IGF-I and Insulin Receptor Families in Cancer

  • Antonino Belfiore
  • Ira D. Goldfine
  • Roberta Malaguarnera
Part of the Energy Balance and Cancer book series (EBAC, volume 1)


Several lines of evidence indicate that dysregulation of the insulin-like growth factor (IGF) system plays a role in the biology of various cancers by regulating cell transformation and metastasis. Thus, new cancer therapies have been devised to target the IGF-I receptor (IGF-IR). This review will focus on recent findings indicating that dysregulation of receptors of the IGF family is more complex than previously thought. Notably, the aberrant expression of insulin receptor isoform A (IR-A) in cancer, interactions between the IGF-IR and IR-A, and cross-talk between the IGF-IR and other tyrosine kinase receptors, all add new complexities to the IGF system in cancer.


Focal Adhesion Kinase Thyroid Cancer Cell Malignant Mammary Tumor Atypical Receptor Androgen Receptor Negative Prostate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was partially supported by grants from the AIRC (Associazione Italiana per la Ricerca sul Cancro) and PRIN-MIUR 2005 (Ministero Italiano Università e Ricerca) to A.B.


  1. 1.
    Calle EE, Kaaks R (2004) Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4:579–591PubMedGoogle Scholar
  2. 2.
    Brogiolo W, Stocker H, Ikeya T et al (2001) An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Curr Biol 11:213–221PubMedGoogle Scholar
  3. 3.
    Ullrich A, Gray A, Tam AW et al (1986) Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. Embo J 5:2503–2512PubMedGoogle Scholar
  4. 4.
    Mynarcik DC, Williams PF, Schaffer L et al (1997) Identification of common ligand binding determinants of the insulin and insulin-like growth factor 1 receptors. Insights into mechanisms of ligand binding. J Biol Chem 272:18650–18655PubMedGoogle Scholar
  5. 5.
    Seino S, Seino M, Nishi S et al (1989) Structure of the human insulin receptor gene and characterization of its promoter. Proc Natl Acad Sci U S A 86:114–118PubMedGoogle Scholar
  6. 6.
    Mosthaf L, Vogt B, Haring HU et al (1991) Altered expression of insulin receptor types A and B in the skeletal muscle of non-insulin-dependent diabetes mellitus patients. Proc Natl Acad Sci U S A 88:4728–4730PubMedGoogle Scholar
  7. 7.
    Hubbard SR, Wei L, Ellis L et al (1994) Crystal structure of the tyrosine kinase domain of the human insulin receptor. Nature 372:746–754PubMedGoogle Scholar
  8. 8.
    Pawson T (1994) Signal transduction. Look at a tyrosine kinase. Nature 372:726–727PubMedGoogle Scholar
  9. 9.
    Cheng I, Stram DO, Penney KL et al (2006) Common genetic variation in IGF1 and prostate cancer risk in the Multiethnic Cohort. J Natl Cancer Inst 98:123–134PubMedGoogle Scholar
  10. 10.
    White MF (1998) The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol Cell Biochem 182:3–11PubMedGoogle Scholar
  11. 11.
    Chiang SH, Baumann CA, Kanzaki M et al (2001) Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. Nature 410:944–948PubMedGoogle Scholar
  12. 12.
    Backer JM, Myers MG Jr, Shoelson SE et al (1992) Phosphatidylinositol 3’-kinase is activated by association with IRS-1 during insulin stimulation. Embo J 11:3469–3479PubMedGoogle Scholar
  13. 13.
    Skolnik EY, Lee CH, Batzer A et al (1993) The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling. Embo J 12:1929–1936PubMedGoogle Scholar
  14. 14.
    Kornfeld S (1992) Structure and function of the mannose 6-phosphate/insulinlike growth factor II receptors. Annu Rev Biochem 61:307–330PubMedGoogle Scholar
  15. 15.
    Dhillon AS, Hagan S, Rath O et al (2007) MAP kinase signalling pathways in cancer. Oncogene 26:3279–3290PubMedGoogle Scholar
  16. 16.
    Wellbrock C, Karasarides M, Marais R (2004) The RAF proteins take centre stage. Nat Rev Mol Cell Biol 5:875–885PubMedGoogle Scholar
  17. 17.
    Harrington LS, Findlay GM, Lamb RF (2005) Restraining PI3K: mTOR signalling goes back to the membrane. Trends Biochem Sci 30:35–42PubMedGoogle Scholar
  18. 18.
    Bjornsti MA, Houghton PJ (2004) The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4:335–348PubMedGoogle Scholar
  19. 19.
    Holland EC, Sonenberg N, Pandolfi PP et al (2004) Signaling control of mRNA translation in cancer pathogenesis. Oncogene 23:3138–3144PubMedGoogle Scholar
  20. 20.
