Breast Cancer Research and Treatment

, Volume 112, Issue 1, pp 109–122 | Cite as

Common genetic variation in the IGF-1 gene, serum IGF-I levels and breast density

  • Martijn Verheus
  • James D. McKay
  • Rudolf Kaaks
  • Federico Canzian
  • Carine Biessy
  • Mattias Johansson
  • Diederick E. Grobbee
  • Petra H. M. Peeters
  • Carla H. van Gils
Epidemiology

Abstract

Introduction High breast density is one of the strongest known risk factors for developing breast cancer. Insulin-like growth factor I (IGF-I) is a strong mitogen and has been suggested to increase breast cancer risk by increasing the amount of dense tissue in the female breast. Objectives We wanted to investigate the effect of common variation in the IGF-1 gene on serum IGF-I levels and on breast density. Design and methods Mammograms and blood samples of 1,928 premenopausal participants of the Dutch Prospect-EPIC cohort were collected at baseline. Using a haplotype tagging approach, 16 single nucleotide polymorphisms (SNP) from three blocks covering the IGF-1 gene were genotyped in all study participants. Breast density was assessed using a quantitative computer-assisted method. For a subgroup of women, who went through menopause within 5 years after recruitment (n = 656), premenopausal IGF-I levels and additionally postmenopausal breast density were determined. False positive report probabilities (FPRP) for statistically significant relations were calculated using the Wacholder method. Results The minor alleles of five SNPs in block 3 were significantly associated with elevated levels of IGF-I (rs9989002, rs2033178, rs7136446, rs978458, rs6220; P-values: 0.01–0.04). The same SNPs were related with modestly higher percent breast density before menopause and—in the subgroup of women that became postmenopausal during follow-up—with a modestly higher percent breast density after menopause. The most significant result, i.e. the relation between rs6220 and IGF-I levels, had an FPRP  <0.5 assuming prior probabilities of 0.01 and higher. Conclusion Common genetic variation in the IGF-1 gene is related to circulating levels of IGF-I, but the relationship with breast density is indecisive.

Keywords

Insulin-like growth factor I SNP Circulating levels Breast density Menopause Prospective study Prospect-EPIC 

Notes

Acknowledgements

This study was supported by Grant Number 2002/11 of the World Cancer Research fund (WCRF).

