Breast Cancer Research and Treatment

, Volume 99, Issue 3, pp 323–331 | Cite as

An association between a common variant (G972R) in the IRS-1 gene and sex hormone levels in post-menopausal breast cancer survivors

  • Jing Fan
  • Roberta McKean-Cowdin
  • Leslie Bernstein
  • Frank Z. Stanczyk
  • Arthur Xuejun Li
  • Rachel Ballard-Barbash
  • Anne McTiernan
  • Richard Baumgartner
  • Frank Gilliland


Insulin receptor substrate-1 (IRS-1) is a key downstream signaling molecule common to both the insulin and IGF signaling pathways that can interact with the estrogen pathway to regulate breast cell growth. We investigated whether a putative functional variant for IRS-1 (G972R) influences circulating levels of sex hormones, sex hormone binding globulin (SHBG), C-peptide, and insulin-like growth factor 1 (IGF-1) levels among post-menopausal African-American and non-Hispanic white breast cancer patients enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study. Circulating levels of sex hormones and growth factors can influence breast cancer recurrence and survival. Serum estrone, estradiol, testosterone, SHBG, IGF-1 and C-peptide were measured in 468 patients at 30+ months post diagnosis. Non-protein bound hormone levels (free estradiol, free testosterone) were calculated. In African-American patients, the IRS-1 variant was associated with increased serum levels of estrone (p=0.02), free estradiol (p=0.04), total testosterone (p=0.04), free testosterone (p=0.006) and decreased levels of sex hormone-binding globulin (p=0.02). No association was present for white patients. Our findings provide suggestive evidence that IRS-1 G972R variant may be associated with circulating levels of sex hormones and SHBG in African American breast cancer survivors.


African-American Breast cancer IRS-1 Polymorphism Sex hormones 



Coefficient of variation






Estrogen receptor


Health, Eating, Activity, and Lifestyle Study


Hormone replacement therapy


Insulin receptor substrate-1


Insulin-like growth factor 1


Insulin-like growth factor 1 receptor


IGF binding proteins


Sex hormone binding globulin




Amino acid change (glycine to arginine) at codon 972


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, under Contract Nos. N01-PC-35139, N01-PC-35139 and NIH/NCI/PC-67010. Initial data collection for the Los Angeles County patients was supported by the National Institute of Child Health and Human Development through contract N01 HD 3–3175.

The collection of California cancer incidence data used in this publication was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. The ideas and opinions expressed herein are those of the author, and no endorsement by the State of California, Department of Health Services is intended or should be inferred.


