Breast Cancer Research and Treatment

, Volume 74, Issue 1, pp 65–76 | Cite as

Insulin-like growth factor binding proteins 1 and 3 and breast cancer outcomes

  • Pamela J. Goodwin
  • Marguerite Ennis
  • Kathleen I. Pritchard
  • Maureen E. Trudeau
  • Jarley Koo
  • Warren Hartwick
  • Barry Hoffman
  • Nicky Hood


The IGF family of growth factors is believed to play a role in the development and progression of breast cancer. We recently identified an adverse prognostic effect of insulin in breast cancer; we now report prognostic effects of circulating IGFBP's 1 and 3. 512 women with T1-3, N0-1, M0 breast cancer provided fasting blood which was analysed for IGFBP's 1 and 3. Information on body size, diet and traditional prognostic factors and treatment was obtained; women were followed for recurrence and death. IGFBP-1 levels correlated inversely with insulin levels (Spearman r = −0.60, p < 0.0001), reflecting known inhibition of IGFBP-1 gene expression by insulin. Insulin explained 36% of the variance in IGFBP-1 levels. IGFBP-1 levels were also correlated with obesity and diet. Levels of IGFBP-1 significantly predicted distant recurrence and death, hazard ratio (95% CI) for lower versus upper quartile 2.08 (1.20–3.61) and 3.0 (1.45–6.21), respectively. These effects persisted after adjustment for tumor-related variables and treatment but were not independent of insulin levels. High levels of IGFBP-3 predicted distant recurrence (hazard ratio upper v.s. lower quartile 1.8, 95% CI 1.1–3.0) but not death (hazard ratio 1.0, 95% CI 0.5–1.9). The effect on distant recurrence was restricted to postmenopausal women (hazard ratio 3.8, 95% CI 1.6–9.0) and to those with estrogen receptor positive tumors (p = 0.002). Prognostic effects of IGFBP-1 appear related to the known effect of insulin on IGFBP-1 gene expression. The adverse effect of IGFBP-3 on distant recurrence in postmenopausal women with estrogen receptor positive breast cancer should be further investigated.