    O’Reilly KE, Rojo F, She QB et al (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66:1500–1508PubMedGoogle Scholar
  21. 21.
    Foster FM, Traer CJ, Abraham SM et al (2003) The phosphoinositide (PI) 3-kinase family. J Cell Sci 116:3037–3040PubMedGoogle Scholar
  22. 22.
    Yin Y, Shen WH (2008) PTEN: a new guardian of the genome. Oncogene 27:5443–5453PubMedGoogle Scholar
  23. 23.
    Zapf A, Hsu D, Olefsky JM (1994) Comparison of the intracellular itineraries of insulin-like growth factor-I and insulin and their receptors in Rat-1 fibroblasts. Endocrinology 134:2445–2452PubMedGoogle Scholar
  24. 24.
    Dupont J, Khan J, Qu BH et al (2001) Insulin and IGF-1 induce different patterns of gene expression in mouse fibroblast NIH-3T3 cells: identification by cDNA microarray analysis. Endocrinology 142:4969–4975PubMedGoogle Scholar
  25. 25.
    Siddle K, Urso B, Niesler CA et al (2001) Specificity in ligand binding and intracellular signalling by insulin and insulin-like growth factor receptors. Biochem Soc Trans 29:513–525PubMedGoogle Scholar
  26. 26.
    Frasca F, Pandini G, Malaguarnera R et al (2007) Role of c-Abl in directing metabolic versus mitogenic effects in insulin receptor signaling. J Biol Chem 282:26077–26088PubMedGoogle Scholar
  27. 27.
    Najjar SM, Blakesley VA, Li Calzi S et al (1997) Differential phosphorylation of pp 120 by insulin and insulin-like growth factor-1 receptors: role for the C-terminal domain of the beta-subunit. Biochemistry 36:6827–6834PubMedGoogle Scholar
  28. 28.
    O’Neill TJ, Zhu Y, Gustafson TA (1997) Interaction of MAD2 with the carboxyl terminus of the insulin receptor but not with the IGFIR. Evidence for release from the insulin receptor after activation. J Biol Chem 272:10035–10040PubMedGoogle Scholar
  29. 29.
    Koval AP, Blakesley VA, Roberts CT Jr et al (1998) Interaction in vitro of the product of the c-Crk-II proto-oncogene with the insulin-like growth factor I receptor. Biochem J 330(Pt 2):923–932PubMedGoogle Scholar
  30. 30.
    Dupont J, Fernandez AM, Glackin CA et al (2001) Insulin-like growth factor 1 (IGF-1)-induced twist expression is involved in the anti-apoptotic effects of the IGF-1 receptor. J Biol Chem 276:26699–26707PubMedGoogle Scholar
  31. 31.
    Mosthaf L, Grako K, Dull TJ et al (1990) Functionally distinct insulin receptors generated by tissue-specific alternative splicing. Embo J 9:2409–2413PubMedGoogle Scholar
  32. 32.
    Yamaguchi Y, Flier JS, Yokota A et al (1991) Functional properties of two naturally occurring isoforms of the human insulin receptor in Chinese hamster ovary cells. Endocrinology 129:2058–2066PubMedGoogle Scholar
  33. 33.
    Kosaki A, Pillay TS, Xu L et al (1995) The B isoform of the insulin receptor signals more efficiently than the A isoform in HepG2 cells. J Biol Chem 270:20816–20823PubMedGoogle Scholar
  34. 34.
    Frasca F, Pandini G, Scalia P et al (1999) Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol 19:3278–3288PubMedGoogle Scholar
  35. 35.
    Benyoucef S, Surinya KH, Hadaschik D et al (2007) Characterization of insulin/IGF hybrid receptors: contributions of the insulin receptor L2 and Fn1 domains and the alternatively spliced exon 11 sequence to ligand binding and receptor activation. Biochem J 403:603–613PubMedGoogle Scholar
  36. 36.
    Yamaguchi Y, Flier JS, Benecke H et al (1993) Ligand-binding properties of the two isoforms of the human insulin receptor. Endocrinology 132:1132–1138PubMedGoogle Scholar
  37. 37.
    Blanquart C, Achi J, Issad T (2008) Characterization of IRA/IRB hybrid insulin receptors using bioluminescence resonance energy transfer. Biochem Pharmacol 76:873–883PubMedGoogle Scholar
  38. 38.
    Nevado C, Benito M, Valverde AM (2008) Role of insulin receptor and balance in insulin receptor isoforms A and B in regulation of apoptosis in simian virus 40-immortalized neonatal hepatocytes. Mol Biol Cell 19:1185–1198PubMedGoogle Scholar
  39. 39.
