Skip to main content

Advertisement

SpringerLink
Log in

Genetic variation in IGF1, IGFBP3, IRS1, IRS2 and risk of breast cancer in women living in Southwestern United States

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

Abstract

Background

An insulin-related pathway to breast cancer has been hypothesized.

Methods

We examine the 19 CA repeat of the IGF1 gene, the -202 C > A IGFBP3, the G972R IRS, and the G1057D IRS2 polymorphisms among 1,175 non-Hispanic white (NHW) and 576 Hispanic newly diagnosed breast cancer cases and 1,330 NHW and 727 Hispanic controls living in Arizona, Colorado, New Mexico, and Utah.

Results

Among post-menopausal women not recently exposed to hormones, not having the 19 CA repeat of IGF1 gene was associated with breast cancer among NHW women [odds ratio (OR) 2.14, 95% confidence interval (CI) 1.21–3.79] and having an R allele of G972R IRS1 increased breast cancer risk among Hispanic women (OR 2.70, 95% CI 1.13–6.46). Among post-menopausal Hispanic women recently exposed to hormones the A allele of the -202 C > A IGFBP3 polymorphism increased risk of breast cancer (OR 1.57, 95% CI 1.06–2.33). The IGF1 19 CA repeat polymorphism interacted with hormone replacement therapy (HRT) among NHW post-menopausal women; women who had the 19/19 IGF1 genotype were at reduced risk of breast cancer (OR 0.64, 95% CI 0.47–0.88) if they did not use HRT. We also observed interaction between body mass index and IGF1 19 CA repeat (p=0.06) and between weight gain and the -202 C > A IGFBP3 polymorphism (p=0.05) in NHW post-menopausal women not recently exposed to hormones.

Conclusions

Our data suggest that associations between insulin-related genes and breast cancer risk among women living in the Southwestern United States may be dependent on estrogen exposure and may differ by ethnicity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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

References

  1. Kaaks R, Toniolo P, Akhmedkhanov A, Lukanova A, Biessy C, Dechaud H, Rinaldi S, Zeleniuch-Jacquotte A, Shore RE, Riboli E (2000) Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women. J Natl Cancer Inst 92(19):1592–1600

    Article  PubMed  CAS  Google Scholar 

  2. Singh P, Rubin N (1993) Insulin like growth factors and binding proteins in colon cancer. Gastroenterology 105(4):1218–1237

    PubMed  CAS  Google Scholar 

  3. Rui L, Fisher TL, Thomas J, White MF (2001) Regulation of insulin/insulin-like growth factor-1 signaling by proteasome-mediated degradation of insulin receptor substrate-2. J Biol Chem 276(43):40362–40367

    PubMed  CAS  Google Scholar 

  4. Werner H, Le Roith D (1997) The insulin-like growth factor-I receptor signaling pathways are important for tumorigenesis and inhibition of apoptosis. Crit Rev Oncog 8(1):71–92

    PubMed  CAS  Google Scholar 

  5. Kelley KM, Oh Y, Gargosky SE, Gucev Z, Matsumoto T, Hwa V, Ng L, Simpson DM, Rosenfeld RG (1996) Insulin-like growth factor-binding proteins (IGFBPs) and their regulatory dynamics. Int J Biochem Cell Biol 28(6):619–637

    Article  PubMed  CAS  Google Scholar 

  6. Burks D, White M (2001) IRS proteins and beta-cell function. Diabetes 50(90001):S140–S145

    Article  PubMed  CAS  Google Scholar 

  7. White MF (2003) Insulin signaling in health and disease. Science 302(5651):1710–1711

    Article  PubMed  CAS  Google Scholar 

  8. Shpakov AO, Pertseva MN (2000) Structural and functional characterization of insulin receptor substrate proteins and the molecular mechanisms of their interaction with insulin superfamily tyrosine kinase receptors and effector proteins. Membr Cell Biol 13(4):455–484

    PubMed  CAS  Google Scholar 

  9. Withers DJ, Burks DJ, Towery HH, Altamuro SL, Flint CL, White MF (1999) Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Nat Genet 23(1):32–40

    Article  PubMed  CAS  Google Scholar 

  10. Waters SB, Pessin JE (1996) Insulin receptor substrate 1 and 2 (IRS1 and IRS2): what a tangled web we weave. Trends Cell Biol 6(1):1–4

