Breast Cancer Research and Treatment

, Volume 71, Issue 1, pp 59–65

Organochlorines, p53 mutations in relation to breast cancer risk and survival. A Danish cohort-nested case-controls study

  • Annette Pernille Høyer
  • Anne-Marie Gerdes
  • Torben Jørgensen
  • Fritz Rank
  • Helle Bøggild Hartvig
Article

Abstract

Epidemiological studies integrating genetic susceptibility with biological measurements of organochlorine exposure may provide new clues regarding these substances influence on breast cancer etiology. Initial attempts pursuing this avenue has dealt with polymorphisms in the carcinogen-metabolizing enzymes cytochrome P450 (CYPlAl). This study examined if mutations in the tumor suppressor gene p53 affected organochlorine exposure related breast cancer risk and survival. The material consisted of 162 breast cancer cases and 316 matched controls, who had participated, in the Copenhagen City Heart Study (CCHS) between 1976 and 1978. Cases diagnosed between study initiation and 1993 were identified by linkage to the Danish Cancer Registry. The case group served as a cohort in the survival analyses. Information on known and suspected breast cancer risk factors was obtained from CCHS, and the Danish Breast Cancer Cooperative Group provided information on tumor characteristics. Lipid adjusted serum concentrations of selected organochlorines were compared between cases and controls while stratifing by p53 mutation status. A non-significant increased risk of breast cancer was observed in the highest exposure level of dieldrin and polychlorinated biphenyls among women who developed a tumor with mutant p53 (odds ratio (OR) = 3.53, 95% confidence interval (CI) = 0.79–15.79 and OR = 3.00, 95% CI = 0.66–13.62). There was no clear difference in overall survival between breast cancer cases with 'wild-type' and mutant p53, although a significant dose-response relationship appeared for dieldrin exposure in tumors with 'wild-type' p53. These preliminary results suggest that p53 mutations may have a modifying effect on at least the breast cancer risk associated with exposures to organochlorines.