    Kosaki A, Webster NJ (1993) Effect of dexamethasone on the alternative splicing of the insulin receptor mRNA and insulin action in HepG2 hepatoma cells. J Biol Chem 268:21990–21996PubMedGoogle Scholar
  40. 40.
    Entingh AJ, Taniguchi CM, Kahn CR (2003) Bi-directional regulation of brown fat adipogenesis by the insulin receptor. J Biol Chem 278:33377–33383PubMedGoogle Scholar
  41. 41.
    Sciacca L, Prisco M, Wu A et al (2003) Signaling differences from the A and B isoforms of the insulin receptor (IR) in 32D cells in the presence or absence of IR substrate-1. Endocrinology 144:2650–2658PubMedGoogle Scholar
  42. 42.
    Leibiger B, Leibiger IB, Moede T et al (2001) Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells. Mol Cell 7:559–570PubMedGoogle Scholar
  43. 43.
    Morrione A, Valentinis B, Xu SQ et al (1997) Insulin-like growth factor II stimulates cell proliferation through the insulin receptor. Proc Natl Acad Sci U S A 94:3777–3782PubMedGoogle Scholar
  44. 44.
    Sciacca L, Mineo R, Pandini G et al (2002) In IGF-I receptor-deficient leiomyosarcoma cells autocrine IGF-II induces cell invasion and protection from apoptosis via the insulin receptor isoform A. Oncogene 21:8240–8250PubMedGoogle Scholar
  45. 45.
    Pandini G, Medico E, Conte E et al (2003) Differential gene expression induced by insulin and insulin-like growth factor-II through the insulin receptor isoform A. J Biol Chem 278:42178–42189PubMedGoogle Scholar
  46. 46.
    Ullrich A, Bell JR, Chen EY et al (1985) Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313:756–761PubMedGoogle Scholar
  47. 47.
    Soos MA, Siddle K (1989) Immunological relationships between receptors for insulin and insulin-like growth factor I. Evidence for structural heterogeneity of insulin-like growth factor I receptors involving hybrids with insulin receptors. Biochem J 263:553–563PubMedGoogle Scholar
  48. 48.
    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
  49. 49.
    Soos MA, Whittaker J, Lammers R et al (1990) Receptors for insulin and insulin-like growth factor-I can form hybrid dimers. Characterisation of hybrid receptors in transfected cells. Biochem J 270:383–390PubMedGoogle Scholar
  50. 50.
    Soos MA, Nave BT, Siddle K (1993) Immunological studies of type I IGF receptors and insulin receptors: characterisation of hybrid and atypical receptor subtypes. Adv Exp Med Biol 343:145–157PubMedGoogle Scholar
  51. 51.
    Soos MA, Field CE, Siddle K (1993) Purified hybrid insulin/insulin-like growth factor-I receptors bind insulin-like growth factor-I, but not insulin, with high affinity. Biochem J 290(Pt 2):419–426PubMedGoogle Scholar
  52. 52.
    Moxham CP, Duronio V, Jacobs S (1989) Insulin-like growth factor I receptor beta-subunit heterogeneity. Evidence for hybrid tetramers composed of insulin-like growth factor I and insulin receptor heterodimers. J Biol Chem 264:13238–13244PubMedGoogle Scholar
  53. 53.
    Frattali AL, Treadway JL, Pessin JE (1992) Insulin/IGF-1 hybrid receptors: implications for the dominant-negative phenotype in syndromes of insulin resistance. J Cell Biochem 48:43–50PubMedGoogle Scholar
  54. 54.
    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 32:13531–13536PubMedGoogle Scholar
  55. 55.
    Pandini G, Frasca F, Mineo R et al (2002) Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J Biol Chem 277:39684–39695PubMedGoogle Scholar
  56. 56.
    Slaaby R, Schaffer L, Lautrup-Larsen I et al (2006) Hybrid receptors formed by insulin receptor (IR) and insulin-like growth factor I receptor (IGF-IR) have low insulin and high IGF-1 affinity irrespective of the IR splice variant. J Biol Chem 281:25869–25874PubMedGoogle Scholar
  57. 57.
    Garcia-de Lacoba M, Alarcon C, de la Rosa EJ et al (1999) Insulin/insulin-like growth factor-I hybrid receptors with high affinity for insulin are developmentally regulated during neurogenesis. Endocrinology 140:233–243PubMedGoogle Scholar
  58. 58.
    Alexandrides TK, Smith RJ (1989) A novel fetal insulin-like growth factor (IGF) I receptor. Mechanism for increased IGF I- and insulin-stimulated tyrosine kinase activity in fetal muscle. J Biol Chem 264:12922–12930PubMedGoogle Scholar
  59. 59.
