Breast Cancer Research and Treatment

, Volume 132, Issue 1, pp 131–142 | Cite as

Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes

  • Rinat Yerushalmi
  • Karen A. Gelmon
  • Samuel Leung
  • Dongxia Gao
  • Maggie Cheang
  • Michael Pollak
  • Gulisa Turashvili
  • Blakes C. Gilks
  • Hagen Kennecke
Preclinical Study


Insulin-like growth factor-1 receptor (IGF-1R) is expressed in normal and malignant breast tissue and has been implicated in cell survival and resistance to cytotoxic therapies. We sought to assess the prognostic impact of IGF-1R expression among patients with early breast cancer and among breast cancer subtypes. Patients with stages I–III breast cancer with archival tumor tissue were included. Paraffin tissue blocks were used to construct a tissue microarray that was stained for ER, PR, Ki-67, HER2, EGFR, and cytokeratins 5/6 to classify the breast subgroups and for expression of IGF-1R, p27, and Bcl2 by immunohistochemistry. Kaplan–Meier plots were created by subtypes. Associations between IGF-1R and prognostic variables were examined in multivariate analysis. Among 2,871 eligible women the prognostic cut point for IGF-1R expression for breast-cancer-specific survival (BCSS) was Allred score <7 versus ≥7. IGF-1R was ≥7 in 52% (LuminalA), 57.5% (LuminalB), 44.8% (LuminalHER2), 9.7% HER2-enriched, and 22.5% (Basal-like), P = 1.3 × 10−52. IGF-1R+ was associated with age ≥50, lower histopathology grade, ER+, HER2 negativity (−), high p27 and high Bcl2 score. IGF-1R ≥7 was associated with better BCSS among LuminalB patients, hazard ratio = 0.64 (0.49–0.84); P = 1.2 × 10−3, and worse outcome in the HER2-enriched subtype, hazard ratio = 2.37 (1.21–4.64); P = 0.012. IGF-1R correlates with good prognostic markers among patients with early breast cancer and is differentially expressed with variable prognostic impact among breast cancer subtypes. Results may have relevance to the development of therapeutics targeting IGF-1R.


Insulin-like growth factor receptor IGF-1R, breast cancer Subtypes Basal-like, HER2 



Thanks to Prof. Torsten Nielsen’s (MD/PHD) helpful comments. GPEC lab is supported through unrestricted educational funds from Sanofi Aventis Canada.

Conflict of interest

No conflict of interest; declared by all authors.

Supplementary material

10549_2011_1529_MOESM1_ESM.docx (73 kb)
Supplementary material 1 (DOCX 72 kb)
10549_2011_1529_MOESM2_ESM.xlsx (59 kb)
Supplementary material 2 (XLSX 59 kb)


