Skip to main content

Breast Tissue Organochlorine Levels and Metabolic Genotypes in Relation to Breast Cancer Risk Canada

Cancer Causes & Control volume 15, pages 399–418 (2004)Cite this article

Abstract

Genes that metabolize the rate of clearance of environmental carcinogens may be candidate genes for cancer susceptibility. There is some data to suggest that exposure to environmental pesticides and other organochlorine pollutants is a risk factor to breast cancer. It is therefore reasonable to ask if variants in the genes responsible for the metabolic activation of organochlorines are associated with different tissue burdens of organochlorines and if these variants modify the risk of breast cancer in the population. We conducted a case–control study of women who underwent an excision biopsy for suspected breast cancer in a Toronto hospital from 1995 to 1997. Patients are residents of the Greater Toronto Area and are primarily Caucasian of European descent. Cases were women with invasive breast cancer (n = 70) and controls (n = 69) were women diagnosed with benign disease, frequency matched by age to cases. Levels of organochlorines were measured in benign breast tissue and seven polymorphisms in five candidate genes were genotyped. In general, women who carried inactive alleles of the GSTM1 had higher levels of breast organochlorines, and were at modestly increased risk of breast cancer (odds ratio = 2.2; 95% CI = 1.1–4.4). However, multiple comparisons were made and generally our data do not support the hypothesis that organochlorines increase the risk of breast cancer among subgroups of women with specific metabolic genotypes.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Narod SA (2002) Modifiers of risk of hereditary breast and ovarian cancer. Nature Rev Cancer. 2: 113–123.

    Google Scholar 

  2. Malkin D, Li FP, Strong LC, et al. (1990) Gemline p53 mutations in a familial syndrome of breast cancer, sarcomas and other neoplasms. Science 250: ¦.

  3. Chevinex-Trench G, Spurdle AB, Gatei M, et al. (2002) Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 6: 205–215.

    Google Scholar 

  4. Meijers-Heijboer H, van den Ouewland A, Klijn A. et al. (2002) Low penetrance susceptibility to breast cancer due to CHEK2(*) 1100delC in non-carriers of BRCA1 and BRCA2 mutations. Nat Genet 1: 55–59.

    Google Scholar 

  5. Cosma G, Crofts F, Taioli E, et al. (1993). Relationship between genotype and function of the human CYP1A1 gene. J Toxicol Environ Health 40: 309–316.

    PubMed  Google Scholar 

  6. Drahushuk AT, Choy CO, Kumar S, Mcreynolds JH, Olson JR (1997) Modulation of cytochrome P450 by 5,5'-bis-triflouromethyl-2-2'-dichlorobiphenyl, a unique environmental contaminant. Toxicology 120: 197–205.

    PubMed  Google Scholar 

  7. 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  Google Scholar 

  8. Rebbeck TM, Rosvold EA, Duggan DJ, et al. (1994) Genetics of CYP1A1: coamplification of specific alleles by polymerase chain reaction and association with breast cancer. Cancer Epidemiol Biomark Prev 3: 511–514.

    Google Scholar 

  9. Ambrosone CB, Freudenheim JL, Graham S, et al. (1995) Cytochrome P4501A1 and glutathione s-transferase (M1) genetic polymorphisms and postmenopausal breast cancer risk. Cancer Res 55: 3483–3485.

    PubMed  Google Scholar 

  10. Huang CS, Shen CY, Chang KJ, et al. (1999) Cytochrome P4501A1 polymorphism as a susceptibility factor for breast cancer in postmenopausal Chinese women in Taiwan. Brit J Cancer 80: 1838–1843.

    PubMed  Google Scholar 

  11. Landi MT, Sinha R, Lang NP, Kadlubar FF (1999) Human cytochrome P4501A2. IARC Scientific Publications (148), pp. 173–195.

  12. Nakajima M, Yokoi T, Mizutani M, et al. (1999) Genetic polymorphism in the 5'-flanking region of human CYP1A2 gene: e.ect on CYP1A2 inducibility in humans. J Biochem 4: 803–808.

    Google Scholar 

  13. Guengerich FP, et al. (1986) Characterization of rat and human liver micorsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. J Biol Chem 261: 5051–5060.