breast cancer risk and survival dieldrin genetic susceptibility mutations in the tumor suppressor gene p53 oganochlorine exposure polychlorinated biphenyls 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    Ahlborg UG, Lipworth L, Titus-Ernstoff L: Organochlorine compounds in relation to breast cancer, endometrial cancer, and endometriosis: an assessment of the biological and epidemiological evidence. Crit Rev Toxicol 25: 463–531, 1995Google Scholar
  2. 2.
    Wolff MS, Toniolo PG, Lee EW, Rivera LM, Dubin N: Blood levels of organochlorine residues and risk of breast cancer. J Natl Cancer Inst 85: 648–652, 1993Google Scholar
  3. 3.
    Kreiger N, Wolff MS, Haitt RA, Rivera M, Vogelman J, Orentreich N: Breast cancer and serum organochlorines: a prospective study among White, Black, and Asian women. J Natl Cancer Inst 86: 589–599, 1994Google Scholar
  4. 4.
    Hunter DJ, Hankinson SE, Laden F, Colditz GA, Manson JE, Wilett WC, Speizer FE, Wolff MS: Plasma organochlorine levels and risk of breast cancer. N Engl J Med 18: 1253–1258, 1997Google Scholar
  5. 5.
    van't Veer P, Lobbezoo IE, Martin-Moreno JM, Guallar E, Gomez-Aracena J, Kardinall AFM, Kohlmeier L, Martin BC, Strain JJ, Thamm M, van Zoonen P, Baumaun BA, Huttunen JK, Kok FJ: DDT (dicophane), and postmenopausal breast cancer in Europe: case-control study. Br Med J 315: 81–85, 1997Google Scholar
  6. 6.
    Zheng T, Holford TR, Mayne ST, Ward B, Carter D, Owens PH, Dubrow R, Zahn SH, Boyle P, Archibeque S, Tessari J: DDE and DDT in breast adipose tissue and risk of female breast cancer. Am J Epidemiol 150(5): 453–458, 1999Google Scholar
  7. 7.
    Dorgan JF, Brock JW, Rothman N, Needham LL, Miller R, Stephenson HE, Schussler N, Taylor PR: Serum organochlorine pesticides and PCBs and breast cancer risk: results from a prospective analysis (USA). Cancer Causes Cortrol 10: 1–11, 1999Google Scholar
  8. 8.
    Dewailly E, Dobin S, Verreault R, Ayotte P, Sauve L, Morin J: High organochlorine body burden in women with estrogen receptor positive breast cancer. J Natl Cancer Inst 86: 232–234, 1994Google Scholar
  9. 9.
    Helzlsour KJ, Alberg AJ, Huang H-A, Hoffman SC, Trickland PT, Brock JW, Burse VW, Needham LL, Bell DA, Lavigne JA, Yager JD, Comstock GW: Serum concentrations of organochlorine compounds and the subsequent development of breast cancer. Cancer Epidemiol Biomark Prev 8: 525–532, 1999Google Scholar
  10. 10.
    Høyer AP, Jørgensen T, Grandjean AP, Hartvig HB: Repeated measurements of organochlorine exposure and breast cancer risk Cancer Causes Control 11: 177–184, 2000Google Scholar
  11. 11.
    Moysich KB, Ambrosone CB, Vena JE, Shields PG, Mendola P, Kostyniak P, Greizerstein H, Graham H, Marshall JR, Schisterman EF, Freudenheim JL: Environmental organochlorine exposure and postmenopausal breast cancer risk. Cancer Epidemiol Biomark Prev 7: 181–188, 1998Google Scholar
  12. 12.
    Zheng T, Holford TR, Mayne ST, Tessari J, Owens PH, Zahm SH, Zhang B, Dubrow R, Ward B, Carter D, Boyle P: Environmental exposure to Hexachlorobenzene (HCB) and risk of female breast cancer in Connecticut. Cancer Epidemiol Biomark Prev 8: 407–411, 1999Google Scholar
  13. 13.
    Høyer AP, Grandjean AP, Jørgensen T, Brock JW, Hartvig HB: Organochlorine exposure and risk of breast cancer. Lancet 352: 1816–1820, 1998Google Scholar
  14. 14.
    Høyer AP, Jørgensen T, Brock JW, Grandjean AP: Organochlorine exposure and breast cancer survival. J Clin Epidemiol 53: 323–330, 2000Google Scholar
  15. 15.
    Millikan R, DeVoto E, Newman B, Savitz D: Studying environmental influences and breast cancer risk: suggestions for an integrated population-based approach. Breast Cancer Res Treat 35: 789–789 1995Google Scholar
  16. 16.
    Biggs PJ, Warren W, Venitt S, Stratton MR: Does a genotoxic carcinogen contribute to human breast cancer? The value of mutational spectra in unravelling the aetiology of cancer. Mutagenesis 8(4): 275–283, 1993Google Scholar
