Skip to main content

Advertisement

Log in

Polymorphisms in the IGF-1 and IGFBP3 promoter and the risk of breast cancer

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

Summary

Binding of IGF-1 to the type I IGF receptor starts a signalling cascade that plays an important role in regulating cell proliferation, differentiation and apoptosis. The interaction between the IGF-1 and its receptor is mainly regulated by a binding protein, IGFBP3. We studied a CA repeat polymorphism 969 bp upstream of the transcription start site in the IGF-1 gene and an A-202C polymorphism in the IGFBP3 gene and tested their association with breast cancer risk using four case–control series with a total of 787 cases and 900 controls. We did not find any association between the breast cancer risk and the IGF-1 repeat length (19 versus non-19) or the IGFBP3 A-202C polymorphism in the postmenopausal breast cancer series or in women diagnosed for breast cancer under the age of 50. In the familial breast cancer series we observed a non-significantly increased odds-ratio (OR) in homozygotes for the non-19 alleles of the IGF-1 gene (OR 1.51, 95% CI 0.96–2.39, p=0.07). Similarly, in the familial breast cancer series we detected an increased frequency of the IGFBP3 −202C allele carriers (OR 1.50, 95% CI 1.05–2.14, p=0.03). The association was stronger in individuals homozygous for these alleles (OR 3.76, 95% CI 1.44–9.81, p=0.006). Thus, the polymorphisms in the IGF-1 and IGFBP3 genes associated with an increased risk of breast cancer in familial cases carrying the variant alleles.

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

Abbreviations

CI:

95% confidence interval

HWE:

Hardy–Weinberg equilibrium

IGF-1:

insulin-like growth factor

IGFBP3:

insulin-like growth factor binding protein

IGF-1R/IGF-2R:

insulin-like growth factor-1/2 receptor

OR:

odds-ratio

RFLP:

restriction fragment length polymorphism

References

  1. P Lichtenstein NV Holm PK Verkasalo A Iliadou J Kaprio M Koskenvuo E Pukkala A Skytthe K Hemminki (2000) ArticleTitleEnvironmental and heritable factors in the causation of cancer-analyses of cohorts of twins from Sweden, Denmark, and Finland N Engl J␣Med 343 78–85

    Google Scholar 

  2. K Hemminki C Granstrom (2003) ArticleTitleFamilial breast cancer: scope for more susceptibility genes Breast Cancer Res Treat 82 17–22

    Google Scholar 

  3. J Peto N Collins R Barfoot S Seal W Warren N Rahman DF Easton C Evans J Deacon MR Stratton (1999) ArticleTitleof BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer J Natl Cancer Inst 91 943–949

    Google Scholar 

  4. AC Antoniou PD Pharoah G McMullan NE Day BA Ponder D Easton (2001) ArticleTitleEvidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study Genet Epidemiol 21 1–18

    Google Scholar 

  5. MM de Jong IM Nolte GJ te Meerman WT der Graaf Particlevan JC Oosterwijk JH Kleibeuker M Schaapveld EG Vries Particlede (2002) ArticleTitleGenes other than BRCA1 and BRCA2 involved in breast cancer susceptibility J Med Genet 39 225–242

    Google Scholar 

  6. DL Kleinberg (1998) ArticleTitleRole of IGF-I in normal mammary development Breast Cancer Res Treat 47 201–208

    Google Scholar 

  7. C Laban SA Bustin PJ Jenkins (2003) ArticleTitleThe GH-IGF-I axis and breast cancer Trends Endocrinol Metab 14 28–34

    Google Scholar 

  8. L Jerome L Shiry B Leyland-Jones (2003) ArticleTitleDeregulation of the IGF axis in cancer: epidemiological evidence and potential therapeutic interventions Endocr Relat Cancer 10 561–578

    Google Scholar 

  9. MN Pollak ES Schernhammer SE Hankinson (2004) ArticleTitleInsulin-like␣growth factors and neoplasia Nat Rev Cancer 4 505–518

    Google Scholar 

  10. VS Sivaraman H Wang GJ Nuovo CC Malbon (1997) ArticleTitleHyperexpression of mitogen-activated protein kinase in human breast cancer J␣Clin Invest 99 1478–1483

    Google Scholar 

  11. H Yu T Rohan (2000) ArticleTitleRole of the insulin-like growth factor family in cancer development and progression J Natl Cancer Inst 92 1472–1489

