Breast Cancer Research and Treatment

, Volume 129, Issue 3, pp 725–736 | Cite as

Divergent effects of insulin-like growth factor-1 receptor expression on prognosis of estrogen receptor positive versus triple negative invasive ductal breast carcinoma

  • Hermien Hartog
  • Hugo M. Horlings
  • Bert van der Vegt
  • Bas Kreike
  • Abderrahim Ajouaou
  • Marc J. van de Vijver
  • H. Marike Boezen
  • Geertruida H. de Bock
  • Winette T. A. van der Graaf
  • Jelle WesselingEmail author
Preclinical study


The insulin-like growth factor type 1 receptor (IGF1R) is involved in progression of breast cancer and resistance to systemic treatment. Targeting IGF1R signaling may, therefore, be beneficial in systemic treatment. We report the effect of IGF1R expression on prognosis in invasive ductal breast carcinoma (IDC), the most common type of breast cancer. Immunohistochemistry was performed on tumor tissue of a consecutive cohort of 429 female patients treated for operable primary IDC. Associations between IGF1R expression with clinicopathological parameters, disease free survival (DFS) and breast cancer specific survival (BCSS) were evaluated by multivariate analyses focusing on ER-positive and triple negative IDC (TN-IDC). To enlarge the TN-IDCs cohort, we analyzed a combined dataset of 51 TN-IDC tumors from our series with 64 TN-IDCs with similar clinicopathological parameters. Patients with tumors expressing cytoplasmic IGF1R have a longer DFS and BCSS (DFS: HR 0.46, 95% CI 0.27–0.49, P = 0.005, BCSS: HR 0.38, 95% CI 0.19–0.74, P = 0.005). This effect was most prominent in ER-positive tumors. However, in a combined series of 105 TN-IDCs cytoplasmic IGF1R expression was associated with a shorter DFS (HR = 2.29, 95% CI 1.08–4.84, P = 0.03), also when combined in a multivariate model, including well-known prognostic factors (HR 2.06; 95% CI 0.95–4.47; P = 0.07). IGF1R expression in ER-positive IDC is strongly related to a favorable DFS and BCSS, but to a shorter DFS in TN-IDC tumors. This divergent effect of IGF1R expression in subgroups of IDC may affect selection of patients for IGF1R targeted therapy.


Insulin-like growth factor type 1 receptor Breast cancer Ductal type Prognosis Triple negative breast tumors Estrogen receptor 


Conflict of interest

No potential conflict of interest relevant to this article was reported.

Supplementary material

10549_2010_1256_MOESM1_ESM.doc (117 kb)
Supplementary material 1 (DOC 117 kb)