  17. 17.
    Mukhopadhyay T, Maxwell SA, Roth JA p53 Suppressor Gene. Springer-Verlag, New York, Berlin, Heidelberg, London, Paris, Tokyo, Hong Kong, Barcelona, Budapest, 1995Google Scholar
  18. 18.
    Barnes DM, Camplejohn RS:p53, apotosis, and breast cancer. J Mamm Gland Biol Neoplasia 1(2): 163–175, 1996Google Scholar
  19. 19.
    Appleyard M: The Copenhagen City Heart Study.Østerbroundersøgelsen. Scand J Soc Med (suppl) 41: 1987Google Scholar
  20. 20.
    Østerlind A, Jensen OM: Evaluation of registration of cancer cases in 1977: preliminary evaluation of registration of cancer cases by the Cancer and National Pateint Registry. Ugeskr Læg, Denmark 147: 2483, 1985Google Scholar
  21. 21.
    Brock JW, Burse VW, Ashley DL, Najam AR, Greem VE, Korver MP, Powell MK, Hodge CC, Needham LL: An improved analysis for chlorinated pesticdes and polychiorinated biphenyls (PCBs) in human and bovine sera using solid-phase extraction. J Anal Toxicol 20: 528–536, 1996Google Scholar
  22. 22.
    Philipps DL, Pirkle JL, Burse VW, Bernert JT, Henderson O, Needham LL: Chlorinated hydrocarbon levels in human serum: effects of fasting and feeding. Arch Environ Contam Toxicol 18: 495–500, 1989Google Scholar
  23. 23.
    Chamberlain JS, Boehnke M, Frank TS, Kiosis S, Xu J, Guo SW, Hauser ER, Norum RA, Helmbold EA, Markel DS: BRCA 1 maps proximal to D17S579 on chromosome 17q21 by genetic analysis. Am J Hum Genet 52: 792–798, 1993Google Scholar
  24. 24.
    Gerdes A-M, Nielsen O, Mohr U, Pfeiffer P, Knoop A, Rose C, Horder M, Clausen PP: Correlation between molecular genetics analyses and immunohistochemical evaluation of the epidemal growth factor receptor and p185 (HBR2). Anticancer Res 18: 2529–2534, 1998Google Scholar
  25. 25.
    Guldberg P, Nedergaard T, Nielsen HJ, Olsen AC, Ahrenkiel V, Zeuthen J: Single-step DGGE-based mutation scanning of the p53 gene: application to genetic diagnosis of colorectal cancer. Hum Mutat 9: 348–355, 1997Google Scholar
  26. 26.
    Møller M, Ino Y, Gerdes A-M, Skjødt K, Louis DN, Pedersen NT: Abberations of the p53 pathway components p53, MDM2 and CDKN2A appear independent in diffuse large B cell lymphoma. Leukemia 13: 453–459, 1999Google Scholar
  27. 27.
    SAS Statistical Technical Report p-217. SAS/STAT Software, Version 6. SAS Institute, Cary, NC, USA, 1991Google Scholar
  28. 28.
    SPSS Base 7.5 Advanced Statistics. SPSS, Chicago, USA, 1997Google Scholar
  29. 29.
    Myosich KB, Shields PG, Freudenheim JL, Schisterman EF, Vena JF, Kostiniak P, Greiserstein H, Marshall JR, Graham S, Ambrosone CB: Polychlorinated biphenyls, cytochrome P4501A1 polymorphism, and postmenopausal breast cancer risk. Cancer Epidemiol Biomark Prev 8: 41–44, 1999Google Scholar
  30. 30.
    Pharoan PDP, Day NE, Caldas C: Somatc mutations in the p53 gene and prognosis in breast cancer: a meta-analysis. Br J Cancer 80(12): 1968–1972, 1999Google Scholar
  31. 31.
    Wright D, Manos M: Sample preparation from paraffinembedded tissues. In: Innis M (ed) PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, 1990Google Scholar
  32. 32.
    Williams C, Ponten F, Moberg C, Soderkvist P, Uhlen M, Poten J, Sitbon G, Lundberg J: A high frequency of sequence alterations is due to formalin fixation of archival specimens. Am J Pathol 155: 1467–1471, l999Google Scholar
  33. 33.
    Ewertz M: Survival of Danish cancer patients 1943–1987: breast. APMIS 33(101): 99–106, 1993Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Annette Pernille Høyer
    • 1
  • Anne-Marie Gerdes
    • 2
  • Torben Jørgensen
    • 3
  • Fritz Rank
    • 4
  • Helle Bøggild Hartvig
    • 5
  1. 1.The Copenhagen Center for Prospective Population StudiesDenmark
  2. 2.Department of Clinical GeneticsDenmark
  3. 3.Centre of Preventive MedicineKAS GlostrupGlostrup
  4. 4.Department of Pathologythe Copenhagen University HospitalCopenhagen
  5. 5.Department of BiostatisticsAarhus UniversityAarhus, Denmark

Personalised recommendations