Breast Cancer Research and Treatment

, Volume 104, Issue 3, pp 309–319 | Cite as

Genetic variation in IGF1, IGF-1R, IGFALS, and IGFBP3 in breast cancer survival among Chinese women: a report from the Shanghai Breast Cancer Study

  • Sandra L. Deming
  • Zefang Ren
  • Wanqing Wen
  • Xiao Ou Shu
  • Qiuyin Cai
  • Yu-Tang Gao
  • Wei Zheng


Disruption of the balance of IGF (Insulin like growth factor) pathway constituents has been implicated in the etiology and progression of breast and other cancers. We hypothesized that genetic polymorphisms in IGF system members may be associated with breast cancer survival and evaluated this hypothesis in a cohort of 1,455 women diagnosed with breast cancer between 1996 and 1998 in Shanghai, China. Nineteen functional or potentially functional polymorphisms were evaluated in the IGF-1, IGF-1R, IGFALS, and IGFBP3 genes. Disease recurrence and vital status were obtained with a median follow-up time of 7.1 years. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Overall, no significant association was noted between any of the 19 polymorphisms and survival. However, subgroup analyses demonstrated apparent interactions between menopausal status and survival for several (Single nucleotide polymorphism) SNPs in the IGF-1R and IGFBP3 genes. Carriers of the A/G or G/G genotypes (rs951715) in the IGF-1R gene had an increased risk of death among post-menopausal women (HR = 1.7, 95% CI = 1.1–2.7). Significant associations with breast cancer survival in pre-menopausal women were found for two IGFBP3 polymorphisms (rs2854744 and rs3110697), with an additional polymorphism (rs6413441) reaching borderline significance (P = 0.05). Hazard ratios for overall survival among pre-menopausal women were 1.5 (95% CI = 1.1–2.0) for the C/T–T/T genotypes (rs3110697), 1.4 (95% CI = 1.0–1.9) for the A/C–C/C genotypes (rs2854744), and 1.4 (95% CI = 1.0–1.9) for the N/A–A/A genotypes (rs6413441). Taken together, these data suggest that polymorphisms in the IGF-1R and IGFBP3 genes may be associated with altered survival among subgroups of breast cancer patients defined by menopausal status.


IGF Polymorphisms Breast Cancer Survival 



The authors wish to express their gratitude to Drs. Qi Dai and Fan Jin for the contributions in coordinating data and specimen collection in Shanghai, Bethanie Hull for her technical assistance in the preparation of this manuscript, and all of the study participants and research staff of the Shanghai Breast Cancer Study.


