–40

    Article  PubMed  Google Scholar 

  13. Pakakasama S, Chen TT, Frawley W et al (2003) Myeloperoxidase promotor polymorphism and risk of hepatoblastoma. Int J Cancer 106:205–207

    Article  PubMed  CAS  Google Scholar 

  14. Larsen JE, Colosimo ML, Yang IA et al (2006) CYP1A1 Ile462Val and MPO G-463A interact to increase risk of adenocarcinoma but not squamous cell carcinoma of the lung. Carcinogenesis 27:525–532

    Article  PubMed  CAS  Google Scholar 

  15. Olson SH, Carlson MD, Ostrer H et al (2004) Genetic variants in SOD2, MPO, and NQO1, and risk of ovarian cancer. Gynecol Oncol 93:615–620

    Article  PubMed  CAS  Google Scholar 

  16. Hung RJ, Boffetta P, Brennan P et al (2004) Genetic polymorphisms of MPO, COMT, MnSOD, NQO1, interactions with environmental exposures and bladder cancer risk. Carcinogenesis 25:973–978

    Article  PubMed  CAS  Google Scholar 

  17. Ahn J, Gammon MD, Santella RM et al (2004) Myeloperoxidase genotype, fruit and vegetable consumption, and breast cancer risk. Cancer Res 64:7634–7639

    Article  PubMed  CAS  Google Scholar 

  18. Lin SC, Chou YC, Wu MH et al (2005) Genetic variants of myeloperoxidase and catechol-O-methyltransferase and breast cancer risk. Eur J Cancer Prev 14:257–261

    Article  PubMed  Google Scholar 

  19. Yang J, Ambrosone CB, Hong CC et al (2007) Relationships between polymorphisms in NOS3 and MPO genes, cigarette smoking and risk of post-menopausal breast cancer. Carcinogenesis 28:1247–1253

    Article  PubMed  CAS  Google Scholar 

  20. Hu YJ, Diamond AM (2003) Role of glutathione peroxidase 1 in breast cancer: loss of heterozygosity and allelic differences in the response to selenium. Cancer Res 63:3347–3351

    PubMed  CAS  Google Scholar 

  21. Sutton A, Khoury H, Prip-Buus C et al (2003) The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria. Pharmacogenetics 13:145–157

    Article  PubMed  CAS  Google Scholar 

  22. Sutton A, Imbert A, Igoudjil A et al (2005) The manganese superoxide dismutase Ala16Val dimorphism modulates both mitochondrial import and mRNA stability. Pharmacogenet Genomics 15:311–319

    PubMed  CAS  Google Scholar 

  23. Creveling CR (2003) The role of catechol-O-methyltransferase in the inactivation of catecholestrogen. Cell Mol Neurobiol 23:289–291

    Article  PubMed  CAS  Google Scholar 

  24. Guldberg HC, Marsden CA (1975) Catechol-O-methyl transferase: pharmacological aspects and physiological role. Pharmacol Rev 27:135–206

    PubMed  CAS  Google Scholar 

  25. Zhu BT (2002) Catechol-O-Methyltransferase (COMT)-mediated methylation metabolism of endogenous bioactive catechols and modulation by endobiotics and xenobiotics: importance in pathophysiology and pathogenesis. Curr Drug Metab 3:321–349

    Article  PubMed  CAS  Google Scholar 

  26. Lotta T, Vidgren J, Tilgmann C et al (1995) Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 34:4202–4210

    Article  PubMed  CAS  Google Scholar 

  27. Egan KM, Stampfer MJ, Hunter D et al (2002) Active and passive smoking in breast cancer: prospective results from the Nurses’ Health Study. Epidemiology 13:138–145

    Article  PubMed  Google Scholar 

  28. Willett WC, Sampson L, Browne ML et al (1988) The use of a self-administered questionnaire to assess diet four years in the past. Am J Epidemiol 127:188–199

    PubMed  CAS  Google Scholar 

  29. Willett W, Stampfer MJ (1986) Total energy intake: implications for epidemiologic analyses. Am J Epidemiol 124:17–27

    PubMed  CAS  Google Scholar 

  30. Hu FB, Stampfer MJ, Rimm E et al (1999) Dietary fat and coronary heart disease: a comparison of approaches for adjusting for total energy intake and modeling repeated dietary measurements. Am J Epidemiol 149:531–540