  1. 1.
    Hartog H, Wesseling J, Boezen HM, van der Graaf WT (2007) The insulin-like growth factor 1 receptor in cancer: old focus, new future. Eur J Cancer 43:1895–1904PubMedCrossRefGoogle Scholar
  2. 2.
    Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928PubMedCrossRefGoogle Scholar
  3. 3.
    Cohen BD, Baker DA, Soderstrom C, Tkalcevic G, Rossi AM, Miller PE, Tengowski MW, Wang F, Gualberto A, Beebe JS, Moyer JD (2005) Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751, 871. Clin Cancer Res 11:2063–2073PubMedCrossRefGoogle Scholar
  4. 4.
    Milano A, Dal LagoL, Sotiriou C, Piccart M, Cardoso F (2006) What clinicians need to know about antioestrogen resistance in breast cancer therapy. Eur J Cancer 42:2692–2705PubMedCrossRefGoogle Scholar
  5. 5.
    Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ (2005) Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res 65:11118–11128PubMedCrossRefGoogle Scholar
  6. 6.
    Hubbard SR, Miller WT (2007) Receptor tyrosine kinases: mechanisms of activation and signaling. Curr Opin Cell Biol 19:117–123PubMedCrossRefGoogle Scholar
  7. 7.
    Dupont J, LeRoith D (2001) Insulin and insulin-like growth factor I receptors: similarities and differences in signal transduction. Horm Res 55(2):22–26PubMedCrossRefGoogle Scholar
  8. 8.
    Jones JI, Clemmons DR (1995) Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16:3–34PubMedGoogle Scholar
  9. 9.
    Weber MM, Fottner C, Liu SB, Jung MC, Engelhardt D, Baretton GB (2002) Overexpression of the insulin-like growth factor I receptor in human colon carcinomas. Cancer 95:2086–2095PubMedCrossRefGoogle Scholar
  10. 10.
    Chong YM, Colston K, Jiang WG, Sharma AK, Mokbel K (2006) The relationship between the insulin-like growth factor-1 system and the oestrogen metabolising enzymes in breast cancer tissue and its adjacent non-cancerous tissue. Breast Cancer Res Treat 99:275–288PubMedCrossRefGoogle Scholar
  11. 11.
    Garcia-Echeverria C, Pearson MA, Marti A, Meyer T, Mestan J, Zimmermann J, Gao J, Brueggen J, Capraro HG, Cozens R, Evans DB, Fabbro D, Furet P, Porta DG, Liebetanz J, Martiny-Baron G, Ruetz S, Hofmann F (2004) In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell 5:231–239PubMedCrossRefGoogle Scholar
  12. 12.
    Haluska P, Carboni JM, Loegering DA, Lee FY, Wittman M, Saulnier MG, Frennesson DB, Kalli KR, Conover CA, Attar RM, Kaufmann SH, Gottardis M, Erlichman C (2006) In vitro and in vivo antitumor effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417. Cancer Res 66:362–371PubMedCrossRefGoogle Scholar
  13. 13.
    Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Akiyama M, Hideshima T, Chauhan D, Joseph M, Libermann TA, Garcia-Echeverria C, Pearson MA, Hofmann F, Anderson KC, Kung AL (2004) Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell 5:221–230PubMedCrossRefGoogle Scholar
  14. 14.
    Pandini G, Wurch T, Akla B, Corvaia N, Belfiore A, Goetsch L (2007) Functional responses and in vivo anti-tumour activity of h7C10: a humanised monoclonal antibody with neutralising activity against the insulin-like growth factor-1 (IGF-1) receptor and insulin/IGF-1 hybrid receptors. Eur J Cancer 43:1318–1327Google Scholar
  15. 15.
    Camirand A, Lu Y, Pollak M (2002) Co-targeting HER2/ErbB2 and insulin-like growth factor-1 receptors causes synergistic inhibition of growth in HER2-overexpressing breast cancer cells. Med Sci Monit 8:BR521–BR526PubMedGoogle Scholar
  16. 16.
    Chakraborty AK, Liang K, DiGiovanna MP (2008) Co-targeting insulin-like growth factor I receptor and HER2: dramatic effects of HER2 inhibitors on nonoverexpressing breast cancer. Cancer Res 68:1538–1545PubMedCrossRefGoogle Scholar