    Navarro M, Joulia D, Fedon Y et al (2008) The atypical alpha2beta2 IGF receptor expressed in inducible c2.7 myoblasts is derived from post-translational modifications of the mouse IGF-I receptor. Growth Horm IGF Res 18:412–423PubMedGoogle Scholar
  60. 60.
    Milazzo G, Yip CC, Maddux BA et al (1992) High-affinity insulin binding to an atypical insulin-like growth factor-I receptor in human breast cancer cells. J Clin Invest 89:899–908PubMedGoogle Scholar
  61. 61.
    Jonas HA, Cox AJ, Harrison LC (1989) Delineation of atypical insulin receptors from classical insulin and type I insulin-like growth factor receptors in human placenta. Biochem J 257:101–107PubMedGoogle Scholar
  62. 62.
    Jonas HA, Cox AJ (1991) Insulin receptor sub-types in a human lymphoid-derived cell line (IM-9): differential regulation by insulin, dexamethasone and monensin. J Recept Res 11:813–829PubMedGoogle Scholar
  63. 63.
    Werner H, Le Roith D (2000) New concepts in regulation and function of the insulin-like growth factors: implications for understanding normal growth and neoplasia. Cell Mol Life Sci 57:932–942PubMedGoogle Scholar
  64. 64.
    Zhao H, Dupont J, Yakar S et al (2004) PTEN inhibits cell proliferation and induces apoptosis by downregulating cell surface IGF-IR expression in prostate cancer cells. Oncogene 23:786–794PubMedGoogle Scholar
  65. 65.
    Hwang PH, Kim SY, Lee JC et al (2005) PTEN/MMAC1 enhances the growth inhibition by anticancer drugs with downregulation of IGF-II expression in gastric cancer cells. Exp Mol Med 37:391–398PubMedGoogle Scholar
  66. 66.
    Yi HK, Kim SY, Hwang PH et al (2005) Impact of PTEN on the expression of insulin-like growth factors (IGFs) and IGF-binding proteins in human gastric adenocarcinoma cells. Biochem Biophys Res Commun 330:760–767PubMedGoogle Scholar
  67. 67.
    Buckbinder L, Talbott R, Velasco-Miguel S et al (1995) Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature 377:646–649PubMedGoogle Scholar
  68. 68.
    Ahmad T, Farnie G, Bundred NJ et al (2004) The mitogenic action of insulin-like growth factor I in normal human mammary epithelial cells requires the epidermal growth factor receptor tyrosine kinase. J Biol Chem 279:1713–1719PubMedGoogle Scholar
  69. 69.
    Balana ME, Labriola L, Salatino M et al (2001) Activation of ErbB-2 via a hierarchical interaction between ErbB-2 and type I insulin-like growth factor receptor in mammary tumor cells. Oncogene 20:34–47PubMedGoogle Scholar
  70. 70.
    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 65:11118–11128PubMedGoogle Scholar
  71. 71.
    Roudabush FL, Pierce KL, Maudsley S et al (2000) Transactivation of the EGF receptor mediates IGF-1-stimulated shc phosphorylation and ERK1/2 activation in COS-7 cells. J Biol Chem 275:22583–22589PubMedGoogle Scholar
  72. 72.
    Sisci D, Surmacz E (2007) Crosstalk between IGF signaling and steroid hormone receptors in breast cancer. Curr Pharm Des 13:705–717PubMedGoogle Scholar
  73. 73.
    Umayahara Y, Kawamori R, Watada H et al (1994) Estrogen regulation of the insulin-like growth factor I gene transcription involves an AP-1 enhancer. J Biol Chem 269:16433–16442PubMedGoogle Scholar
  74. 74.
    Dupont J, Karas M, LeRoith D (2000) The potentiation of estrogen on insulin-like growth factor I action in MCF-7 human breast cancer cells includes cell cycle components. J Biol Chem 275:35893–35901PubMedGoogle Scholar
  75. 75.
    Pandini G, Mineo R, Frasca F et al (2005) Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells. Cancer Res 65:1849–1857PubMedGoogle Scholar
  76. 76.
    Pandini G, Genua M, Frasca F et al (2007) 17beta-estradiol up-regulates the insulin-like growth factor receptor through a nongenotropic pathway in prostate cancer cells. Cancer Res 67:8932–8941PubMedGoogle Scholar
  77. 77.
    Sell C, Dumenil G, Deveaud C et al (1994) Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts. Mol Cell Biol 14:3604–3612PubMedGoogle Scholar
  78. 78.
    Baserga R, Hongo A, Rubini M et al (1997) The IGF-I receptor in cell growth, transformation and apoptosis. Biochim Biophys Acta 1332:F105–F126PubMedGoogle Scholar
  79. 79.