  1. 1.
    Kasuya J, Paz IB, Maddux BA et al (1993) Characterization of human placental insulin-like growth factor-I/insulin hybrid receptors by protein microsequencing and purification. Biochemistry 32:13531–13536PubMedCrossRefGoogle Scholar
  2. 2.
    Pandini G, Vigneri R, Costantino A et al (1999) Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: evidence for a second mechanism of IGF-I signaling. Clin Cancer Res 5:1935–1944PubMedGoogle Scholar
  3. 3.
    Adams TE, Epa VC, Garrett TP et al (2000) Structure and function of the type 1 insulin-like growth factor receptor. Cell Mol Life Sci 57:1050–1093PubMedCrossRefGoogle Scholar
  4. 4.
    Shang Y, Mao Y, Batson J et al (2008) Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake. Mol Cancer Ther 7:2599–2608PubMedCrossRefGoogle Scholar
  5. 5.
    Fagan DH, Yee D (2008) Crosstalk between IGF1R and estrogen receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia 13:423–429PubMedCrossRefGoogle Scholar
  6. 6.
    Werner H, Maor S (2006) The insulin-like growth factor-I receptor gene: a downstream target for oncogene and tumor suppressor action. Trends Endocrinol Metab 17:236–242PubMedCrossRefGoogle Scholar
  7. 7.
    Ouban A, Muraca P, Yeatman T et al (2003) Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas. Hum Pathol 34:803–808PubMedCrossRefGoogle Scholar
  8. 8.
    Law JH, Habibi G, Hu K et al (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
  9. 9.
    Shimizu C, Hasegawa T, Tani Y et al (2004) Expression of insulin-like growth factor 1 receptor in primary breast cancer: immunohistochemical analysis. Hum Pathol 35:1537–1542PubMedCrossRefGoogle Scholar
  10. 10.
    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
  11. 11.
    Papa V, Gliozzo B, Clark GM et al (1993) Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer. Cancer Res 53:3736–3740PubMedGoogle Scholar
  12. 12.
    Shin A, Ren Z, Shu XO et al (2007) Expression patterns of insulin-like growth factor 1 (IGF-I) and its receptor in mammary tissues and their associations with breast cancer survival. Breast Cancer Res Treat 105:55–61PubMedCrossRefGoogle Scholar
  13. 13.
    Bonneterre J, Peyrat JP, Beuscart R et al (1990) Prognostic significance of insulin-like growth factor 1 receptors in human breast cancer. Cancer Res 50:6931–6935PubMedGoogle Scholar
  14. 14.
    Gualberto A, Pollak M (2009) Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions. Oncogene 28:3009–3021PubMedCrossRefGoogle Scholar
  15. 15.
    Blum G, Gazit A, Levitzki A (2000) Substrate competitive inhibitors of IGF-1 receptor kinase. Biochemistry 39:15705–15712PubMedCrossRefGoogle Scholar
  16. 16.
    Garcia-Echeverria C, Pearson MA, Marti A et al (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
  17. 17.
    Mitsiades CS, Mitsiades NS, McMullan CJ et 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
  18. 18.
    Yuen JS, Macaulay VM (2008) Targeting the type 1 insulin-like growth factor receptor as a treatment for cancer. Expert Opin Ther Targets 12:589–603PubMedCrossRefGoogle Scholar
  19. 19.
    Stephen RL, Shaw LE, Larsen C et al (2001) Insulin-like growth factor receptor levels are regulated by cell density and by long term estrogen deprivation in MCF7 human breast cancer cells. J Biol Chem 276:40080–40086PubMedCrossRefGoogle Scholar
  20. 20.
    Sachdev D, Singh R, Fujita-Yamaguchi Y et al (2006) Down-regulation of insulin receptor by antibodies against the type I insulin-like growth factor receptor: implications for anti-insulin-like growth factor therapy in breast cancer. Cancer Res 66:2391–2402PubMedCrossRefGoogle Scholar
  21. 21.
    Burtrum D, Zhu Z, Lu D et al (2003) A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. Cancer Res 63:8912–8921PubMedGoogle Scholar
  22. 22.
    Pandini G, Wurch T, Akla B et al (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 43:1318–1327PubMedCrossRefGoogle Scholar
  23. 23.
    Sachdev D, Drug evaluation (2007) CP-751871, a human antibody against type I insulin-like growth factor receptor for the potential treatment of cancer. Curr Opin Mol Ther 9:299–304PubMedGoogle Scholar
  24. 24.
    Jin Q, Esteva FJ (2008) Cross-talk between the ErbB/HER family and the type I insulin-like growth factor receptor signaling pathway in breast cancer. J Mammary Gland Biol Neoplasia 13:485–498PubMedCrossRefGoogle Scholar
  25. 25.