  1. 1.
    Persson I (2000) Estrogens in the causation of breast, endometrial and ovaria0n cancers – evidence and hypotheses from epidemiological findings. J Steroid Biochem Mol Biol 74(5):357–364PubMedCrossRefGoogle Scholar
  2. 2.
    Lonning PE, Helle SI, Johannessen DC, Ekse D, Adlercreutz H (1996) Influence of plasma estrogen levels on the length of the disease-free interval in postmenopausal women with breast cancer. Breast Cancer Res Treat 39(3):335–341PubMedCrossRefGoogle Scholar
  3. 3.
    Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy (1992) 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists’ Collaborative Group. Lancet 339(8784):1–15Google Scholar
  4. 4.
    Tamoxifen for early breast cancer: an overview of the randomised trials (1998) Early Breast Cancer Trialists’ Collaborative Group. Lancet 351(9114):1451–1467Google Scholar
  5. 5.
    Baum M, Buzdar A, Cuzick J, Forbes J, Houghton J, Howell A, Sahmoud T (2003) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 98(9):1802–1810PubMedCrossRefGoogle Scholar
  6. 6.
    Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, et al (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350(11):1081–1092PubMedCrossRefGoogle Scholar
  7. 7.
    Hamelers IH, Steenbergh PH (2003) Interactions between estrogen and insulin-like growth factor signaling pathways in human breast tumor cells. Endocr Relat Cancer 10(2):331–345PubMedCrossRefGoogle Scholar
  8. 8.
    Yee D (1994) The insulin-like growth factor system as a target in breast cancer. Breast Cancer Res Treat 32(1):85–95PubMedCrossRefGoogle Scholar
  9. 9.
    Lee AV, Hilsenbeck SG, Yee D (1998) IGF system components as prognostic markers in breast cancer. Breast Cancer Res Treat 47(3):295–302PubMedCrossRefGoogle Scholar
  10. 10.
    Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madarnas Y, Hartwick W, Hoffman B, Hood N (2002) Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol 20(1):42–51PubMedCrossRefGoogle Scholar
  11. 11.
    Lee AV, Jackson JG, Gooch JL, Hilsenbeck SG, Coronado-Heinsohn E, Osborne CK, Yee D (1999) Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo. Mol Endocrinol 13(5):787–796PubMedCrossRefGoogle Scholar
  12. 12.
    Ando S, Panno ML, Salerno M, Sisci D, Mauro L, Lanzino M, Surmacz E (1998) Role of IRS-1 signaling in insulin-induced modulation of estrogen receptors in breast cancer cells. Biochem Biophys Res Commun 253(2):315–319PubMedCrossRefGoogle Scholar
  13. 13.
    Freiss G, Puech C, Vignon F (1998) Extinction of Insulin-like growth factor-i mitogenic signaling by antiestrogen-stimulated Fas-associated protein tyrosine phosphatase-1 in human breast cancer cells. Mol Endocrinol 12(4):568–579PubMedCrossRefGoogle Scholar
  14. 14.
    Stewart A, Johnson M, May F, Westley B (1990) Role of insulin-like growth factors and the type I insulin-like growth factor receptor in the estrogen-stimulated proliferation of human breast cancer cells. J Biol Chem 265(34):21172–21178PubMedGoogle Scholar
  15. 15.
    Huynh H, Nickerson T, Pollak M, Yang X (1996) Regulation of insulin-like growth factor I receptor expression by the pure antiestrogen ICI 182780. Clin Cancer Res 2(12):2037–2042PubMedGoogle Scholar
  16. 16.
    Molloy CA, May FEB, Westley BR (2000) Insulin receptor substrate-1 expression is regulated by estrogen in the MCF-7 human breast cancer cell line. J Biol Chem 275(17):12565–12571PubMedCrossRefGoogle Scholar
  17. 17.
    Perks C, Holly J (2000) Insulin-like growth factor binding proteins (IGFBPs) in breast cancer. J Mammary Gland Biol Neoplasia 5(1):75–84PubMedCrossRefGoogle Scholar
  18. 18.
    Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H (2001) Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha . A new model for anti-estrogen resistance. J Biol Chem 276(13):9817–9824PubMedCrossRefGoogle Scholar
  19. 19.
    Endoh H, Maruyama K, Masuhiro Y, Kobayashi Y, Goto M, Tai H, Yanagisawa J, Metzger D, Hashimoto S, Kato S (1999) Purification and identification of p68 RNA helicase acting as a transcriptional coactivator specific for the activation function 1 of human estrogen receptor alpha. Mol Cell Biol 19(8):5363–5372PubMedGoogle Scholar