breast cancer distant recurrence IGFBP1 IGFBP3 survival 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Yee D: The insulin-like growth factors and breast cancer revisited. Br Cancer Res Treat 47: 197–199, 1998Google Scholar
  2. 2.
    Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madarnas Y, Hartwick W, Hoffman B, Hood N: Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol 20: 42–51, 2002Google Scholar
  3. 3.
    Del Giudice ME, Fantus IG, Ezzat S, McKeown-Eyssen G, Page D, Goodwin PJ: Insulin and related factors in premenopausal breast cancer risk. Breast Canc Res Treat 47: 111–120, 1998Google Scholar
  4. 4.
    Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M: Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 351: 1393–1396, 1998Google Scholar
  5. 5.
    Petridou E, Papadiamantas Y, Markopoulos C, Spanos E, Dessypris N, Trichopoulos D: Leptin and insulin growth factor I in relation to breast cancer (Greece). Cancer Causes Cont 11: 383–388, 2000Google Scholar
  6. 6.
    Bruning PF, Van Doorn J, Bonfrer JMG, Van Noord PAH, Korse CM, Linders TC, Hart AAM: Insulin-like growthfactor-binding protein 3 is decreased in early-stage operable breast cancer. Int J Cancer 62: 266–270, 1995Google Scholar
  7. 7.
    Bohlke K, Cramer DW, Trichopoulos D, Mantzoros CS: Insulin-like growth factor-I in relation to premenopausal ductal carcinoma in situ of the breast. Epidemiology 9: 570–573, 1998Google Scholar
  8. 8.
    Toniolo P, Bruning PF, Akhmedkhanov A, Bonfrer JM, Koenig KL, Lukanova A, Shore RE, Zeleniuch-Jacquotte A: Serum insulin-like growth factor-I and breast cancer. Int J Cancer 88: 828–832, 2000Google Scholar
  9. 9.
    Agurs-Collins T, Adams-Campbell LL, Kim KS, Cullen KJ: Insulin-like growth factor-1 and breast cancer risk in postmenopausal African-American women. Cancer Detect Prev 24: 199–206, 2000Google Scholar
  10. 10.
    Li BD, Khosravi MJ, Berkel HJ, Diamandi A, Dayton MA, Smith M, Yu H: Free insulin-like growth factor-I and breast cancer risk. Int J Cancer 91: 736–739, 2001Google Scholar
  11. 11.
    Jernstrom H, Barrett-Connor E: 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: 1265–1272, 1999Google Scholar
  12. 12.
    Rasmussen AA, Cullen KJ: Paracrine/autocrine regulation of breast cancer by the insulin-like growth factors. Breast Canc Res Treat 47: 219–233, 1998Google Scholar
  13. 13.
    Oh Y: IGF-independent regulation of breast cancer growth by IGF binding proteins. Br Cancer Res Treat 47: 283–293, 1998Google Scholar
  14. 14.
    Jones JI, Clemmons DR: Insulin-like growth factors and their binding proteins: biological actions. Endocrine Rev 16: 3–34, 1995Google Scholar
  15. 15.
    Figueroa JA, Jackson JG, McGuire WL, Krywicki RF, Yee D: Expression of insulin-like growth factor binding proteins in human breast cancer correlates with estrogen receptor status. J Cell Biochem 52: 196–205, 1993Google Scholar
  16. 16.
    Ng E-H, Ji C-Y, Tan P-H, Lin V, Soo K-C, Lee K-O: Altered serum levels of insulin-like growth-factor binding proteins in breast cancer patients. Ann Surg Oncol 5: 194–201, 1998Google Scholar
  17. 17.
    Holdaway IM, Mason BH, Lethaby AE, Singh V, Harman JE, MacCormick M, Civil ID: Serum levels of insulin-like growth factor binding protein-3 in benign andmalignant breast disease. Aust N Z J Surg 69: 495–500, 1999Google Scholar
  18. 18.
    Rocha RL, Hilsenbeck SG, Jackson JG, VanDenBerg CL, Weng C-N, Lee AV, Yee D: Insulin-like growth factor binding protein-3 and insulin receptor substrate-1 in breast cancer: correlation with clinical parameters and disease-free survival. Clin Cancer Res 3: 103–109, 1997Google Scholar
  19. 19.
    Vadgama JV, Wu Y, Datta G, Khan H, Chillar R: 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: 330–340, 1999Google Scholar
  20. 20.
    Rocha RL, Hilsenbeck SG, Jackson JG, Lee AV, Figueroa JA, Yee D: Correlation of insulin-like growth factor-binding protein-3 messenger RNA with protein expression in primary breast cancer tissues: detection of higher levels in tumors with poor prognostic features. J Natl Cancer Inst 88: 601–606, 1996Google Scholar
  21. 21.