    Schillaci R, Salatino M, Cassataro J et al (2006) Immunization with murine breast cancer cells treated with antisense oligodeoxynucleotides to type I insulin-like growth factor receptor induced an antitumoral effect mediated by a CD8+ response involving Fas/Fas ligand cytotoxic pathway. J Immunol 176:3426–3437PubMedGoogle Scholar
  26. 26.
    Capodanno A, Camerini A, Orlandini C et al (2009) Dysregulated PI3 K/Akt/PTEN pathway is a marker of a short disease-free survival in node-negative breast carcinoma. Hum Pathol 40:1408–1417PubMedCrossRefGoogle Scholar
  27. 27.
    Charpin C, Giusiano S, Secq V et al (2009) Quantitative immunocytochemical profile to predict early outcome of disease in triple-negative breast carcinomas. Int J Oncol 34:983–993PubMedCrossRefGoogle Scholar
  28. 28.
    Vendrell JA, Robertson KE, Ravel P et al (2008) A candidate molecular signature associated with tamoxifen failure in primary breast cancer. Breast Cancer Res 10:R88PubMedCrossRefGoogle Scholar
  29. 29.
    Bremer TM, Jacquemier J, Charafe-Jauffret E et al (2009) Prognostic marker profile to assess risk in stage I-III hormone receptor-positive breast cancer patients. Int J Cancer 124:896–904PubMedCrossRefGoogle Scholar
  30. 30.
    Fleming ID, Cooper JS, Henson DE et al (1997) AJCC Cancer Staging Manual, 5th edn. Lippincott-Raven, PhiladelphiaGoogle Scholar
  31. 31.
    Bearhs OH, Henson DE, Hutter RVP et al (1992) AJCC Cancer Staging Manual, 5th edn. Lippincott-Raven, PhiladelphiaGoogle Scholar
  32. 32.
    Cheang MC, Treaba DO, Speers CH et al (2006) Immunohistochemical detection using the new rabbit monoclonal antibody SP1 of estrogen receptor in breast cancer is superior to mouse monoclonal antibody 1D5 in predicting survival. J Clin Oncol 24:5637–5644PubMedCrossRefGoogle Scholar
  33. 33.
    Voduc D, Cheang M, Nielsen T (2008) GATA-3 expression in breast cancer has a strong association with estrogen receptor but lacks independent prognostic value. Cancer Epidemiol Biomarkers Prev 17:365–373PubMedCrossRefGoogle Scholar
  34. 34.
    Mulligan AM, O’Malley FP, Ennis M et al (2007) Insulin receptor is an independent predictor of a favorable outcome in early stage breast cancer. Breast Cancer Res Treat 106:39–47PubMedCrossRefGoogle Scholar
  35. 35.
    Hakam A, Fang Q, Karl R et al (2003) Coexpression of IGF-1R and c-src proteins in human pancreatic ductal adenocarcinoma. Dig Dis Sci 48:1972–1978PubMedCrossRefGoogle Scholar
  36. 36.
    Power KA, Chen JM, Saarinen NM et al (2008) Changes in biomarkers of estrogen receptor and growth factor signaling pathways in MCF-7 tumors after short- and long-term treatment with soy and flaxseed. J Steroid Biochem Mol Biol 112:13–19PubMedCrossRefGoogle Scholar
  37. 37.
    Harvey JM, Clark GM, Osborne CK et al (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17:1474–1481PubMedGoogle Scholar
  38. 38.
    Cheang MC, Chia SK, Voduc D et al (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101:736–750PubMedCrossRefGoogle Scholar
  39. 39.
    Cheang MC, Voduc D, Bajdik C et al (2008) Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 14:1368–1376PubMedCrossRefGoogle Scholar
  40. 40.
    Nielson TO, Hsu FD, Jensen K et al (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10:5367–5374CrossRefGoogle Scholar
  41. 41.
    Rajput AB, Turbin DA, Cheang MC et al (2008) Stromal mast cells in invasive breast cancer are a marker of favourable prognosis: a study of 4, 444 cases. Breast Cancer Res Treat 107:249–257PubMedCrossRefGoogle Scholar
  42. 42.
    Camp RL, Dolled-Filhart M, Rimm DL (2004) X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 10:7252–7259PubMedCrossRefGoogle Scholar
  43. 43.
    Govindarajulu US, Malloy EJ, Gangali B et al. (2009) The comparison of alternative smoothing methods for fitting non-linear exposure-response relationships with cox models in a simulation study. Int J Biostat 5. doi:  10.2202/1557-4679.1104
  44. 44.
    McShane LM, Altman DG, Sauerbei W et al (2005) Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 23:9067–9072PubMedCrossRefGoogle Scholar
  45. 45.
    Hayes DF, Ethier S, Lippman ME (2006) New guidelines for reporting of tumor marker studies in breast cancer research and treatment: REMARK. Breast Cancer Res Treat 100:237–238PubMedCrossRefGoogle Scholar
  46. 46.
    Robert A, Toupance B, Tremblay M et al (2009) Impact of inbreeding on fertility in a pre-industrial population. Eur J Hum Genet 17:673–681PubMedCrossRefGoogle Scholar