    PubMed  CAS  Google Scholar 

  31. Willett WC (1998) Nutritional epidemiology. Oxford University Press, New York

    Google Scholar 

  32. Stryker WS, Kaplan LA, Stein EA et al (1988) The relation of diet, cigarette smoking, and alcohol consumption to plasma beta-carotene and alpha-tocopherol levels. Am J Epidemiol 127:283–296

    PubMed  CAS  Google Scholar 

  33. Michaud DS, Giovannucci EL, Ascherio A et al (1998) Associations of plasma carotenoid concentrations and dietary intake of specific carotenoids in samples of two prospective cohort studies using a new carotenoid database. Cancer Epidemiol Biomarkers Prev 7:283–290

    PubMed  CAS  Google Scholar 

  34. El-Sohemy A, Baylin A, Kabagambe E et al (2002) Individual carotenoid concentrations in adipose tissue and plasma as biomarkers of dietary intake. Am J Clin Nutr 76:172–179

    PubMed  CAS  Google Scholar 

  35. Tamimi RM, Hankinson SE, Campos H et al (2005) Plasma carotenoids, retinol, and tocopherols and risk of breast cancer. Am J Epidemiol 161:153–160

    Article  PubMed  Google Scholar 

  36. Han J, Tranah GJ, Hankinson SE et al (2006) Polymorphisms in O6-methylguanine DNA methyltransferase and breast cancer risk. Pharmacogenet Genomics 16:469–474

    Article  PubMed  CAS  Google Scholar 

  37. Albano E (2006) Alcohol, oxidative stress and free radical damage. Proc Nutr Soc 65:278–290

    Article  PubMed  CAS  Google Scholar 

  38. IARC (2000) Tobacco smoke and involuntary smoking (83). In Monographs on The Evaluation of The Carcinogenic Risk of Chemicals to Humans. IRAC Scientific Publications, Lyon

    Google Scholar 

  39. Piedrafita FJ, Molander RB, Vansant G et al (1996) An Alu element in the myeloperoxidase promoter contains a composite SP1-thyroid hormone-retinoic acid response element. J Biol Chem 271:14412–14420

    Article  PubMed  CAS  Google Scholar 

  40. Reynolds WF, Chang E, Douer D et al (1997) An allelic association implicates myeloperoxidase in the etiology of acute promyelocytic leukemia. Blood 90:2730–2737

    PubMed  CAS  Google Scholar 

  41. Van Schooten FJ, Boots AW, Knaapen AM et al (2004) Myeloperoxidase (MPO) -463G→ A reduces MPO activity and DNA adduct levels in bronchoalveolar lavages of smokers. Cancer Epidemiol Biomarkers Prev 13:828–833

    PubMed  Google Scholar 

  42. Bekesi G, Kakucs R, Varbiro S et al (2001) Induced myeloperoxidase activity and related superoxide inhibition during hormone replacement therapy. Bjog 108:474–481

    Article  PubMed  CAS  Google Scholar 

  43. Marcozzi FG, Madia F, Del Bianco G et al (2000) Lacrimal fluid peroxidase activity during the menstrual cycle. Curr Eye Res 20:178–182

    Article  PubMed  CAS  Google Scholar 

  44. Reynolds WF, Rhees J, Maciejewski D et al (1999) Myeloperoxidase polymorphism is associated with gender specific risk for Alzheimer’s disease. Exp Neurol 155:31–41

    Article  PubMed  CAS  Google Scholar 

  45. Norris J, Fan D, Aleman C et al (1995) Identification of a new subclass of Alu DNA repeats which can function as estrogen receptor-dependent transcriptional enhancers. J Biol Chem 270:22777–22782

    Article  PubMed  CAS  Google Scholar 

  46. Porter W, Saville B, Hoivik D et al (1997) Functional synergy between the transcription factor Sp1 and the estrogen receptor. Mol Endocrinol 11:1569–1580

    Article  PubMed  CAS  Google Scholar 

  47. Creveling CR (2001) Estrogen metabolism: Does the formation of estrogen quinone provide a potential pathway to breast carcinogenesis? Proceedings of the 9th international catecholamine symposium, Kyoto, Japan

  48. Dawling S, Roodi N, Mernaugh RL et al (2001) Catechol-O-methyltransferase (COMT)-mediated metabolism of catechol estrogens:comparison of wild-type and variant COMT isoforms. Cancer Res 61:6716–6722

    PubMed  CAS  Google Scholar 

  49. Lachman HM, Papolos DF, Saito T et al (1996) Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6:243–250

    Article  PubMed  CAS  Google Scholar 

  50. Raftogianis R, Creveling C, Weinshilboum R et al (2000) Estrogen metabolism by conjugation. J Natl Cancer Inst Monogr:113–124

