Advertisement

Potential Mechanisms Linking Insulin to Cancer

  • Yael Babichev
  • Sarah Khalid
  • I. George FantusEmail author
Chapter
Part of the Energy Balance and Cancer book series (EBAC, volume 1)

Abstract

The association between obesity and the incidence of various forms of cancer is well established [11, 20, 86]. Although this association is present for several cancers in both men and women, at least three primary cancers of women show this link, namely uterine, ovarian, and mammary cancers [11]. Previous chapters have reviewed the epidemiological data in detail. The focus of this chapter is to review and discuss the potential pathophysiology and biological mechanisms, which could account for this relationship. It appears unlikely that an identical and unique mechanism will explain the impact of obesity on cancer development and progression in these different tumors. Some examples of effects on different tumors have been mentioned, which support specific mechanisms [11], the focus here will be on breast cancer (BC).

Keywords

Breast Cancer Insulin Resistance Breast Cancer Cell Insulin Receptor Insulin Glargine 
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.

Notes

Acknowledgments

This work was supported by a Translational Acceleration Grant from the CBCRA (Canadian Breast Cancer Research Alliance) and CIHR (Canada Institutes for Health Research) to IGF. (Grant # 016512). SK was supported in part by CBCRA and the Marvelle Koffler Breast Centre, Mount Sinai Hospital.