    Kaleko M, Rutter WJ, Miller AD (1990) Overexpression of the human insulinlike growth factor I receptor promotes ligand-dependent neoplastic transformation. Mol Cell Biol 10:464–473PubMedGoogle Scholar
  80. 80.
    Rubini M, Hongo A, D’Ambrosio C et al (1997) The IGF-I receptor in mitogenesis and transformation of mouse embryo cells: role of receptor number. Exp Cell Res 230:284–292PubMedGoogle Scholar
  81. 81.
    Giorgino F, Belfiore A, Milazzo G et al (1991) Overexpression of insulin receptors in fibroblast and ovary cells induces a ligand-mediated transformed phenotype. Mol Endocrinol 5:452–459PubMedGoogle Scholar
  82. 82.
    Ish-Shalom D, Christoffersen CT, Vorwerk P et al (1997) Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor. Diabetologia 40(Suppl 2):S25–S31PubMedGoogle Scholar
  83. 83.
    Drejer K (1992) The bioactivity of insulin analogues from in vitro receptor binding to in vivo glucose uptake. Diabetes Metab Rev 8:259–285PubMedGoogle Scholar
  84. 84.
    Milazzo G, Sciacca L, Papa V et al (1997) ASPB10 insulin induction of increased mitogenic responses and phenotypic changes in human breast epithelial cells: evidence for enhanced interactions with the insulin-like growth factor-I receptor. Mol Carcinog 18:19–25PubMedGoogle Scholar
  85. 85.
    Carboni JM, Lee AV, Hadsell DL et al (2005) Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor. Cancer Res 65:3781–3787PubMedGoogle Scholar
  86. 86.
    Jones RA, Campbell CI, Gunther EJ et al (2007) Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation. Oncogene 26:1636–1644PubMedGoogle Scholar
  87. 87.
    Mathews LS, Hammer RE, Behringer RR et al (1988) Growth enhancement of transgenic mice expressing human insulin-like growth factor I. Endocrinology 123:2827–2833PubMedGoogle Scholar
  88. 88.
    DiGiovanni J, Kiguchi K, Frijhoff A et al (2000) Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice. Proc Natl Acad Sci U S A 97:3455–3460PubMedGoogle Scholar
  89. 89.
    Hadsell DL, Greenberg NM, Fligger JM et al (1996) Targeted expression of des(1-3) human insulin-like growth factor I in transgenic mice influences mammary gland development and IGF-binding protein expression. Endocrinology 137:321–330PubMedGoogle Scholar
  90. 90.
    Hadsell DL, Murphy KL, Bonnette SG et al (2000) Cooperative interaction between mutant p53 and des(1-3)IGF-I accelerates mammary tumorigenesis. Oncogene 19:889–898PubMedGoogle Scholar
  91. 91.
    Bates P, Fisher R, Ward A et al (1995) Mammary cancer in transgenic mice expressing insulin-like growth factor II (IGF-II). Br J Cancer 72:1189–1193PubMedGoogle Scholar
  92. 92.
    Moorehead RA, Fata JE, Johnson MB et al (2001) Inhibition of mammary epithelial apoptosis and sustained phosphorylation of Akt/PKB in MMTV-IGF-II transgenic mice. Cell Death Differ 8:16–29PubMedGoogle Scholar
  93. 93.
    Peyrat JP, Bonneterre J, Beuscart R et al (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
  94. 94.
    Cullen KJ, Yee D, Sly WS et al (1990) Insulin-like growth factor receptor expression and function in human breast cancer. Cancer Res 50:48–53PubMedGoogle Scholar
  95. 95.
    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
  96. 96.
    Koda M, Sulkowski S, Garofalo C et al (2003) Expression of the insulin-like growth factor-I receptor in primary breast cancer and lymph node metastases: correlations with estrogen receptors alpha and beta. Horm Metab Res 35:794–801PubMedGoogle Scholar
  97. 97.
    Resnik JL, Reichart DB, Huey K et al (1998) Elevated insulin-like growth factor I receptor autophosphorylation and kinase activity in human breast cancer. Cancer Res 58:1159–1164PubMedGoogle Scholar
  98. 98.
    Rasmussen AA, Cullen KJ (1998) Paracrine/autocrine regulation of breast cancer by the insulin-like growth factors. Breast Cancer Res Treat 47:219–233PubMedGoogle Scholar
  99. 99.
    Vella V, Pandini G, Sciacca L et al (2002) A novel autocrine loop involving IGF-II and the insulin receptor isoform-A stimulates growth of thyroid cancer. J Clin Endocrinol Metab 87:245–254PubMedGoogle Scholar
  100. 100.