    Article  PubMed  CAS  Google Scholar 

  11. Schubert M, Brazil DP, Burks DJ, Kushner JA, Ye J, Flint CL, Farhang-Fallah J, Dikkes P, Warot XM, Rio C, et al (2003) Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci 23(18):7084–7092

    PubMed  CAS  Google Scholar 

  12. Van Obberghen E, Baron V, Scimeca JC, Kaliman P (1993) Insulin receptor: receptor activation and signal transduction. Adv Second Messenger Phosphoprotein Res 28:195–201

    PubMed  Google Scholar 

  13. Vendrell JA, Magnino F, Danis E, Duchesne MJ, Pinloche S, Pons M, Birnbaum D, Nguyen C, Theillet C, Cohen PA (2004) Estrogen regulation in human breast cancer cells of new downstream gene targets involved in estrogen metabolism, cell proliferation and cell transformation. J Mol Endocrinol 32(2):397–414

    Article  PubMed  CAS  Google Scholar 

  14. Slattery ML, Baumgartner KB, Byers T, Guiliano A, Sweeney C, Herrick J, Curtin K, Murtaugh M, Wolff R (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

    Article  PubMed  CAS  Google Scholar 

  15. Sandhu MS, Dunger DB, Giovannucci EL (2002) Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer. J Natl Cancer Inst 94(13):972–980

    PubMed  CAS  Google Scholar 

  16. Ma J, Giovannucci E, Pollak M, Chan JM, Gaziano JM, Willett W, Stampfer MJ (2001) Milk intake, circulating levels of insulin-like growth factor-I, and risk of colorectal cancer in men. J Natl Cancer Inst 93(17):1330–1336

    Article  PubMed  CAS  Google Scholar 

  17. McCarty MF (1997) Up-regulation of IGF binding protein-1 as an anticarcinogenic strategy: relevance to caloric restriction, exercise, and insulin sensitivity. Med Hypotheses 48(4):297–308

    Article  PubMed  CAS  Google Scholar 

  18. Giovannucci E, Pollak M, Liu Y, Platz EA, Majeed N, Rimm EB, Willett WC (2003) Nutritional predictors of insulin-like growth factor I and their relationships to cancer in men. Cancer Epidemiol Biomarkers Prev 12(2):84–89

    PubMed  CAS  Google Scholar 

  19. Probst-Hensch NM, Wang H, Goh VHH, Seow A, Lee H-P, Yu MC (2003) Determinants of circulating insulin-like growth factor I and insulin-like growth factor binding protein 3 concentrations in a cohort of Singapore men and women. Cancer Epidemiol Biomarkers Prev 12(8):739–746

    PubMed  CAS  Google Scholar 

  20. Giovannucci E (2001) Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutr 131(Suppl. 11):3109S–3120S

    PubMed  CAS  Google Scholar 

  21. Rosen CJ, Glowacki J, Craig W (1998) Sex steroids, the insulin-like growth factor regulatory system, and aging: implications for the management of older postmenopausal women. J Nutr Health Aging 2(1):39–44

    PubMed  CAS  Google Scholar 

  22. Kido Y, Nakae J, Hribal ML, Xuan S, Efstratiadis A, Accili D (2002) Effects of mutations in the insulin-like growth factor signaling system on embryonic pancreas development and beta-cell compensation to insulin resistance. J Biol Chem 277(39):36740–36747

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  24. Jernstrom H, Deal C, Wilkin F, Chu W, Tao Y, Majeed N, Hudson T, Narod SA, Pollak M (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):377–384

    PubMed  CAS  Google Scholar 

  25. Zou T, Fleisher AS, Kong D, Yin J, Souza RF, Wang S, Smolinski KN, Abraham JM, Meltzer SJ (1998) Sequence alterations of insulin-like growth factor binding protein 3 in neoplastic and normal gastrointestinal tissues. Cancer Res 58(21):4802–4804

    PubMed  CAS  Google Scholar 

  26. Sweeney C, Murtaugh MA, Baumgartner KB, Byers T, Giuliano AR, Herrick JS, Wolff R, Caan BJ, Slattery ML (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

    Article  PubMed  CAS  Google Scholar 

  27. Slattery ML, Samowitz W, Hoffman M, Ma KN, Levin TR, Neuhausen S (2004) Aspirin, NSAIDs, and colorectal cancer: possible involvement in an insulin-related pathway. Cancer Epidemiol Biomarkers Prev 13(4):538–545