    Google Scholar 

  12. R Shi H Yu J McLarty J Glass (2004) ArticleTitleIGF-I and breast cancer: a meta-analysis Int J Cancer 111 418–423

    Google Scholar 

  13. AG Renehan M Zwahlen C Minder ST O’Dwyer SM Shalet M Egger (2004) ArticleTitleInsulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis Lancet 363 1346–1353

    Google Scholar 

  14. M Harrela H Koistinen J Kaprio M Lehtovirta J Tuomilehto J Eriksson L Toivanen M Koskenvuo P Leinonen R Koistinen M Seppala (1996) ArticleTitleGenetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3 J Clin Invest 98 2612–2615

    Google Scholar 

  15. TL McCarthy C Ji H Shu S Casinghino K Crothers P Rotwein M Centrella (1997) ArticleTitle17beta-estradiol potently suppresses cAMP-induced insulin-like growth factor-I gene activation in primary rat osteoblast cultures J Biol Chem 272 18132–18139

    Google Scholar 

  16. H Yu BD Li M Smith R Shi HJ Berkel I Kato (2001) ArticleTitlePolymorphic CA repeats in the IGF-I gene and breast cancer Breast Cancer Res Treat 70 117–122

    Google Scholar 

  17. SA Missmer CA Haiman DJ Hunter WC Willett GA Colditz FE Speizer MN Pollak SE Hankinson (2002) ArticleTitleA sequence repeat in the insulin-like growth factor-1 gene and risk of breast cancer Int J␣Cancer 100 332–336

    Google Scholar 

  18. H Jernstrom W Chu D Vesprini Y Tao N Majeed C Deal M Pollak SA Narod (2001) ArticleTitleGenetic factors related to racial variation in plasma levels of insulin-like growth factor-1: implications for premenopausal breast cancer risk Mol Genet Metab 72 144–154

    Google Scholar 

  19. CJ Rosen ES Kurland D Vereault RA Adler PJ Rackoff WY Craig S Witte J Rogers JP Bilezikian (1998) ArticleTitlebetween serum insulin growth factor-I (IGF-I) and a simple sequence repeat in IGF-I gene: implications for genetic studies of bone mineral density J␣Clin Endocrinol Metab 83 2286–2290

    Google Scholar 

  20. C Deal J Ma F Wilkin J Paquette F Rozen B Ge T Hudson M Stampfer M Pollak (2001) ArticleTitleNovel promoter polymorphism in insulin-like growth factor-binding protein-3: correlation with serum levels and interaction with known regulators J Clin Endocrinol Metab 86 1274–1280

    Google Scholar 

  21. ES Schernhammer SE Hankinson DJ Hunter MJ Blouin MN Pollak (2003) ArticleTitlePolymorphic variation at the −202 locus in IGFBP3: Influence on serum levels of insulin-like growth factors, interaction with plasma retinol and vitamin D and breast cancer risk Int J Cancer 107 60–64

    Google Scholar 

  22. Z Ren Q Cai XO Shu H Cai C Li H Yu YT Gao W Zheng (2004) ArticleTitleGenetic polymorphisms in the IGFBP3 gene: association with breast cancer risk and blood IGFBP-3 protein levels among Chinese women Cancer Epidemiol Biomarkers Prev 13 1290–1295

    Google Scholar 

  23. K Holli R Valavaara G Blanco V Kataja P Hietanen M Flander E Pukkala H Joensuu (2000) ArticleTitleSafety and efficacy results of a␣randomized trial comparing adjuvant toremifene and tamoxifen in postmenopausal patients with node-positive breast cancer.␣Finnish breast cancer group J Clin Oncol 18 3487–3494

    Google Scholar 

  24. Q Jin K Hemminki E Grzybowska R Klaes M Säderberg H Zientek J Rogozinska-Szczepka B Utracka-Hutka J Pamula W Pekala A Försti (2004) ArticleTitlePolymorphisms and haplotype structures in genes for transforming growth factor 1 and its receptors in familial and unselected breast cancers Int J Cancer 112 94–99

    Google Scholar 

  25. A Forsti Q Jin E Grzybowska M Soderberg H Zientek M Sieminska J Rogozinska-Szczepka E Chmielik B Utracka-Hutka K Hemminki (2002) ArticleTitleSex hormone-binding globulin polymorphisms in familial and sporadic breast cancer Carcinogenesis 23 1315–1320

    Google Scholar 

  26. P Vaittinen K Hemminki (2000) ArticleTitleRisk factors and age-incidence relationships for contralateral breast cancer Int J Cancer 88 998–1002