    Strammiello R, Benini S, Manara MC et al (2003) Impact of IGF-I/IGF-IR circuit on the angiogenetic properties of Ewing’s sarcoma cells. Horm Metab Res 35:675–684PubMedGoogle Scholar
  101. 101.
    Heuson JC, Legros N, Heimann R (1972) Influence of insulin administration on growth of the 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in intact, oophorectomized, and hypophysectomized rats. Cancer Res 32:233–238PubMedGoogle Scholar
  102. 102.
    Nandi S, Guzman RC, Yang J (1995) Hormones and mammary carcinogenesis in mice, rats, and humans: a unifying hypothesis. Proc Natl Acad Sci U S A 92:3650–3657PubMedGoogle Scholar
  103. 103.
    Pillemer G, Lugasi-Evgi H, Scharovsky G et al (1992) Insulin dependence of murine lymphoid T-cell leukemia. Int J Cancer 50:80–85PubMedGoogle Scholar
  104. 104.
    Sharon R, Pillemer G, Ish-Shalom D et al (1993) Insulin dependence of murine T-cell lymphoma. II. Insulin-deficient diabetic mice and mice fed low-energy diet develop resistance to lymphoma growth. Int J Cancer 53:843–849PubMedGoogle Scholar
  105. 105.
    Papa V, Pezzino V, Costantino A et al (1990) Elevated insulin receptor content in human breast cancer. J Clin Invest 86:1503–1510PubMedGoogle Scholar
  106. 106.
    Milazzo G, Giorgino F, Damante G et al (1992) Insulin receptor expression and function in human breast cancer cell lines. Cancer Res 52:3924–3930PubMedGoogle Scholar
  107. 107.
    Sciacca L, Costantino A, Pandini G et al (1999) Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism. Oncogene 18:2471–2479PubMedGoogle Scholar
  108. 108.
    Kalli KR, Falowo OI, Bale LK et al (2002) Functional insulin receptors on human epithelial ovarian carcinoma cells: implications for IGF-II mitogenic signaling. Endocrinology 143:3259–3267PubMedGoogle Scholar
  109. 109.
    Diaz LE, Chuan YC, Lewitt M et al (2007) IGF-II regulates metastatic properties of choriocarcinoma cells through the activation of the insulin receptor. Mol Hum Reprod 13:567–576PubMedGoogle Scholar
  110. 110.
    Li Y, Chang Q, Rubin BP et al (2007) Insulin receptor activation in solitary fibrous tumours. J Pathol 211:550–554PubMedGoogle Scholar
  111. 111.
    Arcaro A, Doepfner KT, Boller D et al (2007) Novel role for insulin as an autocrine growth factor for malignant brain tumour cells. Biochem J 406:57–66PubMedGoogle Scholar
  112. 112.
    Vella V, Sciacca L, Pandini G et al (2001) The IGF system in thyroid cancer: new concepts. Mol Pathol 54:121–124PubMedGoogle Scholar
  113. 113.
    Belfiore A, Pandini G, Vella V et al (1999) Insulin/IGF-I hybrid receptors play a major role in IGF-I signaling in thyroid cancer. Biochimie 81:403–407PubMedGoogle Scholar
  114. 114.
    Avnet S, Sciacca L, Salerno M et al (2009) Insulin receptor isoform A and insulin-like growth factor II as additional treatment targets in human osteosarcoma. Cancer Res 69:2443–2452PubMedGoogle Scholar
  115. 115.
    Shiono S, Ishii G, Nagai K et al (2006) Immunohistochemical prognostic factors in resected colorectal lung metastases using tissue microarray analysis. Eur J Surg Oncol 32:308–309PubMedGoogle Scholar
  116. 116.
    Almeida A, Muleris M, Dutrillaux B et al (1994) The insulin-like growth factor I receptor gene is the target for the 15q26 amplicon in breast cancer. Genes Chromosomes Cancer 11:63–65PubMedGoogle Scholar
  117. 117.
    Papa V, Milazzo G, Goldfine ID et al (1997) Sporadic amplification of the insulin receptor gene in human breast cancer. J Endocrinol Invest 20:531–536PubMedGoogle Scholar
  118. 118.
    Zhang J, Trent JM, Meltzer PS (1993) Rapid isolation and characterization of amplified DNA by chromosome microdissection: identification of IGF1R amplification in malignant melanoma. Oncogene 8:2827–2831PubMedGoogle Scholar
  119. 119.
    Armengol G, Knuutila S, Lluis F et al (2000) DNA copy number changes and evaluation of MYC, IGF1R, and FES amplification in xenografts of pancreatic adenocarcinoma. Cancer Genet Cytogenet 116:133–141PubMedGoogle Scholar
  120. 120.