  20. 20.
    Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, et al (1995) Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 270(5241): 1491–1494PubMedCrossRefGoogle Scholar
  21. 21.
    Dufourny B, Alblas J, van Teeffelen HAAM, van Schaik FMA, van der Burg B, Steenbergh PH, Sussenbach JS (1997) Mitogenic signaling of insulin-like growth factor I in MCF-7 human breast cancer cells requires phosphatidylinositol 3-kinase and is independent of mitogen-activated protein kinase. J Biol Chem 272(49):31163–31171PubMedCrossRefGoogle Scholar
  22. 22.
    Bezerra RMN, de Castro V, Sales T, Passini R Jr, Marba STM, Saad STO, Saad MJA (2002) The Gly972Arg polymorphism in insulin receptor substrate-1 is associated with decreased birth weight in a population-based sample of Brazilian newborns. Diabetes Care 25(3):550–553PubMedCrossRefGoogle Scholar
  23. 23.
    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):9994–10003PubMedCrossRefGoogle Scholar
  24. 24.
    Sesti G, Federici M, Hribal ML, Lauro D, Sbraccia P, Lauro R (2001) Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. Faseb J 15(12):2099–2111PubMedCrossRefGoogle Scholar
  25. 25.
    Almind K, Inoue G, Pedersen O, Kahn CR (1996) A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. Evidence from transfection studies. J␣Clin Invest 97(11):2569–2575PubMedCrossRefGoogle Scholar
  26. 26.
    Clausen JO, Hansen T, Bjorbaek C, Echwald SM, Urhammer SA, Rasmussen S, Andersen CB, Hansen L, Almind K, Winther K, et al (1995) Insulin resistance: interactions between obesity and a common variant of insulin receptor substrate-1. Lancet 346(8972):397–402PubMedCrossRefGoogle Scholar
  27. 27.
    Baroni MG, Arca M, Sentinelli F, Buzzetti R, Capici F, Lovari S, Vitale M, Romeo S, Di Mario U (2001) The G972R variant of the insulin receptor substrate-1 (IRS-1) gene, body fat distribution and insulin-resistance. Diabetologia 44(3):367–372PubMedCrossRefGoogle Scholar
  28. 28.
    Almind K, Bjorbaek C, Vestergaard H, Hansen T, Echwald S, Pedersen O (1993) Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus. Lancet 342(8875):828–832PubMedCrossRefGoogle Scholar
  29. 29.
    Jellema A, Zeegers MP, Feskens EJ, Dagnelie PC, Mensink RP (2003) Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies. Diabetologia 46(7):990–995PubMedCrossRefGoogle Scholar
  30. 30.
    Baroni MG, D’Andrea MP, Montali A, Pannitteri G, Barilla F, Campagna F, Mazzei E, Lovari S, Seccareccia F, Campa PP, et al (1999) A common mutation of the insulin receptor substrate-1 gene is a risk factor for coronary artery disease. Arterioscler Thromb Vasc Biol 19(12):2975–2980PubMedGoogle Scholar
  31. 31.
    Holzl B, Iglseder B, Stadlmayr A, Hedegger M, More E, Reiter R, Sandhofer F, Paulweber B (2003) Intima media thickness of carotid arteries is reduced in heterozygous carriers of the Gly972Arg variant in the insulin receptor substrate-1 gene. Eur J Clin Invest 33(2):110–116PubMedCrossRefGoogle Scholar
  32. 32.
    Porzio O, Federici M, Hribal ML, Lauro D, Accili D, Lauro R, Borboni P, Sesti G (1999) The Gly972–>Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. J Clin Invest 104(3):357–364PubMedCrossRefGoogle Scholar
  33. 33.
    McTiernan A, Rajan KB, Tworoger SS, Irwin M, Bernstein L, Baumgartner R, Gilliland F, Stanczyk FZ, Yasui Y, Ballard-Barbash R (2003) Adiposity and sex hormones in postmenopausal breast cancer survivors. J Clin Oncol 21(10):1961–1966PubMedCrossRefGoogle Scholar
  34. 34.
    Tsai C-T, Hwang J-J, Lai L-P, Chiang F-T, Tseng Y-Z (2002) IRS-1 Gly971Arg variant is not a new risk factor for coronary artery disease in the Taiwanese population. Arterioscler Thromb Vasc Biol 22(1):194PubMedGoogle Scholar
  35. 35.
    Sodergard R, Backstrom T, Shanbhag V, Carstensen H (1982) Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature. J␣Steroid Biochem 16(6):801–810PubMedCrossRefGoogle Scholar
  36. 36.
    Falk RT, Dorgan JF, Kahle L, Potischman N, Longcope C (1997) Assay reproducibility of hormone measurements in postmenopausal women. Cancer Epidemiol Biomarkers Prev 6(6):429–432PubMedGoogle Scholar