    PubMed  CAS  Google Scholar 

  28. Rosen CJ, Kurland ES, Vereault D, Adler RA, Rackoff PJ, Craig WY, Witte S, Rogers J, Bilezikian JP (1998) Association between 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(7):2286–2290

    Article  PubMed  CAS  Google Scholar 

  29. Chokkalingam AP, McGlynn KA, Gao Y-T, Pollak M, Deng J, Sesterhenn IA, Mostofi FK, Fraumeni JF Jr, Hsing AW (2001) Vitamin D receptor gene polymorphisms, insulin-like growth factors, and prostate cancer risk: a population-based case-control study in China. Cancer Res 61(11):4333–4336

    PubMed  CAS  Google Scholar 

  30. Cussenot O, Valeri A (2001) Heterogeneity in genetic susceptibility to prostate cancer. 12(1):11–16

  31. DeLellis K, Ingles S, Kolonel L, McKean-Cowdin R, Henderson B, Stanczyk F, Probst-Hensch NM (2003) IGF1 genotype, mean plasma level and breast cancer risk in the Hawaii/Los Angeles multiethnic cohort. Br J Cancer 88(2):277–282

    Article  PubMed  CAS  Google Scholar 

  32. Jernstrom H, Chu W, Vesprini D, Tao Y, Majeed N, Deal C, Pollak M, Narod SA (2001) Genetic factors related to racial variation in plasma levels of insulin-like growth factor-1: implications for premenopausal breast cancer risk. Mol Genet Metab 72(2):144–154

    Article  PubMed  CAS  Google Scholar 

  33. Howard CA, Samet JM, Buechley RW, Schrag SD, Key CR (1983) Survey research in New Mexico Hispanics: some methodological issues. Am J Epidemiol 117(1):27–34

    PubMed  CAS  Google Scholar 

  34. Slattery ML, Caan BJ, Duncan D, Berry TD, Coates A, Kerber R (1994) A computerized diet history questionnaire for epidemiologic studies. J Am Diet Assoc 94(7):761–766

    Article  PubMed  CAS  Google Scholar 

  35. Slattery MLS, Edwards S, Herrieck J, Baumgartner K, Wolff R, Murtaugh M, Baumgartner R, Giuliano A, Byers T (2006) Body size, weight change, fat distribution and breast cancer risk in Hispanic and non-Hispanic white women. Breast Cancer Res Treat

  36. Ainsworth BE, Irwin ML, Addy CL, Whitt MC, Stolarczyk LM (1999) Moderate physical activity patterns of minority women: the Cross-Cultural Activity Participation Study. J Womens Health Gend Based Med 8(6):805–813

    Article  PubMed  CAS  Google Scholar 

  37. Ainsworth BE, Haskell WL, Whitt MC, Irwin ML, Swartz AM, Strath SJ, O’Brien WL, Bassett DR Jr, Schmitz KH, Emplaincourt PO, et al (2000) Compendium of physical activities: an update of activity codes and MET intensities. Med Sci Sports Exerc 32(Suppl. 9):S498–S504

    PubMed  CAS  Google Scholar 

  38. Almind K, Bjorbaek C, Vestergaard H, Hansen T, Echwald S, Pedersen O (1993) Amino acid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus. Lancet 342(8875):828–832

    Article  PubMed  CAS  Google Scholar 

  39. Ehrmann DA, Tang X, Yoshiuchi I, Cox NJ, Bell GI (2002) Relationship of insulin receptor substrate-1 and -2 genotypes to phenotypic features of polycystic ovary syndrome. J Clin Endocrinol Metab 87(9):4297–4300

    Article  PubMed  CAS  Google Scholar 

  40. Lee S, Mohsin SK, Mao S, Hilsenbeck SG, Medina D, Allred DC (2006) Hormones, receptors, and growth in hyperplastic enlarged lobular units: early potential precursors of breast cancer. Breast Cancer Res 8(1):R6

    Article  PubMed  CAS  Google Scholar 

  41. Jackson JG, White MF, Yee D (1998) Insulin receptor substrate-1 is the predominant signaling molecule activated by insulin-like growth factor-I, insulin, and interleukin-4 in estrogen receptor-positive human breast cancer cells. J Biol Chem 273(16):9994–10003

