Breast Cancer Research and Treatment

, Volume 116, Issue 2, pp 413–423

Association between IGF1 CA microsatellites and mammographic density, anthropometric measures, and circulating IGF-I levels in premenopausal Caucasian women

  • Gordon Fehringer
  • Hilmi Ozcelik
  • Julia A. Knight
  • Andrew D. Paterson
  • Norman F. Boyd


Background Results from several studies indicate that mammographic density, a strong risk factor for breast cancer, is greater in premenopausal women with higher circulating IGF-I levels. Both mammographic density and circulating IGF-I levels appear to be partly heritable traits. We hypothesized that in premenopausal women, IGF1 variants are associated with circulating IGF-I concentration, which in turn influences variation in breast density. Therefore, we examined the association of IGF1 polymorphisms with circulating IGF-I levels and mammographic density. Methods Percentage density, amounts of dense and non-dense (fat) tissue, IGF-I levels, and BMI were measured in 163 premenopausal women. Three CA repeat polymorphisms were genotyped, one each at the 5′ and 3′ ends of IGF1 and one in intron 2. Results The number of 19 alleles at the 5′ polymorphism was associated with lower circulating levels of IGF-I (P = 0.02), whereas the number of 185 alleles at the 3′ polymorphism was associated with higher percentage density (P = 0.03) and a smaller amount of non-dense tissue (P = 0.02). The strength of the effect of the 185 allele at 3′ on percentage density was greatly reduced and statistical significance lost when BMI was included in regression models. Conclusions Our results suggest an association between the number of 185 alleles at 3′ with percentage density. This association appears to be mediated by body composition and particularly body fat, as indicated by the association of 3′ IGF1 genotype with non-dense (fat) tissue and the mediating effect of BMI on the association of 3′ genotype with percentage density.


Mammographic density Insulin-like growth factor-I Polymorphism Anthropometric Microsatellite 

Supplementary material

10549_2008_146_MOESM1_ESM.pdf (27 kb)
(PDF 28 kb)