  37. 37.
    McShane LM, Dorgan JF, Greenhut S, Damato JJ (1996) Reliability and validity of serum sex hormone measurements. Cancer Epidemiol Biomarkers Prev 5(11):923–928PubMedGoogle Scholar
  38. 38.
    Livak KJ (1999) Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet Anal 14(5–6):143–149PubMedGoogle Scholar
  39. 39.
    Ogden CL, Flegal KM, Carroll MD, Johnson CL (2002) Prevalence and trends in overweight among US children and adolescents, 1999–2000. JAMA 288(14):1728–1732PubMedCrossRefGoogle Scholar
  40. 40.
    El Mkadem SA, Lautier C, Macari F, Molinari N, Lefebvre P, Renard E, Gris JC, Cros G, Daures JP, Bringer J, et al (2001) Role of allelic variants Gly972Arg of IRS-1 and Gly1057Asp of IRS-2 in moderate-to-severe insulin resistance of women with polycystic ovary syndrome. Diabetes 50(9):2164–2168PubMedCrossRefGoogle Scholar
  41. 41.
    Weiss SE, Tartter PI, Ahmed S, Brower ST, Brusco C, Bossolt K, Amberson JB, Bratton J (1995) Ethnic differences in risk and prognostic factors for breast cancer. Cancer 76(2):268–274PubMedCrossRefGoogle Scholar
  42. 42.
    O’Malley CD, Le GM, Glaser SL, Shema SJ, West DW (2003) Socioeconomic status and breast carcinoma survival in four racial/ethnic groups: a population-based study. Cancer 97(5):1303–1311PubMedCrossRefGoogle Scholar
  43. 43.
    Simon MS, Severson RK (1996) Racial differences in survival of female breast cancer in the Detroit metropolitan area. Cancer 77(2):308–314PubMedCrossRefGoogle Scholar
  44. 44.
    Natarajan N, Nemoto T, Mettlin C, Murphy GP (1985) Race-related differences in breast cancer patients. Results of the 1982 national survey of breast cancer by the American College of Surgeons. Cancer 56(7):1704–1709PubMedCrossRefGoogle Scholar
  45. 45.
    Maskarinec G, Pagano IS, Yamashiro G, Issell BF (2003) Influences of ethnicity, treatment, and comorbidity on breast cancer survival in Hawaii. J Clin Epidemiol 56(7):678–685PubMedCrossRefGoogle Scholar
  46. 46.
    Ademuyiwa FO, Olopade OI (2003) Racial differences in genetic factors associated with breast cancer. Cancer Metastasis Rev 22(1):47–53PubMedCrossRefGoogle Scholar
  47. 47.
    Siiteri PK, Simberg N, Murai J (1986) Estrogens and breast cancer. Ann NY Acad Sci 464:100–105PubMedCrossRefGoogle Scholar
  48. 48.
    Feigelson HS, Henderson BE (1996) Estrogens and breast cancer. Carcinogenesis 17(11):2279–2284PubMedCrossRefGoogle Scholar
  49. 49.
    Zhang Y, Wat N, Stratton IM, Warren-Perry MG, Orho M, Groop L, Turner RC (1996) UKPDS 19: heterogeneity in NIDDM: separate contributions of IRS-1 and b3-adrenergic-receptor mutations to insulin resistance and obesity respectively with no evidence for glycogen synthase gene mutations. Diabetologia 39(12):1505–1511PubMedCrossRefGoogle Scholar
  50. 50.
    Ito K, Katsuki A, Furuta M, Fujii M, Tsuchihashi K, Hori Y, Yano Y, Sumida Y, Adachi Y (1999) Insulin sensitivity is not affected by mutation of codon 972 of the human IRS-1 gene. Horm Res 52(5):230–234PubMedCrossRefGoogle Scholar
  51. 51.
    Previs SF, Withers DJ, Ren J-M, White MF, Shulman GI (2000) Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo. J Biol Chem 275(50):38990–38994PubMedCrossRefGoogle Scholar
  52. 52.
    Yamauchi T, Tobe K, Tamemoto H, Ueki K, Kaburagi Y, Yamamoto-Honda R, Takahashi Y, Yoshizawa F, Aizawa S, Akanuma Y, et al (1996) Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice. Mol Cell Biol 16(6):3074–3084PubMedGoogle Scholar
  53. 53.
    Porzio O, Federici M, Hribal ML, Lauro D, Accili D, Lauro R, Borboni P, Sesti G (1999) The Gly972->Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic {beta} cells. J Clin Invest 104(3):357–364PubMedCrossRefGoogle Scholar
  54. 54.
    Stoll BA (2002) Upper abdominal obesity, insulin resistance and breast cancer risk. Int J Obes Relat Metab Disord 26(6):747–753PubMedCrossRefGoogle Scholar
  55. 55.
    Imai Y, Philippe N, Sesti G, Accili D, Taylor SI (1997) Expression of variant forms of insulin receptor substrate-1 identified in patients with noninsulin-dependent diabetes mellitus. J␣Clin Endocrinol Metab 82(12):4201–4207PubMedCrossRefGoogle Scholar
  56. 56.