  17. 17.
    Jones HE, Goddard L, Gee JM, Hiscox S, Rubini M, Barrow D, Knowlden JM, Williams S, Wakeling AE, Nicholson RI (2004) Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr Relat Cancer 11:793–814PubMedCrossRefGoogle Scholar
  18. 18.
    Bartucci M, Morelli C, Mauro L, Ando S, Surmacz E (2001) Differential insulin-like growth factor I receptor signaling and function in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells. Cancer Res 61:6747–6754PubMedGoogle Scholar
  19. 19.
    Oesterreich S, Zhang P, Guler RL, Sun X, Curran EM, Welshons WV, Osborne CK, Lee AV (2001) Re-expression of estrogen receptor alpha in estrogen receptor alpha-negative MCF-7 cells restores both estrogen and insulin-like growth factor-mediated signaling and growth. Cancer Res 61:5771–5777PubMedGoogle Scholar
  20. 20.
    Yee D, Lee AV (2000) Crosstalk between the insulin-like growth factors and estrogens in breast cancer. J Mammary Gland Biol Neoplasia 5:107–115PubMedCrossRefGoogle Scholar
  21. 21.
    Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717Google Scholar
  22. 22.
    Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lonning PE, Brown PO, Borresen-Dale AL, Botstein D (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100:8418–8423PubMedCrossRefGoogle Scholar
  23. 23.
    Happerfield LC, Miles DW, Barnes DM, Thomsen LL, Smith P, Hanby A (1997) The localization of the insulin-like growth factor receptor 1 (IGFR-1) in benign and malignant breast tissue. J Pathol 183:412–417PubMedCrossRefGoogle Scholar
  24. 24.
    Koda M, Przystupa W, Jarzabek K, Wincewicz A, Kanczuga-Koda L, Tomaszewski J, Sulkowska M, Wolczynski S, Sulkowski S (2005) Expression of insulin-like growth factor-I receptor, estrogen receptor alpha, Bcl-2 and Bax proteins in human breast cancer. Oncol Rep 14:93–98PubMedGoogle Scholar
  25. 25.
    Nielsen TO, Andrews HN, Cheang M, Kucab JE, Hsu FD, Ragaz J, Gilks CB, Makretsov N, Bajdik CD, Brookes C, Neckers LM, Evdokimova V, Huntsman DG, Dunn SE (2004) Expression of the insulin-like growth factor I receptor and urokinase plasminogen activator in breast cancer is associated with poor survival: potential for intervention with 17-allylamino geldanamycin. Cancer Res 64:286–291PubMedCrossRefGoogle Scholar
  26. 26.
    Shimizu C, Hasegawa T, Tani Y, Takahashi F, Takeuchi M, Watanabe T, Ando M, Katsumata N, Fujiwara Y (2004) Expression of insulin-like growth factor 1 receptor in primary breast cancer: immunohistochemical analysis. Hum Pathol 35:1537–1542PubMedCrossRefGoogle Scholar
  27. 27.
    Ueda S, Tsuda H, Sato K, Takeuchi H, Shigekawa T, Matsubara O, Hiraide H, Mochizuki H (2006) Alternative tyrosine phosphorylation of signaling kinases according to hormone receptor status in breast cancer overexpressing the insulin-like growth factor receptor type 1. Cancer Sci 97:597–604PubMedCrossRefGoogle Scholar
  28. 28.
    Schnarr B, Strunz K, Ohsam J, Benner A, Wacker J, Mayer D (2000) Down-regulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer. Int J Cancer 89:506–513PubMedCrossRefGoogle Scholar
  29. 29.
    Fadare O, Tavassoli FA (2008) Clinical and pathologic aspects of basal-like breast cancers. Nat Clin Pract Oncol 5:149–159PubMedCrossRefGoogle Scholar
  30. 30.
    Tavassoli FA, Devilee P (2003) World Health Organization classification of tumours pathology and genetics of tumours of the breast and female genital organs. IARC Press, LyonGoogle Scholar
  31. 31.
    Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H, van de Vijver MJ (2007) Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res 9:R65PubMedCrossRefGoogle Scholar
  32. 32.