    PubMed  Google Scholar 

  14. Guengerich FP (1988) Oxidation of 17 alpha-ethynylestradiol by human liver cytochrome P-450. Mol Pharmacol 33: 500–508.

    PubMed  Google Scholar 

  15. Bork RW, et al. (1989) Characterization of mRNA species related to human liver cytochrome P-450 nifedipine oxidase and the regulation of catalytic activity. J Biol Chem 264: 910–919.

    PubMed  Google Scholar 

  16. Hukkanen J, et al. (1998) Expression of cytochrome P450 genes encoding enzymes active in metabolism of tamoxifen in human uterine endometrium. Pharmacol Toxicol 82: 93–97.

    PubMed  Google Scholar 

  17. Rebbeck T.R, et al. (1998) Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 90: 1225–1229.

    PubMed  Google Scholar 

  18. Spurdle AB, Goodwin B, Hodgson E, et al. (2002) The CYP3A4*1B polymorphism has no functional significance and is not associated with risk of breast or ovarian cancer. Pharmacogenetics 5: 355–366.

    Google Scholar 

  19. Amirimani B, Walker AH, Weber BL, Rebbeck TR (1999) RESPONSE: re modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 91: 1588–1590.

    PubMed  Google Scholar 

  20. Raunio H, Husgafvel-Pursiainen K, Anttila S, et al. (1995) Diagnosis of polymorphisms in carcinogen-activating and inactivating enzymes and cancer susceptibility: a review. Gene (Amst) 159: 113–121.

    Google Scholar 

  21. Seidegard J, Pero RW, Markowitz MM, et al. (1990) Isoenzymes of glutathione transferase (class l) as a marker for the susceptibility to lung cancer: a follow-up study. Carcinogenesis (Lond.) 11: 33–36.

    Google Scholar 

  22. Bailey LR, Roodi N, Verrier CS, et al. (1988) Breast cancer and CYP1A1, G-STM1, and GSTT1 polymorphisms: Evidence of a lack of association in Caucasians and African Americans. Cancer Res 58: 65–70.

    Google Scholar 

  23. Garcia-Closas M, Kelsey KT, Hankinson HE, et al. (1999) Glutathione s-transferase mu and theta polymorphisms and breast cancer susceptibility. J Natl Cancer Inst 91: 1960–1964.

    PubMed  Google Scholar 

  24. Curran JE, Weinstein SR, Griffiths LR (2000) Polymorphisms of glutathione s-transferase genes (GSTM1, GSTP1 and GSTT1) and breast cancer susceptibility. Cancer Lett 153: 113–120.

    PubMed  Google Scholar 

  25. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (1976) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemical to Humans: polychlorinated Biphenyls and Polybrominated Biphenyls, Vol. 18. Lyon, France: IARC.

    Google Scholar 

  26. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (1987) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans: overall Evaluations of Carcinogenicity: an Updating of IARC Monographs, Vol. 1-42 (Suppl. 007). Lyon, France: IARC.

    Google Scholar 

  27. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (1991) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans: occupational Exposures in Insecticide Application, and Some Pesticides, Vol. 53. Lyon, France: IARC.

    Google Scholar 

  28. Woolcott CG, Aronson KJ (2001) Organochlorines: a Meta-analysis. In: review of Lifestyle and Environmental Risk Factors for Breast Cancer: report of the Working Group on Primary Prevention of Breast Cancer. Health Canada (ISBN 0-662-30817-4).

  29. Laden FG, Collman G, Iwamoto K, et al. (2001) 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene and polychlorinated biphenyls and breast cancer: combined analysis of five US Studies. J Natl Cancer Inst 93: 768–775.

    PubMed  Google Scholar 

  30. Moysich KB (2001) Research commentary: thoughts on recent findings regarding organochlorines and breast cancer risk. The Ribbon 6: 5–6.

    Google Scholar 

  31. Aronson KJ, Miller AB, Woolcott CG, et al. (2000) Breast adipose tissue concentrations of polychlorinated biphenyls and other organochlorines and breast cancer risk. Cancer Epidemiol Biomark Prev 9: 55–63.

    Google Scholar 

  32. Woolcott CG, Aronson KJ, Hanna WM, et al. (2001) Breast cancer risk and organochlorines by receptor status, tumor size and grade. Cancer Causes Control 12: 395–404.