    Carvalho E, Jansson PA, Axelsen M, Eriksson JW, Huang X, Groop L, Rondinone C, Sjostrom L, Smith U (1999) Low cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM. Faseb J 13(15):2173–2178PubMedGoogle Scholar
  57. 57.
    Hager J, Zouali H, Velho G, Froguel P (1993) Insulin receptor substrate (IRS-1) gene polymorphisms in French NIDDM families. Lancet 342(8884):1430PubMedCrossRefGoogle Scholar
  58. 58.
    Laakso M, Malkki M, Kekalainen P, Kuusisto J, Deeb SS (1994) Insulin receptor substrate-1 variants in non-insulin-dependent diabetes. J Clin Invest 94(3):1141–1146PubMedCrossRefGoogle Scholar
  59. 59.
    Chuang LM, Lai CS, Yeh JI, Wu HP, Tai TY, Lin BJ (1996) No association between the Gly971Arg variant of the insulin receptor substrate 1 gene and NIDDM in the Taiwanese population. Diabetes Care 19(5):446–449PubMedCrossRefGoogle Scholar
  60. 60.
    Armstrong M, Haldane F, Taylor RW, Humphriss D, Berrish T, Stewart MW, Turnbull DM, Alberti KG, Walker M (1996) Human insulin receptor substrate-1: variant sequences in familial non-insulin-dependent diabetes mellitus. Diabet Med 13(2):133–138PubMedCrossRefGoogle Scholar
  61. 61.
    Armstrong M, Haldane F, Avery PJ, Mitcheson J, Stewart MW, Turnbull DM, Walker M (1996) Relationship between insulin sensitivity and insulin receptor substrate-1 mutations in non-diabetic relatives of NIDDM families. Diabet Med 13(4):341–345PubMedCrossRefGoogle Scholar
  62. 62.
    Ura S, Araki E, Kishikawa H, Shirotani T, Todaka M, Isami S, Shimoda S, Yoshimura R, Matsuda K, Motoyoshi S, et al (1996) Molecular scanning of the insulin receptor substrate-1 (IRS-1) gene in Japanese patients with NIDDM: identification of five novel polymorphisms. Diabetologia 39(5):600–608PubMedCrossRefGoogle Scholar
  63. 63.
    Koch M, Rett K, Volk A, Maerker E, Haist K, Deninger M, Renn W, Haring HU (1999) Amino acid polymorphism Gly 972 Arg in IRS-1 is not associated to lower clamp-derived insulin sensitivity in young healthy first degree relatives of patients with type 2 diabetes. Exp Clin Endocrinol Diabetes 107(5):318–322PubMedCrossRefGoogle Scholar
  64. 64.
    Chang Q, Li Y, White MF, Fletcher JA, Xiao S (2002) Constitutive activation of insulin receptor substrate 1 is a frequent event in human tumors: therapeutic implications. Cancer Res 62(21):6035–6038PubMedGoogle Scholar
  65. 65.
    Lee AV, Zhang P, Ivanova M, Bonnette S, Oesterreich S, Rosen JM, Grimm S, Hovey RC, Vonderhaar BK, Kahn CR, et al (2003) Developmental and hormonal signals dramatically alter the localization and abundance of insulin receptor substrate proteins in the mammary gland.Endocrinology 144(6):2683–2694PubMedCrossRefGoogle Scholar
  66. 66.
    Mauro L, Salerno M, Panno ML, Bellizzi D, Sisci D, Miglietta A, Surmacz E, Ando S (2001) Estradiol increases IRS-1 gene expression and insulin signaling in breast cancer cells. Biochem Biophys Res Commun 288(3):685–689PubMedCrossRefGoogle Scholar
  67. 67.
    Dupont J, Le Roith D (2001) Insulin-like growth factor 1 and oestradiol promote cell proliferation of MCF-7 breast cancer cells: new insights into their synergistic effects. Mol Pathol 54(3):149–154PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  • Jing Fan
    • 1
  • Roberta McKean-Cowdin
    • 2
  • Leslie Bernstein
    • 2
  • Frank Z. Stanczyk
    • 3
  • Arthur Xuejun Li
    • 2
  • Rachel Ballard-Barbash
    • 4
  • Anne McTiernan
    • 5
  • Richard Baumgartner
    • 6
  • Frank Gilliland
    • 2
  1. 1.Integrated Substance Abuse Programs, Neuropsychiatric InstituteUniversity of CaliforniaLos AngelesUSA
  2. 2.Department of Preventive MedicineUniversity of Southern California, Keck School of MedicineLos AngelesUSA
  3. 3.Department of Obstetrics/GynecologyUniversity of Southern California, Keck School of MedicineLos AngelesUSA
  4. 4.Applied Research Program, Division of Cancer Control and Population SciencesNational Cancer InstituteBethesdaUSA
  5. 5.Division of Public Health SciencesFred Hutchinson Cancer Research CenterSeattleUSA
  6. 6.Department of Epidemiology and Clinical Investigation ScienceUniversity of LouisvilleLouisvilleUSA

Personalised recommendations