    Camp RL, Charette LA, Rimm DL (2000) Validation of tissue microarray technology in breast carcinoma. Lab Invest 80:1943–1949PubMedCrossRefGoogle Scholar
  33. 33.
    Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844–847PubMedCrossRefGoogle Scholar
  34. 34.
    van der Vegt B, de Roos MA, Peterse JL, Patriarca C, Hilkens J, de Bock GH, Wesseling J (2007) The expression pattern of MUC1 (EMA) is related to tumour characteristics and clinical outcome of invasive ductal breast carcinoma. Histopathology 51:322–335PubMedCrossRefGoogle Scholar
  35. 35.
    Song RX, Chen Y, Zhang Z, Bao Y, Yue W, Wang JP, Fan P, Santen RJ (2010) Estrogen utilization of IGF-1-R and EGF-R to signal in breast cancer cells. J Steroid Biochem Mol Biol 118:219–230PubMedCrossRefGoogle Scholar
  36. 36.
    Broussas M, Dupont J, Gonzalez A, Blaecke A, Fournier M, Corvaia N, Goetsch L (2009) Molecular mechanisms involved in activity of h7C10, a humanized monoclonal antibody, to IGF-1 receptor. Int J Cancer 124:2281–2293PubMedCrossRefGoogle Scholar
  37. 37.
    Lee CY, Jeon JH, Kim HJ, Shin DH, Roh TW, Ahn CM, Chang YS (2008) Clinical significance of insulin-like growth factor-1 receptor expression in stage I non-small-cell lung cancer: immunohistochemical analysis. Korean J Intern Med 23:116–120PubMedCrossRefGoogle Scholar
  38. 38.
    Cunningham MP, Essapen S, Thomas H, Green M, Lovell DP, Topham C, Marks C, Modjtahedi H (2006) Coexpression of the IGF-IR, EGFR and HER-2 is common in colorectal cancer patients. Int J Oncol 28:329–335PubMedGoogle Scholar
  39. 39.
    Nakamura M, Miyamoto S, Maeda H, Zhang SC, Sangai T, Ishii G, Hasebe T, Endoh Y, Saito N, Asaka M, Ochiai A (2004) Low levels of insulin-like growth factor type 1 receptor expression at cancer cell membrane predict liver metastasis in Dukes’ C human colorectal cancers. Clin Cancer Res 10:8434–8441PubMedCrossRefGoogle Scholar
  40. 40.
    Wallborn T, Wuller S, Klammt J, Kruis T, Kratzsch J, Schmidt G, Schlicke M, Muller E, van de Leur HS, Kiess W, Pfaffle R (2010) A heterozygous mutation of the insulin-like growth factor-I receptor causes retention of the nascent protein in the endoplasmic reticulum and results in intrauterine and postnatal growth retardation. J Clin Endocrinol Metab 95:2316–2324PubMedCrossRefGoogle Scholar
  41. 41.
    Sehat B, Tofigh A, Lin Y, Trocme E, Liljedahl U, Lagergren J, Larsson O (2010) SUMOylation mediates the nuclear translocation and signaling of the IGF-1 receptor. Sci Signal 3:ra10PubMedCrossRefGoogle Scholar
  42. 42.
    Aleksic T, Chitnis MM, Perestenko OV, Gao S, Thomas PH, Turner GD, Protheroe AS, Howarth M, Macaulay VM (2010) Type 1 insulin-like growth factor receptor translocates to the nucleus of human tumor cells. Cancer Res 70:6412–6419PubMedCrossRefGoogle Scholar
  43. 43.
    Wang Y, Hailey J, Williams D, Wang Y, Lipari P, Malkowski M, Wang X, Xie L, Li G, Saha D, Ling WL, Cannon-Carlson S, Greenberg R, Ramos RA, Shields R, Presta L, Brams P, Bishop WR, Pachter JA (2005) Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti-IGF-IR antibody. Mol Cancer Ther 4:1214–1221PubMedCrossRefGoogle Scholar
  44. 44.
    Peyrat JP, Bonneterre J, Beuscart R, Djiane J, Demaille A (1988) Insulin-like growth factor 1 receptors in human breast cancer and their relation to estradiol and progesterone receptors. Cancer Res 48:6429–6433PubMedGoogle Scholar
  45. 45.
    Railo MJ, Von Smitten K, Pekonen F (1994) The prognostic value of insulin-like growth factor-I in breast cancer patients. Results of a follow-up study on 126 patients. Eur J Cancer 30A:307–311PubMedCrossRefGoogle Scholar
  46. 46.
    Renehan AG, Zwahlen M, Minder C, O’dwyer ST, Shalet SM, Egger M (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
  47. 47.