    Google Scholar 

  27. S Garte L Gaspari AK Alexandrie C Ambrosone H Autrup JL Autrup H Baranova L Bathum S Benhamou P Boffetta C Bouchardy K Breskvar J Brockmoller I Cascorbi ML Clapper C Coutelle A Daly M Dell’Omo V Dolzan CM Dresler A Fryer A Haugen DW Hein A Hildesheim A Hirvonen LL Hsieh M Ingelman-Sundberg I Kalina D Kang M Kihara C Kiyohara P Kremers P Lazarus L Le Marchand MC Lechner EM Lieshout Particlevan S London JJ Manni CM Maugard S Morita V Nazar-Stewart K Noda Y Oda FF Parl R Pastorelli I Persson WH Peters A Rannug T Rebbeck A Risch L Roelandt M Romkes D Ryberg J Salagovic B Schoket J Seidegard PG Shields E Sim D Sinnet RC Strange I Stucker H Sugimura J To-Figueras P Vineis MC Yu E Taioli (2001) ArticleTitleMetabolic gene polymorphism frequencies in control populations Cancer Epidemiol Biomarkers Prev 10 1239–1248

    Google Scholar 

  28. K Wagner K Hemminki E Grzybowska R Klaes D Butkiewicz J Pamula W Pekala H Zientek D Mielzynska E Siwinska A Forsti (2004) ArticleTitleThe insulin-like growth factor-1 pathway mediator genes: SHC1 Met300Val shows a protective effect in breast cancer Carcinogenesis 25 2473–2478

    Google Scholar 

  29. K DeLellis S Ingles L Kolonel R McKean-Cowdin B Henderson F Stanczyk NM Probst-Hensch (2003) ArticleTitleIGF1 genotype, mean plasma level and breast cancer risk in the Hawaii/Los Angeles multiethnic cohort Br J Cancer 88 277–282

    Google Scholar 

  30. ML Slattery W Samowitz K Curtin KN Ma M Hoffman B Caan S Neuhausen (2004) ArticleTitleAssociations among IRS1, IRS2, IGF1, and IGFBP3 genetic polymorphisms and colorectal cancer Cancer Epidemiol Biomarkers Prev 13 1206–1214

    Google Scholar 

  31. E Giovannucci CA Haiman EA Platz SE Hankinson MN Pollak DJ Hunter (2002) ArticleTitleDinucleotide repeat in the insulin-like growth factor-I gene is not related to risk of colorectal adenoma Cancer Epidemiol Biomarkers Prev 11 1509–1510

    Google Scholar 

  32. RS Houlston J Peto (2003) ArticleTitleThe future of association studies of common cancers Hum Genet 112 434–435

    Google Scholar 

  33. AC Antoniou DF Easton (2003) ArticleTitlePolygenic inheritance of breast cancer: Implications for design of association studies Genet Epidemiol 25 190–202

    Google Scholar 

  34. DB Goldstein JN Hirschhorn (2004) ArticleTitleIn genetic control of disease, does ‘race’ matter? Nat Genet 36 1243–1244

    Google Scholar 

  35. L Li MS Cicek G Casey JS Witte (2004) ArticleTitleNo association between genetic polymorphisms in IGF-I and IGFBP-3 and prostate cancer Cancer Epidemiol Biomarkers Prev 13 497–498

    Google Scholar 

  36. AJ Sigurdson M Hauptmann N Chatterjee BH Alexander MM Doody JL Rutter JP Struewing (2004) ArticleTitleKin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair BRCA1 interacting and growth factor genes BMC Cancer 4 9

    Google Scholar 

  37. L Wang T Habuchi N Tsuchiya K Mitsumori C Ohyama K Sato H Kinoshita T Kamoto A Nakamura O Ogawa T Kato (2003) ArticleTitleInsulin-like growth factor-binding protein-3 gene −202 A/C polymorphism is correlated with advanced disease status in prostate cancer Cancer Res 63 4407–4411

    Google Scholar 

  38. K Hemminki A Forsti J Lorenzo Bermejo (2005) ArticleTitleSingle nucleotide polymorphisms (SNPs) are inherited from parents and they measure heritable events J Carcinog 4 2

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kerstin Wagner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wagner, K., Hemminki, K., Israelsson, E. et al. Polymorphisms in the IGF-1 and IGFBP3 promoter and the risk of breast cancer. Breast Cancer Res Treat 92, 133–140 (2005). https://doi.org/10.1007/s10549-005-2417-x

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-005-2417-x

Key words

Navigation