  51. Cavalieri E, Frenkel K, Liehr JG et al (2000) Estrogens as endogenous genotoxic agents–DNA adducts and mutations. J Natl Cancer Inst Monogr:75–93

  52. Yim DS, Parkb SK, Yoo KY et al (2001) Relationship between the Val158Met polymorphism of catechol O-methyl transferase and breast cancer. Pharmacogenetics 11:279–286

    Article  PubMed  CAS  Google Scholar 

  53. Huang CS, Chern HD, Chang KJ et al (1999) Breast cancer risk associated with genotype polymorphism of the estrogen-metabolizing genes CYP17, CYP1A1, and COMT: a multigenic study on cancer susceptibility. Cancer Res 59:4870–4875

    PubMed  CAS  Google Scholar 

  54. Millikan RC, Pittman GS, Tse CK et al (1998) Catechol-O-methyltransferase and breast cancer risk. Carcinogenesis 19:1943–1947

    Article  PubMed  CAS  Google Scholar 

  55. Wen W, Cai Q, Shu XO et al (2005) Cytochrome P450 1B1 and catechol-O-methyltransferase genetic polymorphisms and breast cancer risk in Chinese women: results from the shanghai breast cancer study and a meta-analysis. Cancer Epidemiol Biomarkers Prev 14:329–335

    Article  PubMed  CAS  Google Scholar 

  56. Mitrunen K, Jourenkova N, Kataja V et al (2001) Polymorphic catechol-O-methyltransferase gene and breast cancer risk. Cancer Epidemiol Biomarkers Prev 10:635–640

    PubMed  CAS  Google Scholar 

  57. Hamajima N, Matsuo K, Tajima K et al (2001) Limited association between a catechol-O-methyltransferase (COMT) polymorphism and breast cancer risk in Japan. Int J Clin Oncol 6:13–18

    Article  PubMed  CAS  Google Scholar 

  58. Wedren S, Rudqvist TR, Granath F et al (2003) Catechol-O-methyltransferase gene polymorphism and post-menopausal breast cancer risk. Carcinogenesis 24:681–687

    Article  PubMed  CAS  Google Scholar 

  59. Thompson PA, Shields PG, Freudenheim JL et al (1998) Genetic polymorphisms in catechol-O-methyltransferase, menopausal status, and breast cancer risk. Cancer Res 58:2107–2110

    PubMed  CAS  Google Scholar 

  60. Hu Z, Song CG, Lu JS et al (2007) A multigenic study on breast cancer risk associated with genetic polymorphisms of ER Alpha, COMT and CYP19 gene in BRCA1/BRCA2 negative Shanghai women with early onset breast cancer or affected relatives. J Cancer Res Clin Oncol 133:969–978

    Article  PubMed  CAS  Google Scholar 

  61. Duthie SJ, Ma A, Ross MA et al (1996) Antioxidant supplementation decreases oxidative DNA damage in human lymphocytes. Cancer Res 56:1291–1295

    PubMed  CAS  Google Scholar 

  62. Pool-Zobel BL, Bub A, Muller H et al (1997) Consumption of vegetables reduces genetic damage in humans: first results of a human intervention trial with carotenoid-rich foods. Carcinogenesis 18:1847–1850

    Article  PubMed  CAS  Google Scholar 

  63. Collins AR, Olmedilla B, Southon S et al (1998) Serum carotenoids and oxidative DNA damage in human lymphocytes. Carcinogenesis 19:2159–2162

    Article  PubMed  CAS  Google Scholar 

  64. Torbergsen AC, Collins AR (2000) Recovery of human lymphocytes from oxidative DNA damage; the apparent enhancement of DNA repair by carotenoids is probably simply an antioxidant effect. Eur J Nutr 39:80–85

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Hardeep Ranu, Craig Labadie, and Pati Soule for their genotyping assistance, Carolyn Guo and Karen Corsano for their programming support. We also thank the participants in the Nurses’ Health Study for their outstanding dedication and commitment. This work was supported by National Institutes of Health grants CA098233, CA118447, CA065725, USA.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chunyan He.

Electronic supplementary material

Below is the link to the electronic supplementary material.

(PDF 473 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

He, C., Tamimi, R.M., Hankinson, S.E. et al. A prospective study of genetic polymorphism in MPO, antioxidant status, and breast cancer risk. Breast Cancer Res Treat 113, 585–594 (2009). https://doi.org/10.1007/s10549-008-9962-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-008-9962-z

Keywords:

Navigation