    Yu H, Levesque MA, Khosravi MJ, Papanastasiou-Diamandi A, Clark GM, Diamandis EP: Associations between insulinlike growth factors and their binding proteins and other prognostic indicators in breast cancer. Br J Cancer 74: 1242–1247, 1996Google Scholar
  22. 22.
    Ho G-H, Ji C-Y, Phang B-H, Lee K-O, Soo K-C, Ng E-H: Tamoxifen alters levels of serum insulin-like growth factors and binding proteins in postmenopausal breast cancer patients: a prospective paired cohort study. Ann Surg Oncol 5: 361–367, 1998Google Scholar
  23. 23.
    Powell DR, Suwanichkul A, Cubbage ML, DePaolis LA, Snuggs MB, Lee PDK: Insulin inhibits transcription of the human gene for insulin-like growth factor-binding protein-1. J Biol Chem 266: 18868–18876, 1991Google Scholar
  24. 24.
    Lahti EI, Knip M, Laatikainen TJ: Plasma insulin-like growth factor I and its binding proteins 1 and 3 in postmenopausal patients with breast cancer receiving long term tamoxifen. Cancer 74: 618–624, 1994Google Scholar
  25. 25.
    Block G, Hartman A, Dresser, Carroll MD, Gannon J, Gardner L: A data based approach to diet questionnaire design and testing. Am J Epidemiol 124: 453–459, 1986Google Scholar
  26. 26.
    Willett WC, Howe GR, Kushi LH: Adjustment for total energy intake in epidemiologic studies. Am J Clin Nutr 65: 1220S–1228S, 1997Google Scholar
  27. 27.
    Busby WH, Snyder DK, Clemmons DR: Radioimmunoassay of a 26,000-Dalton plasma insulin-like growth factor-binding protein: control by nutritional variables. J Clin Endocrinol Metab 67: 1225–1230, 1988Google Scholar
  28. 28.
    Suikkari A-M, Koivisto VA, Rutanen E-M, Yki-Järvinen H, Karonen S-L, Seppälä M: Insulin regulates the serum levels of low molecular weight insulin-like growth factor-binding protein. J Clin Endocrinol Metab 66: 266–272, 1988Google Scholar
  29. 29.
    Pratt SE, Pollak MN: Insulin-like growth factor binding protein 3 (IGF-BP3) inhibits estrogen-stimulated breast cancer cell proliferation. Biochem Biophys Res Commun 198: 292–297, 1994Google Scholar
  30. 30.
    Oh Y, Muller HL, Lamson G, Rosenfeld RG: Insulinlike growth factor (IGF)-independent action of IGF-binding protein-3 in Hs 578T human breast cancer cells. Cell surface binding and growth inhibition. J Biol Chem 268: 14964–14971, 1993Google Scholar
  31. 31.
    Yee D, Lee AV: Crosstalk between the insulin-like growth factors and estrogens in breast cancer. J Mamm Gland Biol Neoplasia 5: 107–115, 2000Google Scholar
  32. 32.
    Barni S, Lissoni P, Brivio F, Fumagalli, Merlini D, Cataldo M, Rovelli F, Tancini G: Serum levels of insulin-like growth factor-I in operable breast cancer in relation to the main prognostic variables and their perioperative changes in relation to those of prolactin. Tumouri 80: 212–215, 1994Google Scholar
  33. 33.
    Toropainen E, Lipponen P, Syrjänen K: Expression of insulinlike growth factor I (IGF-I) in female breast cancer as related to established prognostic factors and long-term prognosis. Eur J Cancer 31A: 1443–1448, 1995Google Scholar
  34. 34.
    Bhatavdekar JM, Patel DD, Karelia NH, Vora HH, Ghosh N, Shah NG, Balar DB, Trivedi SN: Tumor makers in patients with advanced breast cancer as prognosticators: a preliminary study. Breast Canc Res Treat 30: 293–297, 1994Google Scholar
  35. 35.
    Toropainen EM, Lipponen PK, Syrjänen KJ: Expression of insulin-like growth factor II in female breast cancer as related to established prognostic factors and long-term prognosis. Anticancer Res 15: 2669–2674, 1995Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Pamela J. Goodwin
    • 1
    • 2
    • 3
    • 4
  • Marguerite Ennis
    • 1
    • 5
    • 4
  • Kathleen I. Pritchard
    • 1
    • 5
    • 4
  • Maureen E. Trudeau
    • 1
    • 6
    • 4
  • Jarley Koo
    • 7
    • 8
    • 4
  • Warren Hartwick
    • 9
    • 3
    • 4
  • Barry Hoffman
    • 9
    • 3
    • 4
  • Nicky Hood
    • 2
    • 3
  1. 1.Department of MedicineCanada
  2. 2.Division of Clinical EpidemiologySamuel Lunenfeld Research InstituteCanada
  3. 3.Mount Sinai HospitalCanada
  4. 4.University of TorontoCanada
  5. 5.Toronto-Sunnybrook Regional Cancer CentreCanada
  6. 6.Women's College HospitalCanada
  7. 7.Department of SurgeryCanada
  8. 8.St. Michael's HospitalCanada
  9. 9.Department of Pathology and Laboratory MedicineCanada

Personalised recommendations