    Article  PubMed  CAS  Google Scholar 

  42. Del Giudice ME, Fantus IG, Ezzat S, McKeown-Eyssen G, Page D, Goodwin PJ (1998) Insulin and related factors in premenopausal breast cancer risk. Breast Cancer Res Treat 47(2):111–120

    Article  PubMed  Google Scholar 

  43. Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M (1998) Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 351(9113):1393–1396

    Article  PubMed  CAS  Google Scholar 

  44. Bohlke K, Cramer DW, Trichopoulos D, Mantzoros CS (1998) Insulin-like growth factor-I in relation to premenopausal ductal carcinoma in situ of the breast. Epidemiology 9(5):570–573

    Article  PubMed  CAS  Google Scholar 

  45. Muti P, Quattrin T, Grant BJ, Krogh V, Micheli A, Schunemann HJ, Ram M, Freudenheim JL, Sieri S, Trevisan M, et al (2002) Fasting glucose is a risk factor for breast cancer: a prospective study. Cancer Epidemiol Biomarkers Prev 11(11):1361–1368

    PubMed  CAS  Google Scholar 

  46. Krajcik RA, Borofsky ND, Massardo S, Orentreich N (2002) Insulin-like growth factor I (IGF-I), IGF-binding proteins, and breast cancer. Cancer Epidemiol Biomarkers Prev 11(12):1566–1573

    PubMed  CAS  Google Scholar 

  47. Keinan-Boker L, Bueno De Mesquita HB, Kaaks R, Van Gils CH, Van Noord PA, Rinaldi S, Riboli E, Seidell JC, Grobbee DE, Peeters PH (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(1):90–95

    Article  PubMed  CAS  Google Scholar 

  48. Li BD, Khosravi MJ, Berkel HJ, Diamandi A, Dayton MA, Smith M, Yu H (2001) Free insulin-like growth factor-I and breast cancer risk. Int J Cancer 91(5):736–739

    Article  PubMed  CAS  Google Scholar 

  49. Malin A, Dai Q, Yu H, Shu XO, Jin F, Gao YT, Zheng W (2004) Evaluation of the synergistic effect of insulin resistance and insulin-like growth factors on the risk of breast carcinoma. Cancer 100(4):694–700

    Article  PubMed  CAS  Google Scholar 

  50. Daws MR, Westley BR, May FE (1996) Paradoxical effects of overexpression of the type I insulin-like growth factor (IGF) receptor on the responsiveness of human breast cancer cells to IGFs and estradiol. Endocrinology 137(4):1177–1186

    Article  PubMed  CAS  Google Scholar 

  51. Missmer SA, Haiman CA, Hunter DJ, Willett WC, Colditz GA, Speizer FE, Pollak MN, Hankinson SE (2002) A sequence repeat in the insulin-like growth factor-1 gene and risk of breast cancer. Int J Cancer 100(3):332–336

    Article  PubMed  CAS  Google Scholar 

  52. Canzian F, McKay JD, Cleveland RJ, Dossus L, Biessy C, Boillot C, Rinaldi S, Llewellyn M, Chajes V, Clavel-Chapelon F, et al (2005) Genetic variation in the growth hormone synthesis pathway in relation to circulating insulin-like growth factor-I, insulin-like growth factor binding protein-3, and breast cancer risk: results from the European prospective investigation into cancer and nutrition study. Cancer Epidemiol Biomarkers Prev 14(10):2316–2325

    Article  PubMed  CAS  Google Scholar 

  53. Burger AM, Leyland-Jones B, Banerjee K, Spyropoulos DD, Seth AK (2005) Essential roles of IGFBP-3 and IGFBP-rP1 in breast cancer. Eur J Cancer 41(11):1515–1527

    Article  PubMed  CAS  Google Scholar 

  54. Rinaldi S, Toniolo P, Muti P, Lundin E, Zeleniuch-Jacquotte A, Arslan A, Micheli A, Lenner P, Dossus L, Krogh V, et al (2005) IGF-I, IGFBP-3 and breast cancer in young women: a pooled re-analysis of three prospective studies. Eur J Cancer Prev 14(6):493–496

    Article  PubMed  Google Scholar 

  55. Al-Zahrani A, Sandhu MS, Luben RN, Thompson D, Baynes C, Pooley KA, Luccarini C, Munday H, Perkins B, Smith P, 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):1–10