  1. 1.
    Macaulay VM (1992) Insulin-like growth factors and cancer. Br J Cancer 65:311–320PubMedGoogle Scholar
  2. 2.
    Daughaday WH, Rotwein P (1989) Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev 10:68–91PubMedCrossRefGoogle Scholar
  3. 3.
    Renehan AG, Zwahlen M, Minder C et al (2004) Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 363:1346–1353PubMedCrossRefGoogle Scholar
  4. 4.
    Raile K, Hille R, Laue S et al (2003) Insulin-like growth factor I (IGF-I) stimulates proliferation but also increases caspase-3 activity, Annexin-V binding, and DNA-fragmentation in human MG63 osteosarcoma cells: co-activation of pro- and anti-apoptotic pathways by IGF-I. Horm Metab Res 35:786–793PubMedCrossRefGoogle Scholar
  5. 5.
    Raile K, Berthold A, Banning U et al (2003) IGFs, basic FGF, and glucose modulate proliferation and apoptosis induced by IFN gamma but not by IL-1beta in rat INS-1E beta-cells. Horm Metab Res 35:407–414PubMedCrossRefGoogle Scholar
  6. 6.
    LeRoith D, Werner H, Beitner-Johnson D et al (1995) Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 16:143–163PubMedCrossRefGoogle Scholar
  7. 7.
    Werner H, Adamo M, Roberts CT Jr et al (1994) Molecular and cellular aspects of insulin-like growth factor action. Vitam Horm 48:1–58PubMedCrossRefGoogle Scholar
  8. 8.
    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
  9. 9.
    Malin A, Dai Q, Yu H et al (2004) Evaluation of the synergistic effect of insulin resistance and insulin-like growth factors on the risk of breast carcinoma. Cancer 100:694–700PubMedCrossRefGoogle Scholar
  10. 10.
    Bohlke K, Cramer DW, Trichopoulos D et al (1998) Insulin-like growth factor-I in relation to premenopausal ductal carcinoma in situ of the breast. Epidemiology 9:570–573PubMedCrossRefGoogle Scholar
  11. 11.
    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
  12. 12.
    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
  13. 13.
    Peyrat JP, Bonneterre J, Hecquet B et al (1993) Plasma insulin-like growth factor-1 (IGF-1) concentrations in human breast cancer. Eur J Cancer 29A:492–497PubMedCrossRefGoogle Scholar
  14. 14.
    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
  15. 15.
    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
  16. 16.
    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
  17. 17.
    Ren Z, Cai Q, Shu XO et al (2004) Genetic polymorphisms in the IGFBP3 gene: association with breast cancer risk and blood IGFBP-3 protein levels among Chinese women. Cancer Epidemiol Biomarkers Prev 13:1290–1295PubMedGoogle Scholar
  18. 18.
    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
  19. 19.
    Schernhammer ES, Hankinson SE, Hunter DJ et al (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 107:60–64PubMedCrossRefGoogle Scholar
  20. 20.
    Wen W, Gao YT, Shu XO et al (2005) Insulin-like growth factor-I gene polymorphism and breast cancer risk in Chinese women. Int J Cancer 113:307–311PubMedCrossRefGoogle Scholar
  21. 21.
    Canzian F, McKay JD, Cleveland RJ 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 14:2316–2325PubMedCrossRefGoogle Scholar
  22. 22.
    Wagner K, Hemminki K, Israelsson E et al (2005) Polymorphisms in the IGF-1 and IGFBP 3 promoter and the risk of breast cancer. Breast Cancer Res Treat 92:133–140PubMedCrossRefGoogle Scholar
  23. 23.
    Cleveland RJ, Gammon MD, Edmiston SN et al (2006) IGF1 CA repeat polymorphisms, lifestyle factors and breast cancer risk in the Long Island Breast Cancer Study Project. Carcinogenesis 27:758–765PubMedCrossRefGoogle Scholar
  24. 24.
    Missmer SA, Haiman CA, Hunter DJ et al (2002) A sequence repeat in the insulin-like growth factor-1 gene and risk of breast cancer. Int J Cancer 100:332–336PubMedCrossRefGoogle Scholar
  25. 25.
    Gao YT, Shu XO, Dai Q et al (2000) Association of menstrual and reproductive factors with breast cancer risk: results from the Shanghai Breast Cancer Study. Int J Cancer 87:295–300PubMedCrossRefGoogle Scholar
  26. 26.
    Zaykin DV, Westfall PH, Young SS et al (2002) Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Hum Hered 53:79–91PubMedCrossRefGoogle Scholar
  27. 27.
    (2006) The comprehsive R archive network. website Google Scholar
  28. 28.
    Rasmussen SK, Lautier C, Hansen L et al (2000) Studies of the variability of the genes encoding the insulin-like growth factor I receptor and its ligand in relation to type 2 diabetes mellitus. J Clin Endocrinol Metab 85:1606–1610PubMedCrossRefGoogle Scholar
  29. 29.
    Deal C, Ma J, Wilkin F et al (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 86:1274–1280PubMedCrossRefGoogle 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.
    Wang L, Habuchi T, Tsuchiya N et al (2003) Insulin-like growth factor-binding protein-3 gene -202 A/C polymorphism is correlated with advanced disease status in prostate cancer. Cancer Res 63:4407–4411PubMedGoogle Scholar
  32. 32.
    Pollak MN, Huynh HT, Lefebvre SP (1992) Tamoxifen reduces serum insulin-like growth factor I (IGF-I). Breast Cancer Res Treat 22:91–100PubMedCrossRefGoogle Scholar
  33. 33.
    Stewart AJ, Johnson MD, May FE et al (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 265:21172–21178PubMedGoogle Scholar
  34. 34.
    Surmacz E, Bartucci M (2004) Role of estrogen receptor alpha in modulating IGF-I receptor signaling and function in breast cancer. J Exp Clin Cancer Res 23:385–394PubMedGoogle Scholar
  35. 35.
    Vadgama JV, Wu Y, Datta G et al (1999) Plasma insulin-like growth factor-I and serum IGF-binding protein 3 can be associated with the progression of breast cancer, and predict the risk of recurrence and the probability of survival in African-American and Hispanic women. Oncology 57:330–340PubMedCrossRefGoogle Scholar
  36. 36.
    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
  37. 37.
    Gee JM, Robertson JF, Gutteridge E et al (2005) Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer. Endocr Relat Cancer 12 Suppl 1:S99-S111CrossRefGoogle Scholar
  38. 38.
    Milewicz T, Gregoraszczuk EL, Sztefko K et al (2005) Lack of synergy between estrogen and progesterone on local IGF-I, IGFBP-3 and IGFBP-2 secretion by both hormone-dependent and hormone-independent breast cancer explants in vitro. Effect of tamoxifen and mifepristone (RU 486). Growth Horm IGF Res 15:140–147PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Sandra L. Deming
    • 1
  • Zefang Ren
    • 1
    • 2
  • Wanqing Wen
    • 1
  • Xiao Ou Shu
    • 1
  • Qiuyin Cai
    • 1
  • Yu-Tang Gao
    • 3
  • Wei Zheng
    • 1
    • 4
  1. 1.Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology CenterVanderbilt University Medical CenterNashvilleUSA
  2. 2.Guangzhou Center for Disease Prevention and ControlGuangzhouChina
  3. 3.Department of EpidemiologyShanghai Cancer InstituteShanghaiChina
  4. 4.Vanderbilt Epidemiology CenterVanderbilt University Medical CenterNashvilleUSA

Personalised recommendations