    Werner H, Shalita-Chesner M, Abramovitch S et al (2000) Regulation of the insulin-like growth factor-I receptor gene by oncogenes and antioncogenes: implications in human cancer. Mol Genet Metab 71:315–320PubMedGoogle Scholar
  121. 121.
    Maor S, Yosepovich A, Papa MZ et al (2007) Elevated insulin-like growth factor-I receptor (IGF-IR) levels in primary breast tumors associated with BRCA1 mutations. Cancer Lett 257:236–243PubMedGoogle Scholar
  122. 122.
    Hudelist G, Wagner T, Rosner M et al (2007) Intratumoral IGF-I protein expression is selectively upregulated in breast cancer patients with BRCA1/2 mutations. Endocr Relat Cancer 14:1053–1062PubMedGoogle Scholar
  123. 123.
    Paonessa F, Foti D, Costa V et al (2006) Activator protein-2 overexpression accounts for increased insulin receptor expression in human breast cancer. Cancer Res 66:5085–5093PubMedGoogle Scholar
  124. 124.
    Novosyadlyy R, Kurshan N, Lann D et al (2008) Insulin-like growth factor-I protects cells from ER stress-induced apoptosis via enhancement of the adaptive capacity of endoplasmic reticulum. Cell Death Differ 15:1304–1317PubMedGoogle Scholar
  125. 125.
    Samani AA, Yakar S, LeRoith D et al (2007) The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 28:20–47PubMedGoogle Scholar
  126. 126.
    Foekens JA, Portengen H, van Putten WL et al (1989) Prognostic value of receptors for insulin-like growth factor 1, somatostatin, and epidermal growth factor in human breast cancer. Cancer Res 49:7002–7009PubMedGoogle Scholar
  127. 127.
    Maor S, Mayer D, Yarden RI et al (2006) Estrogen receptor regulates insulin-like growth factor-I receptor gene expression in breast tumor cells: involvement of transcription factor Sp1. J Endocrinol 191:605–612PubMedGoogle Scholar
  128. 128.
    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
  129. 129.
    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:307–311PubMedGoogle Scholar
  130. 130.
    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 26:4078–4085PubMedGoogle Scholar
  131. 131.
    Figueroa JA, De Raad S, Speights VO et al (2001) Gene expression of insulin-like growth factors and receptors in neoplastic prostate tissues: correlation with clinico-pathological parameters. Cancer Invest 19:28–34PubMedGoogle Scholar
  132. 132.
    Tennant MK, Thrasher JB, Twomey PA et al (1996) Protein and messenger ribonucleic acid (mRNA) for the type 1 insulin-like growth factor (IGF) receptor is decreased and IGF-II mRNA is increased in human prostate carcinoma compared to benign prostate epithelium. J Clin Endocrinol Metab 81:3774–3782PubMedGoogle Scholar
  133. 133.
    Hellawell GO, Turner GD, Davies DR et al (2002) Expression of the type 1 insulin-like growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease. Cancer Res 62:2942–2950PubMedGoogle Scholar
  134. 134.
    Hellawell GO, Brewster SF (2002) Growth factors and their receptors in prostate cancer. BJU Int 89:230–240PubMedGoogle Scholar
  135. 135.
    Hakam A, Yeatman TJ, Lu L et al (1999) Expression of insulin-like growth factor-1 receptor in human colorectal cancer. Hum Pathol 30:1128–1133PubMedGoogle Scholar
  136. 136.
    Chakravarty G, Santillan AA, Galer C et al (2009) Phosphorylated insulin like growth factor-I receptor expression and its clinico-pathological significance in histologic subtypes of human thyroid cancer. Exp Biol Med (Maywood) 234:372–386Google Scholar
  137. 137.
    Mathieu MC, Clark GM, Allred DC et al (1997) Insulin receptor expression and clinical outcome in node-negative breast cancer. Proc Assoc Am Physicians 109:565–571PubMedGoogle Scholar
  138. 138.
    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 106:39–47PubMedGoogle Scholar
  139. 139.
    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 68:10238–10246PubMedGoogle Scholar
  140. 140.
    Baserga R, Peruzzi F, Reiss K (2003) The IGF-1 receptor in cancer biology. Int J Cancer 107:873–877PubMedGoogle Scholar
  141. 141.
    Hofmann F, Garcia-Echeverria C (2005) Blocking the insulin-like growth factor-I receptor as a strategy for targeting cancer. Drug Discov Today 10:1041–1047PubMedGoogle Scholar
  142. 142.
    Pollak M (2008) Targeting insulin and insulin-like growth factor signalling in oncology. Curr Opin Pharmacol 8:384–392PubMedGoogle Scholar
  143. 143.
    Zhang H, Pelzer AM, Kiang DT et al (2007) Down-regulation of type I insulin-like growth factor receptor increases sensitivity of breast cancer cells to insulin. Cancer Res 67:391–397PubMedGoogle Scholar
  144. 144.