    Article  PubMed  CAS  Google Scholar 

  56. Schernhammer ES, Hankinson SE, Hunter DJ, Blouin MJ, Pollak MN (2003) Polymorphic 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(1):60–64

    Article  PubMed  CAS  Google Scholar 

  57. Wagner K, Hemminki K, Grzybowska E, Klaes R, Butkiewicz D, Pamula J, Pekala W, Zientek H, Mielzynska D, Siwinska E, et al (2004) The insulin-like growth factor-1 pathway mediator genes: SHC1 Met300Val shows a protective effect in breast cancer. Carcinogenesis 25(12):2473–2478

    Article  PubMed  CAS  Google Scholar 

  58. Lahmann PH, Hoffmann K, Allen N, van Gils CH, Khaw KT, Tehard B, Berrino F, Tjonneland A, Bigaard J, Olsen A, et al (2004) Body size and breast cancer risk: findings from the European prospective investigation into cancer and nutrition (EPIC). Int J Cancer 111(5):762–771

    Article  PubMed  CAS  Google Scholar 

  59. Jernstrom H, Barrett-Connor E (1999) Obesity, weight change, fasting insulin, proinsulin, C-peptide, and insulin-like growth factor-1 levels in women with and without breast cancer: the Rancho Bernardo Study. J Womens Health Gend Based Med 8(10):1265–1272

    PubMed  CAS  Google Scholar 

  60. Baumgartner KB, Hunt WC, Baumgartner RN, Crumley DD, Gilliland FD, McTiernan A, Bernstein L, Ballard-Barbash R (2004) Association of body composition and weight history with breast cancer prognostic markers: divergent pattern for Hispanic and non-Hispanic White women. Am J Epidemiol 160(11):1087–1097

    Article  PubMed  CAS  Google Scholar 

  61. Lahmann PH, Schulz M, Hoffmann K, Boeing H, Tjonneland A, Olsen A, Overvad K, Key TJ, Allen NE, Khaw KT, et al (2005) Long-term weight change and breast cancer risk: the European prospective investigation into cancer and nutrition (EPIC). Br J Cancer 93(5):582–589

    Article  PubMed  CAS  Google Scholar 

  62. Huang Z, Hankinson SE, Colditz GA, Stampfer MJ, Hunter DJ, Manson JE, Hennekens CH, Rosner B, Speizer FE, Willett WC (1997) Dual effects of weight and weight gain on breast cancer risk. JAMA 278(17):1407–1411

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was funded by grants: CA 078682, CA 078762, CA 078552, CA 078802. This research also was supported by the Utah Cancer Registry, which is funded by Contract #N01-PC-67000 from the National Cancer Institute, with additional support from the State of Utah Department of Health, the New Mexico Tumor Registry, funded by contract #, and the Arizona and Colorado cancer registries, funded by the Centers for Disease Control and Prevention National Program of Cancer Registries and additional state support. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official view of the National Cancer Institute. We would like to acknowledge the contributions of Sandra Edwards, Roger Edwards, Leslie Palmer. Betsy Risendal, Karen Curtin, Tara Patton, Jason Witter, and Kelly May to this study.

Author information

Author notes

  1. K. Baumgartner

    Present address: University of Louisville, Louisville, KY, USA

  2. A. Giuliano

    Present address: Moffitt Cancer Center, Tampa, FL, USA

Authors and Affiliations

  1. University of Utah, Salt Lake City, Utah, 84108, USA

    M. L. Slattery, C. Sweeney, R. Wolff & J. Herrick

  2. Department of Internal Medicine, The Cancer Research and Treatment Center, Epidemiology and Cancer Prevention Program, University of New Mexico Health Science Center, Albuquerque, NM, USA

    K. Baumgartner

  3. University of Arizona, Tucson, AZ, USA

    A. Giuliano

  4. University of Colorado School of Medicine, Denver, CO, USA

    T. Byers

Authors
  1. M. L. Slattery
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Sweeney
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Wolff
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Herrick
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. Baumgartner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Giuliano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T. Byers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. L. Slattery.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Slattery, M.L., Sweeney, C., Wolff, R. et al. Genetic variation in IGF1, IGFBP3, IRS1, IRS2 and risk of breast cancer in women living in Southwestern United States. Breast Cancer Res Treat 104, 197–209 (2007). https://doi.org/10.1007/s10549-006-9403-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-006-9403-9

Keywords

Search

Navigation