  1. 1.
    Boyd NF, Rommens JM, Vogt K, Lee V, Hopper JL, Yaffe MJ et al (2005) Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol 6(10):798–808. doi:10.1016/S1470-2045(05)70390-9 PubMedCrossRefGoogle Scholar
  2. 2.
    Boyd NF, Dite GS, Stone J, Gunasekara A, English DR, McCredie MR et al (2002) Heritability of mammographic density, a risk factor for breast cancer. N Engl J Med 347(12):886–894. doi:10.1056/NEJMoa013390 PubMedCrossRefGoogle Scholar
  3. 3.
    Diorio C, Pollak M, Byrne C, Masse B, Hebert-Croteau N, Yaffe M et al (2005) Insulin-like growth factor-I, IGF-binding protein-3, and mammographic breast density. Cancer Epidemiol Biomarkers Prev 14(5):1065–1073. doi:10.1158/1055-9965.EPI-04-0706 PubMedCrossRefGoogle Scholar
  4. 4.
    Maskarinec G, Williams AE, Kaaks R (2003) A cross-sectional investigation of breast density and insulin-like growth factor I. Int J Cancer 107(6):991–996. doi:10.1002/ijc.11505 PubMedCrossRefGoogle Scholar
  5. 5.
    Boyd NF, Stone J, Martin LJ, Jong R, Fishell E, Yaffe M et al (2002) The association of breast mitogens with mammographic densities. Br J Cancer 87(8):876–882. doi:10.1038/sj.bjc.6600537 PubMedCrossRefGoogle Scholar
  6. 6.
    Byrne C, Colditz GA, Willett WC, Speizer FE, Pollak M, Hankinson SE (2000) Plasma insulin-like growth factor (IGF) I, IGF-binding protein 3, and mammographic density. Cancer Res 60(14):3744–3748PubMedGoogle Scholar
  7. 7.
    Maskarinec G, Takata Y, Chen Z, Gram IT, Nagata C, Pagano I et al (2007) IGF-I and mammographic density in four geographic locations: a pooled analysis. Int J Cancer 121(8):1786–1792. doi:10.1002/ijc.22834 PubMedCrossRefGoogle Scholar
  8. 8.
    Verheus M, Peeters PH, Kaaks R, van Noord PA, Grobbee DE, van Gils CH (2007) Premenopausal insulin-like growth factor-I serum levels and changes in breast density over menopause. Cancer Epidemiol Biomarkers Prev 16(3):451–457. doi:10.1158/1055-9965.EPI-06-0642 PubMedCrossRefGoogle Scholar
  9. 9.
    dos Santos Silva I, Johnson N, De Stavola B, Torres-Mejia G, Fletcher O, Allen DS et al (2006) The insulin-like growth factor system and mammographic features in premenopausal and postmenopausal women. Cancer Epidemiol Biomarkers Prev 15(3):449–455. doi:10.1158/1055-9965.EPI-05-0555 PubMedCrossRefGoogle Scholar
  10. 10.
    Lai JH, Vesprini D, Zhang W, Yaffe MJ, Pollak M, Narod SA (2004) A polymorphic locus in the promoter region of the IGFBP3 gene is related to mammographic breast density. Cancer Epidemiol Biomarkers Prev 13(4):573–582PubMedGoogle Scholar
  11. 11.
    Harrela M, Koistinen H, Kaprio J, Lehtovirta M, Tuomilehto J, Eriksson 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(11):2612–2615. doi:10.1172/JCI119081 PubMedCrossRefGoogle Scholar
  12. 12.
    Hong Y, Pedersen N, Brismar K, Hall K, de Faire U (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(5):1791–1797. doi:10.1210/jc.81.5.1791 PubMedCrossRefGoogle Scholar
  13. 13.
    Cleveland RJ, Gammon MD, Edmiston SN, Teitelbaum SL, Britton JA, Terry MB et al (2005) IGF1 CA repeat polymorphisms, lifestyle factors and breast cancer risk in the Long Island Breast Cancer Study Project. Carcinogenesis 27(4):758–765. doi:10.1093/carcin/bgi294 PubMedCrossRefGoogle Scholar
  14. 14.
    Wagner K, Hemminki K, Israelsson E, Grzybowska E, Soderberg M, Pamula J et al (2005) Polymorphisms in the IGF-1 and IGFBP 3 promoter and the risk of breast cancer. Breast Cancer Res Treat 92(2):133–140. doi:10.1007/s10549-005-2417-x PubMedCrossRefGoogle Scholar
  15. 15.
    Wen W, Gao YT, Shu XO, Yu H, Cai Q, Smith JR et al (2005) Insulin-like growth factor-I gene polymorphism and breast cancer risk in Chinese women. Int J Cancer 113(2):307–311. doi:10.1002/ijc.20571 PubMedCrossRefGoogle Scholar
  16. 16.
    DeLellis K, Ingles S, Kolonel L, McKean-Cowdin R, Henderson B, Stanczyk F et al (2003) IGF1 genotype, mean plasma level and breast cancer risk in the Hawaii/Los Angeles multiethnic cohort. Br J Cancer 88(2):277–282. doi:10.1038/sj.bjc.6600728 PubMedCrossRefGoogle Scholar