References

  1. 1.
    Sachdev D, Yee D (2001) The IGF system and breast cancer. Endocr Relat Cancer 8:197–209PubMedCrossRefGoogle Scholar
  2. 2.
    Lee AV, Yee D (1995) Insulin-like growth factors and breast cancer. Biomed Pharmacother 49:415–421PubMedCrossRefGoogle Scholar
  3. 3.
    Hankinson SE, Willett WC, Colditz GA et al (1998) Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 351:1393–1396PubMedCrossRefGoogle Scholar
  4. 4.
    Toniolo P, Bruning PF, Akhmedkhanov A et al (2000) Serum insulin-like growth factor-I and breast cancer. Int J Cancer 88:828–832PubMedCrossRefGoogle Scholar
  5. 5.
    Krajcik RA, Borofsky ND, Massardo S et al (2002) Insulin-like growth factor I (IGF-I), IGF-binding proteins, and breast cancer. Cancer Epidemiol Biomarkers Prev 11:1566–1573PubMedGoogle Scholar
  6. 6.
    Muti P, Quattrin T, Grant BJ et al (2002) Fasting glucose is a risk factor for breast cancer: a prospective study. Cancer Epidemiol Biomarkers Prev 11:1361–1368PubMedGoogle Scholar
  7. 7.
    Allen NE, Roddam AW, Allen DS et al (2005) A prospective study of serum insulin-like growth factor-I (IGF-I), IGF-II, IGF-binding protein-3 and breast cancer risk. Br J Cancer 92:1283–1287PubMedCrossRefGoogle Scholar
  8. 8.
    Schernhammer ES, Holly JM, Pollak MN et al (2005) Circulating levels of insulin-like growth factors, their binding proteins, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 14:699–704PubMedCrossRefGoogle Scholar
  9. 9.
    Kaaks R, Lundin E, Rinaldi S et al (2002) Prospective study of IGF-I, IGF-binding proteins, and breast cancer risk, in northern and southern Sweden. Cancer Causes Control 13:307–316PubMedCrossRefGoogle Scholar
  10. 10.
    Rinaldi S, Peeters PH, Berrino F et al (2006) IGF-I, IGFBP-3 and breast cancer risk in women: the European prospective investigation into cancer and nutrition (EPIC). Endocr Relat Cancer 13:593–605PubMedCrossRefGoogle Scholar
  11. 11.
    Schernhammer ES, Holly JM, Hunter DJ et al (2006) Insulin-like growth factor-I, its binding proteins (IGFBP-1 and IGFBP-3), and growth hormone and breast cancer risk in The Nurses Health Study II. Endocr Relat Cancer 13:583–592PubMedCrossRefGoogle Scholar
  12. 12.
    Keinan-Boker L, Bueno De Mesquita HB, Kaaks R et al (2003) Circulating levels of insulin-like growth factor I, its binding proteins-1,-2,-3, C-peptide and risk of postmenopausal breast cancer. Int J Cancer 106:90–95PubMedCrossRefGoogle Scholar
  13. 13.
    Gronbaek H, Flyvbjerg A, Mellemkjaer L et al (2004) Serum insulin-like growth factors, insulin-like growth factor binding proteins, and breast cancer risk in postmenopausal women. Cancer Epidemiol Biomarkers Prev 13:1759–1764PubMedGoogle Scholar
  14. 14.
    Byrne C, Colditz GA, Willett WC et al (2000) Plasma insulin-like growth factor (IGF) I, IGF-binding protein 3, and mammographic density. Cancer Res 60:3744–3748PubMedGoogle Scholar
  15. 15.
    Maskarinec G, Williams AE, Kaaks R (2003) A cross-sectional investigation of breast density and insulin-like growth factor I. Int J Cancer 107:991–996PubMedCrossRefGoogle Scholar
  16. 16.
    Diorio C, Pollak M, Byrne C et al (2005) Insulin-like growth factor-I, IGF-binding protein-3, and mammographic breast density. Cancer Epidemiol Biomarkers Prev 14:1065–1073PubMedCrossRefGoogle Scholar
  17. 17.
    Boyd NF, Stone J, Martin LJ et al (2002) The association of breast mitogens with mammographic densities. Br J Cancer 87:876–882PubMedCrossRefGoogle Scholar
  18. 18.
    Lai JH, Vesprini D, Zhang W et al (2004) A polymorphic locus in the promoter region of the IGFBP3 gene is related to mammographic breast density. Cancer Epidemiol Biomarkers Prev 13:573–582PubMedGoogle Scholar
  19. 19.
    dos Santos Silva I, Johnson N, De Stavola B et al (2006) The insulin-like growth factor system and mammographic features in premenopausal and postmenopausal women. Cancer Epidemiol Biomarkers Prev 15:449–455PubMedCrossRefGoogle Scholar
  20. 20.
    Verheus M, Peeters PH, Kaaks R et al (2007) Premenopausal insulin-like growth factor-I serum levels and changes in breast density over menopause. Cancer Epidemiol Biomarkers Prev 16:451–457PubMedCrossRefGoogle Scholar
  21. 21.
    Goodman-Gruen D, Barrett-Connor E (1997) Epidemiology of insulin-like growth factor-I in elderly men and women. The Rancho Bernardo Study. Am J Epidemiol 145:970–976PubMedGoogle Scholar
  22. 22.
    Rollison DE, Newschaffer CJ, Tao Y et al (2006) Premenopausal levels of circulating insulin-like growth factor I and the risk of postmenopausal breast cancer. Int J Cancer 118:1279–1284PubMedCrossRefGoogle Scholar
  23. 23.
    Tamimi RM, Cox DG, Kraft P et al (2007) Common genetic variation in IGF1, IGFBP-1, and IGFBP-3 in relation to mammographic density: a cross-sectional study. Breast Cancer Res 9:R18PubMedCrossRefGoogle Scholar
  24. 24.