    Pisani P (2008) Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem 114:63–70PubMedGoogle Scholar
  145. 145.
    Goodwin PJ, Ennis M, Pritchard KI et al (2002) Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol 20:42–51PubMedGoogle Scholar
  146. 146.
    Haluska P, Carboni JM, Loegering DA et al (2006) In vitro and in vivo antitumor effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417. Cancer Res 66:362–371PubMedGoogle Scholar
  147. 147.
    Miyamoto S, Nakamura M, Shitara K et al (2005) Blockade of paracrine supply of insulin-like growth factors using neutralizing antibodies suppresses the liver metastasis of human colorectal cancers. Clin Cancer Res 11:3494–3502PubMedGoogle Scholar
  148. 148.
    Feng Y, Zhu Z, Xiao X et al (2006) Novel human monoclonal antibodies to insulin-like growth factor (IGF)-II that potently inhibit the IGF receptor type I signal transduction function. Mol Cancer Ther 5:114–120PubMedGoogle Scholar
  149. 149.
    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 43:1318–1327PubMedGoogle Scholar
  150. 150.
    Ouban A, Muraca P, Yeatman T et al (2003) Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas. Hum Pathol 34:803–808PubMedGoogle Scholar
  151. 151.
    Guo YS, Narayan S, Yallampalli C et al (1992) Characterization of insulinlike growth factor I receptors in human colon cancer. Gastroenterology 102:1101–1108PubMedGoogle Scholar
  152. 152.
    Iwamura M, Sluss PM, Casamento JB et al (1993) Insulin-like growth factor I: action and receptor characterization in human prostate cancer cell lines. Prostate 22:243–252PubMedGoogle Scholar
  153. 153.
    Nickerson T, Chang F, Lorimer D et al (2001) In vivo progression of LAPC-9 and LNCaP prostate cancer models to androgen independence is associated with increased expression of insulin-like growth factor I (IGF-I) and IGF-I receptor (IGF-IR). Cancer Res 61:6276–6280PubMedGoogle Scholar
  154. 154.
    Huff KK, Kaufman D, Gabbay KH et al (1986) Secretion of an insulin-like growth factor-I-related protein by human breast cancer cells. Cancer Res 46:4613–4619PubMedGoogle Scholar
  155. 155.
    Yee D, Paik S, Lebovic GS et al (1989) Analysis of insulin-like growth factor I gene expression in malignancy: evidence for a paracrine role in human breast cancer. Mol Endocrinol 3:509–517PubMedGoogle Scholar
  156. 156.
    Maiorano E, Ciampolillo A, Viale G et al (2000) Insulin-like growth factor 1 expression in thyroid tumors. Appl Immunohistochem Mol Morphol 8:110–119PubMedGoogle Scholar
  157. 157.
    Michell NP, Langman MJ, Eggo MC (1997) Insulin-like growth factors and their binding proteins in human colonocytes: preferential degradation of insulin-like growth factor binding protein 2 in colonic cancers. Br J Cancer 76:60–66PubMedGoogle Scholar
  158. 158.
    Pietrzkowski Z, Mulholland G, Gomella L et al (1993) Inhibition of growth of prostatic cancer cell lines by peptide analogues of insulin-like growth factor 1. Cancer Res 53:1102–1106PubMedGoogle Scholar
  159. 159.
    Paik S (1992) Expression of IGF-I and IGF-II mRNA in breast tissue. Breast Cancer Res Treat 22:31–38PubMedGoogle Scholar
  160. 160.
    Singh P, Dai B, Yallampalli C et al (1994) Expression of IGF-II and IGF-binding proteins by colon cancer cells in relation to growth response to IGFs. Am J Physiol 267:G608–G617PubMedGoogle Scholar
  161. 161.
    Jehle PM, Fussgaenger RD, Blum WF et al (1999) Differential autocrine regulation of intestine epithelial cell proliferation and differentiation by insulin-like growth factor (IGF) system components. Horm Metab Res 31:97–102PubMedGoogle Scholar
  162. 162.
    Li SL, Goko H, Xu ZD et al (1998) Expression of insulin-like growth factor (IGF)-II in human prostate, breast, bladder, and paraganglioma tumors. Cell Tissue Res 291:469–479PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Antonino Belfiore
    • 1
  • Ira D. Goldfine
    • 2
  • Roberta Malaguarnera
    • 1
  1. 1.Department of Clinical and Experimental MedicineUniversity of CatanzaroCatanzaroItaly
  2. 2.Department of Medicine and Diabetes CenterUniversity of California, San Francisco/Mt. Zion Medical CenterSan FranciscoUSA

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