  17. 17.
    Figer A, Karasik YP, Baruch RG, Chetrit A, Papa MZ, Sade RB et al (2002) Insulin-like growth factor I polymorphism and breast cancer risk in Jewish women. Isr Med Assoc J 4(10):759–762PubMedGoogle Scholar
  18. 18.
    Missmer SA, Haiman CA, Hunter DJ, Willett WC, Colditz GA, Speizer FE et al (2002) A sequence repeat in the insulin-like growth factor-1 gene and risk of breast cancer. Int J Cancer 100(3):332–336. doi:10.1002/ijc.10473 PubMedCrossRefGoogle Scholar
  19. 19.
    Yu H, Li BD, Smith M, Shi R, Berkel HJ, Kato I (2001) Polymorphic CA repeats in the IGF-I gene and breast cancer. Breast Cancer Res Treat 70(2):117–122. doi:10.1023/A:1012947027213 PubMedCrossRefGoogle Scholar
  20. 20.
    Byng JW, Boyd NF, Fishell E, Jong RA, Yaffe MJ (1994) The quantitative analysis of mammographic densities. Phys Med Biol 39(10):1629–1638. doi:10.1088/0031-9155/39/10/008 PubMedCrossRefGoogle Scholar
  21. 21.
    Wang L, Hirayasu K, Ishizawa M, Kobayashi Y (1994) Purification of genomic DNA from human whole blood by isopropanol-fractionation with concentrated Nal and SDS. Nucleic Acids Res 22(9):1774–1775. doi:10.1093/nar/22.9.1774 PubMedCrossRefGoogle Scholar
  22. 22.
    The Centre for Applied Genomics (2003) Hospital for Sick Children, Toronto.
  23. 23.
    Guo SW, Thompson EA (1992) Performing the exact test of Hardy-Weinberg proportion for multiple alleles. Biometrics 48(2):361–372. doi:10.2307/2532296 PubMedCrossRefGoogle Scholar
  24. 24.
    Liu K, Muse SV (2005) PowerMarker: an integrated analysis environment for genetic marker analysis. Bioinformatics 21(9):2128–2129PubMedCrossRefGoogle Scholar
  25. 25.
    SAS Institute Inc (1999–2001) SAS release 8.02 (1999–2001). SAS Institute Inc, CaryGoogle Scholar
  26. 26.
    Zaykin DV, Westfall PH, Young SS, Karnoub MA, Wagner MJ, Ehm MG (2002) Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Hum Hered 53(2):79–91. doi:10.1159/000057986 PubMedCrossRefGoogle Scholar
  27. 27.
    Frayling TM, Hattersley AT, McCarthy A, Holly J, Mitchell SM, Gloyn AL et al (2002) A putative functional polymorphism in the IGF-I gene: association studies with type 2 diabetes, adult height, glucose tolerance, and fetal growth in U.K. populations. Diabetes 51(7):2313–2316. doi:10.2337/diabetes.51.7.2313 PubMedCrossRefGoogle Scholar
  28. 28.
    Nam SY, Marcus C (2000) Growth hormone and adipocyte function in obesity. Horm Res 53(Suppl 1):87–97. doi:10.1159/000053211 PubMedCrossRefGoogle Scholar
  29. 29.
    Hadsell DL (2003) The insulin-like growth factor system in normal mammary gland function. Breast Dis 17:3–14PubMedGoogle Scholar
  30. 30.
    Slattery ML, Baumgartner KB, Byers T, Guiliano A, Sweeney C, Herrick J et al (2005) Genetic, anthropometric, and lifestyle factors associated with IGF-1 and IGFBP-3 levels in Hispanic and non-Hispanic white women. Cancer Causes Control 16(10):1147–1157. doi:10.1007/s10552-005-0318-2 PubMedCrossRefGoogle Scholar
  31. 31.
    Jernstrom H, Deal C, Wilkin F, Chu W, Tao Y, Majeed N et al (2001) Genetic and nongenetic factors associated with variation of plasma levels of insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in healthy premenopausal women. Cancer Epidemiol Biomarkers Prev 10(4):377–384PubMedGoogle Scholar
  32. 32.
    Al-Zahrani A, Sandhu MS, Luben RN, Thompson D, Baynes C, Pooley KA et al (2005) IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer. Hum Mol Genet 15(1):1–10. doi:10.1093/hmg/ddi398 PubMedCrossRefGoogle Scholar
  33. 33.
    Patel AV, Cheng I, Canzian F, Le Marchand L, Thun MJ, Berg CD et al (2008) IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer fisk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3). PLoS One 3(7):e2578. doi:10.1371/journal.pone.0002578 PubMedCrossRefGoogle Scholar
  34. 34.