    Riboli E, Kaaks R (1997) The EPIC project: rationale and study design. European prospective investigation into cancer and nutrition. Int J Epidemiol 26 Suppl 1:S6–S14PubMedCrossRefGoogle Scholar
  25. 25.
    Riboli E, Hunt KJ, Slimani N et al (2002) European prospective investigation into cancer and nutrition (EPIC): study populations and data collection. Public Health Nutr 5:1113–1124PubMedCrossRefGoogle Scholar
  26. 26.
    Boker LK, Van Noord PA, van der Schouw YT et al (2001) Prospect-EPIC Utrecht: study design and characteristics of the cohort population. European prospective investigation into cancer and nutrition. Eur J Epidemiol 17:1047–1053PubMedCrossRefGoogle Scholar
  27. 27.
    Johansson M, McKay JD, Stattin P et al (2007) Comprehensive evaluation of genetic variation in the IGF1 gene and risk of prostate cancer. Int J Cancer 120:539–542PubMedCrossRefGoogle Scholar
  28. 28.
    Gabriel SB, Schaffner SF, Nguyen H et al (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229PubMedCrossRefGoogle Scholar
  29. 29.
    Stram DO, Haiman CA, Hirschhorn JN et al (2003) Choosing haplotype-tagging SNPS based on unphased genotype data using a preliminary sample of unrelated subjects with an example from the Multiethnic Cohort Study. Hum Hered 55:27–36PubMedCrossRefGoogle Scholar
  30. 30.
    Al Zahrani A, Sandhu MS, Luben RN et al (2006) IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer. Hum Mol Genet 15:1–10PubMedCrossRefGoogle Scholar
  31. 31.
    Cheng I, Stram DO, Penney KL et al (2006) Common genetic variation in IGF1 and prostate cancer risk in the multiethnic cohort. J Natl Cancer Inst 98:123–134PubMedGoogle Scholar
  32. 32.
    Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12:921–927PubMedGoogle Scholar
  33. 33.
    Stram DO, Leigh PC, Bretsky P et al (2003) Modeling and E–M estimation of haplotype-specific relative risks from genotype data for a case–control study of unrelated individuals. Hum Hered 55:179–190PubMedCrossRefGoogle Scholar
  34. 34.
    Canzian F, McKay JD, Cleveland RJ et al (2006) Polymorphisms of genes coding for insulin-like growth factor 1 and its major binding proteins, circulating levels of IGF-I and IGFBP-3 and breast cancer risk: results from the EPIC study. Br J Cancer 94:299–307PubMedCrossRefGoogle Scholar
  35. 35.
    van Duijnhoven FJ, Peeters PH, Warren RM et al (2006) Influence of estrogen receptor alpha and progesterone receptor polymorphisms on the effects of hormone therapy on mammographic density. Cancer Epidemiol Biomarkers Prev 15:462–467PubMedCrossRefGoogle Scholar
  36. 36.
    Wacholder S, Chanock S, Garcia-Closas M et al (2004) Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst 96:434–442PubMedCrossRefGoogle Scholar
  37. 37.
    Katan MB (2004) Apolipoprotein E isoforms, serum cholesterol, and cancer. Lancet 1986 i:507–508; Int J Epidemiol 33:9Google Scholar
  38. 38.
    Smith GD, Ebrahim S (2004) Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol 33:30–42PubMedCrossRefGoogle Scholar
  39. 39.
    Johansson M, McKay JD, Wiklund F et al (2007) Implications for prostate cancer of IGF1 genetic variation and circulating IGF1 levels. J Clin Endocrinol Metab. doi: 10.1210/jc.2007-0887 PubMedGoogle Scholar
  40. 40.
    Setiawan VW, Cheng I, Stram DO et al (2006) Igf-I genetic variation and breast cancer: the multiethnic cohort. Cancer Epidemiol Biomarkers Prev 15:172–174PubMedCrossRefGoogle Scholar
  41. 41.
    Hong Y, Pedersen NL, Brismar K et al (1996) Quantitative genetic analyses of insulin-like growth factor I (IGF-I), IGF-binding protein-1, and insulin levels in middle-aged and elderly twins. J Clin Endocrinol Metab 81:1791–1797PubMedCrossRefGoogle Scholar
  42. 42.
    Harrela M, Koistinen H, Kaprio J et al (1996) Genetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3. J Clin Invest 98:2612–2615PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2007

Authors and Affiliations

  • Martijn Verheus
    • 1
  • James D. McKay
    • 2
  • Rudolf Kaaks
    • 4
  • Federico Canzian
    • 5
  • Carine Biessy
    • 3
  • Mattias Johansson
    • 6
  • Diederick E. Grobbee
    • 1
  • Petra H. M. Peeters
    • 1
  • Carla H. van Gils
    • 1
  1. 1.Julius Center for Health Sciences and Primary CareUniversity Medical Center UtrechtUtrechtThe Netherlands
  2. 2.Genetic Epidemiology GroupInternational Agency for Research on Cancer (IARC-WHO)LyonFrance
  3. 3.Epidemiology Methods and Support GroupInternational Agency for Research on Cancer (IARC-WHO)LyonFrance
  4. 4.Division of Cancer EpidemiologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  5. 5.Genomic Epidemiology GroupGerman Cancer Research Center (DKFZ)HeidelbergGermany
  6. 6.Department of Surgical and Perioperative Sciences, Urology and AndrologyUmeå University HospitalUmeaSweden

Personalised recommendations