  47. 47.
    Creighton CJ, Fu X, Hennessy BT et al (2010) Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen receptor (ER) levels and activity in ER+ breast cancer. Breast Cancer Res 12:R40. doi: 101186/bcr2594 PubMedCrossRefGoogle Scholar
  48. 48.
    Creighton CJ, Casa A, Lazard Z et al (2008) Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast cancer prognosis. J Clin Oncol 26:4078–4085PubMedCrossRefGoogle Scholar
  49. 49.
    Chu IM, Hengst L, Slingerland JM (2008) The cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer 8:253–267PubMedCrossRefGoogle Scholar
  50. 50.
    Esparis-Ogando A, Ocana A, Rodriguez-Barrueco R et al (2008) Synergic antitumoral effect of an IGF-IR inhibitor and trastuzumab on HER2-overexpressing breast cancer cells. Ann Oncol 19:1860–1869PubMedCrossRefGoogle Scholar
  51. 51.
    Binder C, Marx D, Overhoff R et al (1995) Bcl-2 protein expression in breast cancer in relation to established prognostic factors and other clinicopathological variables. Ann Oncol 6:1005–1010PubMedGoogle Scholar
  52. 52.
    Joensuu H, Pylkkanen L, Toikkanen S (1994) Bcl-2 protein expression and long-term survival in breast cancer. Am J Pathol 145:1191–1198PubMedGoogle Scholar
  53. 53.
    Lee KH, Im SA, Oh DY et al (2007) Prognostic significance of bcl-2 expression in stage III breast cancer patients who had received doxorubicin and cyclophosphamide followed by paclitaxel as adjuvant chemotherapy. BMC Cancer 7:63PubMedCrossRefGoogle Scholar
  54. 54.
    Haluska P, Carboni JM, TenEyck C et al (2008) HER receptor signaling confers resistance to the insulin-like growth factor-I receptor inhibitor, BMS-536924. Mol Cancer Ther 7:2589–2598PubMedCrossRefGoogle Scholar
  55. 55.
    Chakraborty AK, Welsh A, Digiovanna MP (2010) Co-targeting the insulin-like growth factor I receptor enhances growth-inhibitory and pro-apoptotic effects of anti-estrogens in human breast cancer cell lines. Breast Cancer Res Treat 120:327–335PubMedCrossRefGoogle Scholar
  56. 56.
    Weroha SJ, Haluska P (2008) IGF-1 receptor inhibitors in clinical trials—early lessons. J Mammary Gland Biol Neoplasia 13:471–483PubMedCrossRefGoogle Scholar
  57. 57.
    Guix M, Faber AC, Wang SE et al (2008) Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest 118:2609–2619PubMedGoogle Scholar
  58. 58.
    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:BR521-6PubMedGoogle Scholar
  59. 59.
    Jones HE, Goddard L, Gee JM et al (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
  60. 60.
    Nahta R, Yuan LX, Zhang B et al (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
  61. 61.
    Lu Y, Zi X, Zhao Y et al (2001) Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (herceptin). J Natl Cancer Inst 93:1852–1857PubMedCrossRefGoogle Scholar
  62. 62.
    Kaufman PA, Ferrero JM, Bourgeois H et al (2010) A randomized, double-blind, placebo-controlled, phase 2 study of AMG-479 with Exemestane (E) or Fulvestrant (F) in postmenopausal women with hormone receptor positive (HR+) metastatic (M) or locally advanced (LA) breast cancer. In: San Antonio breast cancer symposium, CTRC-AACR, San-Antonio, Texas, December 2010Google Scholar
  63. 63.
    Pitts TM, Tan AK, Kulikowski GN et al (2010) Development of an integrated genomic classifier for novel agent in colorectal cancer: approach to individualized therapy in early development. Clin Cancer Res 16:3193–3204PubMedCrossRefGoogle Scholar
  64. 64.
    Yee D (2010) How to train your biomarker. Clin Cancer Res 16:3091–3093PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Rinat Yerushalmi
    • 1
  • Karen A. Gelmon
    • 1
  • Samuel Leung
    • 2
  • Dongxia Gao
    • 2
  • Maggie Cheang
    • 3
  • Michael Pollak
    • 4
  • Gulisa Turashvili
    • 5
  • Blakes C. Gilks
    • 6
  • Hagen Kennecke
    • 1
  1. 1.Division of Medical OncologyBC Cancer AgencyVancouverCanada
  2. 2.Genetic Pathology Evaluation CenterVancouver Hospital and Health Sciences CenterVancouverCanada
  3. 3.Department of Genetics and Pathology, Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel HillChapel HillUSA
  4. 4.Department of OncologyMcGill University and Jewish General HospitalMontrealCanada
  5. 5.Department of Molecular OncologyVancouverCanada
  6. 6.Department of PathologyVancouver General Hospital and University of British ColumbiaVancouverCanada

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