    Johansson M, McKay JD, Wiklund F, Rinaldi S, Verheus M, van Gils CH et al (2007) Implications for prostate cancer of insulin-like growth factor-I (IGF-I) genetic variation and circulating IGF-I levels. J Clin Endocrinol Metab 92(12):4820–4826. doi:10.1210/jc.2007-0887 PubMedCrossRefGoogle Scholar
  35. 35.
    Diorio C, Brisson J, Berube S, Pollak M (2008) Genetic polymorphisms involved in insulin-like growth factor (IGF) pathway in relation to mammographic breast density and IGF levels. Cancer Epidemiol Biomarkers Prev 17(4):880–888. doi:10.1158/1055-9965.EPI-07-2500 PubMedCrossRefGoogle Scholar
  36. 36.
    Verheus M, McKay JD, Kaaks R, Canzian F, Biessy C, Johansson M (2007) Common genetic variation in the IGF-1 gene, serum IGF-I levels and breast density. Breast Cancer Res Treat. doi:10.1007/s10549-007 PubMedGoogle Scholar
  37. 37.
    Canzian F, McKay JD, Cleveland RJ, Dossus L, Biessy C, Rinaldi S 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(2):299–307. doi:10.1038/sj.bjc.6602936 PubMedCrossRefGoogle Scholar
  38. 38.
    Palles C, Johnson N, Coupland B, Taylor C, Carvajal J, Holly J et al (2008) Identification of genetic variants that influence circulating IGF1 levels: a targeted search strategy. Hum Mol Genet 17(10):1457–1464. doi:10.1093/hmg/ddn034 PubMedCrossRefGoogle Scholar
  39. 39.
    Voorhoeve PG, van Rossum EF, Te Velde SJ, Koper JW, Kemper HC, Lamberts SW et al (2006) Association between an IGF-I gene polymorphism and body fatness: differences between generations. Eur J Endocrinol 154(3):379–388. doi:10.1530/eje.1.02101 PubMedCrossRefGoogle Scholar
  40. 40.
    Sweeney C, Murtaugh MA, Baumgartner KB, Byers T, Giuliano AR, Herrick JS et al (2005) Insulin-like growth factor pathway polymorphisms associated with body size in Hispanic and non-Hispanic white women. Cancer Epidemiol Biomarkers Prev 14(7):1802–1809. doi:10.1158/1055-9965.EPI-05-0149 PubMedCrossRefGoogle Scholar
  41. 41.
    Sun G, Gagnon J, Chagnon YC, Perusse L, Despres JP, Leon AS et al (1999) Association and linkage between an insulin-like growth factor-1 gene polymorphism and fat free mass in the HERITAGE Family Study. Int J Obes Relat Metab Disord 23(9):929–935. doi:10.1038/sj.ijo.0801021 PubMedCrossRefGoogle Scholar
  42. 42.
    Lopez-Alarcon M, Hunter GR, Gower BA, Fernandez JR (2007) IGF-I polymorphism is associated with lean mass, exercise economy, and exercise performance among premenopausal women. Arch Med Res 38(1):56–63. doi:10.1016/j.arcmed.2006.07.002 PubMedCrossRefGoogle Scholar
  43. 43.
    Tamimi RM, Cox DG, Kraft P, Pollak MN, Haiman CA, Cheng I 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(1):R18. doi:10.1186/bcr1655 PubMedCrossRefGoogle Scholar
  44. 44.
    Chen TM, Kuo PL, Hsu CH, Tsai SJ, Chen MJ, Lin CW et al (2007) Microsatellite in the 3′ untranslated region of human fibroblast growth factor 9 (FGF9) gene exhibits pleiotropic effect on modulating FGF9 protein expression. Hum Mutat 28(1):98. doi:10.1002/humu.9471 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Gordon Fehringer
    • 1
    • 2
  • Hilmi Ozcelik
    • 3
    • 4
    • 5
  • Julia A. Knight
    • 6
    • 1
  • Andrew D. Paterson
    • 1
    • 7
  • Norman F. Boyd
    • 8
  1. 1.Dalla Lana School of Public HealthUniversity of TorontoTorontoCanada
  2. 2.Population Studies Cancer Care OntarioTorontoCanada
  3. 3.Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research InstituteMount Sinai HospitalTorontoCanada
  4. 4.Department of Pathology and Laboratory MedicineMount Sinai HospitalTorontoCanada
  5. 5.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  6. 6.Prosserman Centre for Health Research, Samuel Lunenfeld Research InstituteMount Sinai HospitalTorontoCanada
  7. 7.Program in Genetics and Genome BiologyThe Hospital for Sick ChildrenTorontoCanada
  8. 8.Campbell Family Institute for Breast Cancer ResearchTorontoCanada

Personalised recommendations