    Renehan AG, Egger M, Minder C, O’dwyer ST, Shalet SM, Zwahlen M (2005) IGF-I, IGF binding protein-3 and breast cancer risk: comparison of 3 meta-analyses. Int J Cancer 115:1006–1007PubMedCrossRefGoogle Scholar
  48. 48.
    Key TJ, Appleby PN, Reeves GK, Roddam AW (2010) Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. Lancet Oncol 11:530–542PubMedCrossRefGoogle Scholar
  49. 49.
    Parisot JP, Leeding KS, Hu XF, DeLuise M, Zalcberg JR, Bach LA (1999) Induction of insulin-like growth factor binding protein expression by ICI 182, 780 in a tamoxifen-resistant human breast cancer cell line. Breast Cancer Res Treat 55:231–242PubMedCrossRefGoogle Scholar
  50. 50.
    Parisot JP, Hu XF, DeLuise M, Zalcberg JR (1999) Altered expression of the IGF-1 receptor in a tamoxifen-resistant human breast cancer cell line. Br J Cancer 79:693–700PubMedCrossRefGoogle Scholar
  51. 51.
    Brugge J, Hung MC, Mills GB (2007) A new mutational AKTivation in the PI3K pathway. Cancer Cell 12:104–107PubMedCrossRefGoogle Scholar
  52. 52.
    Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, Bernards R (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12:395–402PubMedCrossRefGoogle Scholar
  53. 53.
    Creighton CJ, Casa A, Lazard Z, Huang S, Tsimelzon A, Hilsenbeck SG, Osborne CK, Lee AV (2008) Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast cancer prognosis. J Clin Oncol 26:4078–4085PubMedCrossRefGoogle Scholar
  54. 54.
    Mulligan AM, O’Malley FP, Ennis M, Fantus IG, Goodwin PJ (2007) Insulin receptor is an independent predictor of a favorable outcome in early stage breast cancer. Breast Cancer Res Treat 106:39–47PubMedCrossRefGoogle Scholar
  55. 55.
    Mathieu MC, Clark GM, Allred DC, Goldfine ID, Vigneri R (1997) Insulin receptor expression and clinical outcome in node-negative breast cancer. Proc Assoc Am Physicians 109:565–571PubMedGoogle Scholar
  56. 56.
    Law JH, Habibi G, Hu K, Masoudi H, Wang MY, Stratford AL, Park E, Gee JM, Finlay P, Jones HE, Nicholson RI, Carboni J, Gottardis M, Pollak M, Dunn SE (2008) Phosphorylated insulin-like growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 68:10238–10246PubMedCrossRefGoogle Scholar
  57. 57.
    Klinakis A, Szabolcs M, Chen G, Xuan S, Hibshoosh H, Efstratiadis A (2009) Igf1r as a therapeutic target in a mouse model of basal-like breast cancer. Proc Natl Acad Sci USA 106:2359–2364PubMedCrossRefGoogle Scholar
  58. 58.
    McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 23:9067–9072PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Hermien Hartog
    • 1
  • Hugo M. Horlings
    • 4
  • Bert van der Vegt
    • 2
  • Bas Kreike
    • 4
    • 5
  • Abderrahim Ajouaou
    • 4
  • Marc J. van de Vijver
    • 7
  • H. Marike Boezen
    • 3
  • Geertruida H. de Bock
    • 3
  • Winette T. A. van der Graaf
    • 8
  • Jelle Wesseling
    • 6
    Email author
  1. 1.Department of Medical Oncology, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
  2. 2.Department of Pathology, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
  3. 3.Department of Epidemiology, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
  4. 4.Division of Experimental TherapyNetherlands Cancer Institute/Antoni van Leeuwenhoek HospitalAmsterdamThe Netherlands
  5. 5.Department of RadiotherapyNetherlands Cancer Institute/Antoni van Leeuwenhoek HospitalAmsterdamThe Netherlands
  6. 6.Department of PathologyNetherlands Cancer Institute/Antoni van Leeuwenhoek HospitalAmsterdamThe Netherlands
  7. 7.Department of PathologyAcademic Medical CenterAmsterdam The Netherlands
  8. 8.Department of Medical OncologyRadboud University Nijmegen Medical CenterNijmegenThe Netherlands

Personalised recommendations