    PubMed  Google Scholar 

  33. Demers A, Ayotte P, Brisson J, Dodin S, Robert J, Dewailly E (2002) Plasma concentrations of polychlorinated biphenyls and the risk of breast cancer: a congener-specific analysis. Am J Epidemiol 155: 629–635.

    PubMed  Google Scholar 

  34. Hayashi SI, Watanabe J, Nakachi K, Kawajiri K (1991) PCR detection of an A/G polymorphism within exon 7 of the CYP1A1 gene. Nucleic Acids Res 19: 4797.

    Google Scholar 

  35. Cascorbi I, Brockmoller J, Roots I (1996) A C4887A polymorphism in exon 7 of human CYP1A1: population frequency, mutation linkages, and impact on lung cancer susceptibility. Cancer Res 56: 4965–4969.

  36. Park JY, Muscat JE, Ren O, et al. (1997) CYP1A1 and GSTM1 polymorphisms and oral cancer risk. Cancer Epidemiol Biomarkers Prev 10: 791–797.

    Google Scholar 

  37. Safe S (1989) Polychlorinated biphenyls (PCBs): mutagenicity and carcionogenicity. Mutat Res 224: 79–88.

    PubMed  Google Scholar 

  38. Korytko PJ, Casey AC, Bush B, Quimby FE (1999) Induction of hepatic cytochromes P450 in dogs exposed to a chronic low dose of polychlorinated biphenyls. Toxocol Sci 47: 752–761.

    Google Scholar 

  39. Helzlsouer KJ, Alberg AJ, Huang HY, et al. (1999) Serum concentrations of organochlorine compounds and the subsequent development of breast cancer. Cancer Epidemiol Biomarkers Prev 8: 525–532.

    PubMed  Google Scholar 

  40. Suchar La, Chang RL, Thomas PE, Rosen RE, LechConney AH (1996) Effects of phenobarbitol, dexamethasone and 3' methylcholanthrene administration on the metabolism of 17-ß estradiol on liver microsomes from female rats. Endocrinology 137: 663–667.

    PubMed  Google Scholar 

  41. Oysich KB, Shields PG, Freudenheim JL, et al. (1999) Polychlorinated biphenyls, cytochrome P4501A1 polymorphism, and post-menopausal breast cancer risk. Cancer Epidemiol Biomark Prev 8: 41–44.

    Google Scholar 

  42. Laden F, Ishibe N, Hankinson SE, et al. (2002) Polychlorinated biphenyls, cytocohrome 4501A1 and breast cancer risk in the Nurses Health Study. Cancer Epidemiol Biomark Prev 11: 1560–1565.

    Google Scholar 

  43. Adami HO, Lipworth L, Titus-Ernstor. L, et al. (1995) Organochlorine compounds and estrogen-related cancers in women. Cancer Causes Control 6: 551–566.

    PubMed  Google Scholar 

  44. Davidson EN, Yager JD (1997) Pesticides and breast cancer: fact or fad? J Natl Cancer Inst 89: 1743–1744.

    PubMed  Google Scholar 

  45. Deutch B, Hansen JC (2000) High human plasma levels of organochlorine compounds in Greenland. Regional differences and lifestyle effects. Danish Med Bull 47: 13207.

    Google Scholar 

Download references

Author information

Affiliations

  1. Department of Surgery, University Health Network, Toronto, Ontario

    David McCready

  2. Department of Community Health and Epidemiology and Division of Cancer Care and Epidemiology, Cancer Research Institute, Queen's University, Kingston, Ontario

    Kristan J. Aronson & Wenli Fan

  3. Centre for Research in Women's Health, Sunnybrook and Women's College Hospital, Toronto, Ontario

    William Chu, Danny Vesprini & Steven A. Narod

Authors
  1. David McCready
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kristan J. Aronson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenli Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Danny Vesprini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Steven A. Narod
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steven A. Narod.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

McCready, D., Aronson, K.J., Chu, W. et al. Breast Tissue Organochlorine Levels and Metabolic Genotypes in Relation to Breast Cancer Risk Canada. Cancer Causes Control 15, 399–418 (2004). https://doi.org/10.1023/B:CACO.0000027505.32564.c2

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:CACO.0000027505.32564.c2

  • breast cancer
  • organochlorines
  • genetics
  • metabolism
  • carcinogenesis