References

  1. 1.
    Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801PubMedPubMedCentralGoogle Scholar
  2. 2.
    Alberti KG, Zimmet P, Shaw J, IDF Epidemiology Task Force Consensus (2005) The metabolic syndrome: a new worldwide definition. Lancet 366:1059–1062PubMedGoogle Scholar
  3. 3.
    Belfiore A (2007) The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer. Curr Pharm Des 13:671–686PubMedGoogle Scholar
  4. 4.
    Borisov N, Aksamitiene E, Kiyatkin A et al (2009) Systems-level interactions between insulin-EGF networks amplify mitogenic signaling. Mol Syst Biol 5:256. doi: 10.1038/msb.2009.19 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Borugian MJ, Sheps SB, Kim-Sing C et al (2004) Insulin, macronutrient intake, and physical activity: are potential indicators of insulin resistance associated with mortality from breast cancer? Cancer Epidemiol Biomarkers Prev 13:1163–1172PubMedGoogle Scholar
  6. 6.
    Bowker SL, Majumdar SR, Veugelers P et al (2006) Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29:254–258PubMedGoogle Scholar
  7. 7.
    Brown JR, DuBois RN (2005) Cox-2: a molecular target for colorectal cancer prevention. J Clin Oncol 23:2840–2855PubMedGoogle Scholar
  8. 8.
    Brown KA, Simpson ER (2010) Obesity and breast cancer: progress to understanding the relationship. Cancer Res 70:4–7PubMedGoogle Scholar
  9. 9.
    Burstein HJ, Demetia GD, Mueller E et al (2003) Use of the peroxisome proliferators-activated receptor (PPAR) gamma ligand troglitazone as treatment for refractory breast cancer: a phase II study. Breast Cancer Res Treat 79:391–397PubMedGoogle Scholar
  10. 10.
    Calle EE, Kaaks R (2004) Overweight, obesity, and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4:579–591Google Scholar
  11. 11.
    Calle EE, Rodriguez C, Walker-Thurmond K et al (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625–1638PubMedGoogle Scholar
  12. 12.
    Camirand A, Zakikhani M, Young F et al (2005) Inhibition of insulin-like growth factor-1 receptor signaling enhances growth-inhibitory and proapoptotic effects of gefitinib (Iressa) in human breast cancer cells. Breast Cancer Res 7:R570–R579PubMedPubMedCentralGoogle Scholar
  13. 13.
    Carroll KK, Braden LM (1984) Dietary fat and mammary carcinogenesis. Nutr Cancer 6:254–259PubMedGoogle Scholar
  14. 14.
    Carter CA, Milholland RJ, Shea W et al (1983) Effect of the prostaglandin synthetase inhibitor indomethacin on 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in rats fed different levels of fat. Cancer Res 43:3559–3562PubMedGoogle Scholar
  15. 15.
    Casey PJ (1995) Protein lipidation in cell signaling. Science 268:221–225PubMedGoogle Scholar
  16. 16.
    Cazzaniga M, Bonanni B, Guerrieri-Gona A et al (2009) Is it time to test metformin in breast cancer clinical trials? Cancer Epidermiol Biomarkers Prev 18:701–705Google Scholar
  17. 17.
    Cejas P, Casado E, Belda-Iniesta C et al (2004) Implications of oxidative stress and cell membrane lipid peroxidation in human cancer (Spain). Cancer Causes Control 15:707–719PubMedGoogle Scholar
  18. 18.
    Chappell J, Golovchenko I, Wall K et al (2000) Potentiation of Rho-A-mediated lysophosphatidic acid activity by hyperinsulinemia. J Biol Chem 275:31792–31797PubMedGoogle Scholar
  19. 19.
    Chappell J, Leitner JW, Solomon S et al (2001) Effect of insulin on cell cycle progression in MCF-7 breast cancer cells. J Biol Chem 276:38023–38028PubMedGoogle Scholar
  20. 20.
    Cleary MP, Maihle NJ (1997) The role of body mass index in the relative risk of developing premenopausal versus postmenopausal breast cancer. Proc Soc Exp Biol Med 216:28–43PubMedGoogle Scholar
  21. 21.
    Cleary MP, Grande JP, Maihle NJ (2004) Effect of high fat diet on body weight and mammary tumor latency in MMTV-TGF-alpha mice. Int J Obes Relat Metab Disord 28:956–962PubMedGoogle Scholar
  22. 22.
    Clemons M, Goss P (2001) Estrogen and the risk of breast cancer. N Engl J Med 344:276–285PubMedGoogle Scholar
  23. 23.
    Colhoun H, SDRN Epidemiology Group (2009) Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Network Epidemiology Group. Diabetologia 52:1755–1765Google Scholar
  24. 24.
    Cowey S, Hardy RW (2006) The metabolic syndrome: A high-risk state for cancer? Am J Pathol 169:1505–1522PubMedPubMedCentralGoogle Scholar
  25. 25.
    Currie CJ, Poole CD, Gale EAM (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52:1766–1777PubMedGoogle Scholar
  26. 26.
    DeBerardinis RJ, Lum JJ, Hatzivassiliou G et al (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7:11–20PubMedGoogle Scholar
  27. 27.
    Del Giudice ME, Fantus IG, Ezzat S et al (1998) Insulin and related factors in premenopausal breast cancer risk. Breast Cancer Res Treat 47:111–120PubMedGoogle Scholar
  28. 28.
    Despres JP (2001) Health consequences of visceral obesity. Ann Med 33:534–541PubMedGoogle Scholar
  29. 29.
    DiCristofanoA PPP (2000) The multiple roles of PTEN in tumor suppression. Cell 100:387–390Google Scholar
  30. 30.
    Dieudonne MD, Bussiere M, Dos Santos E et al (2006) Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer cells. Biochem Biophys Res Commun 345:271–279PubMedGoogle Scholar
  31. 31.
    Ding VW, Chen RH, McCormick F (2000) Differential regulation of glycogen synthase kinase 3B by insulin and Wnt signaling. J Biol Chem 275:32475–32481PubMedGoogle Scholar
  32. 32.
    Dowling RJ, Zakikhani M, Fantus IG et al (2007) Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 67:10804–10812PubMedGoogle Scholar
  33. 33.
    Eckel RH, Grundy SM, Zimmet PZ (2005) The metabolic syndrome. Lancet 365:1415–1428PubMedGoogle Scholar
  34. 34.
    Evans JM, Donnelly LA, Emslie-Smith AM et al (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304–1305PubMedPubMedCentralGoogle Scholar
  35. 35.
    Fierz Y, Novosyadlyy R, Vijayakumar A et al (2010) Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression. Diabetes 59:686–693PubMedGoogle Scholar
  36. 36.
    Firth SM, Baxter RC (2002) Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 23:824–854PubMedGoogle Scholar
  37. 37.
    Flegal KM, Carroll MD, Ogden CL et al (2010) Prevalence and trends in obesity among US adults, 1999–2008. JAMA 303:235–241PubMedGoogle Scholar
  38. 38.
    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 19:3278–3288PubMedPubMedCentralGoogle Scholar
  39. 39.
    Frittitta L, Cerrato A, Sacco MG et al (1997) The insulin receptor content is increased in breast cancers initiated by three different oncogenes in transgenic mice. Breast Cancer Res Treat 45:141–147PubMedGoogle Scholar
  40. 40.
    Gallagher EJ, LeRoith D (2010) The proliferating role of insulin and insulin-like growth ­factors in cancer. Trends Endocrinol Metab 21:610–618PubMedPubMedCentralGoogle Scholar
  41. 41.
    Gerstein HC (2010) Does insulin therapy promote, reduce or have a neutral effect on cancers. JAMA 303:446–447PubMedGoogle Scholar
  42. 42.
    Giovannucci E, Harlan DM, Archer MC et al (2010) Diabetes and cancer: A consensus report. Diabetes Care 33:1674–1685PubMedPubMedCentralGoogle Scholar
  43. 43.
    Giovanucci E (2001) Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutri 131:3109S–3120SGoogle Scholar
  44. 44.
    Goalstone ML, Leitner JW, Wall K et al (1998) Effect of insulin on farnesyltransferase. Specificity of insulin action and potentiation of nuclear effects of insulin-like growth factor-1, epidermal growth factor, and platelet-derived growth factor. J Biol Chem 273:23892–23896PubMedGoogle Scholar
  45. 45.
    Goalstone ML, Leitner JW, Golovchenko I et al (1999) Insulin promotes phosphorylation and activation of geranyulgeranyltransferase II. J Biol Chem 274:2880–2884PubMedGoogle Scholar
  46. 46.
    Goalstone ML, Leitner JW, Berhanu P et al (2001) Insulin signals to prenyltransferases via the Shc branch of intracellular signaling. J Biol Chem 276:12805–12812PubMedGoogle Scholar
  47. 47.
    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 20:42–51Google Scholar
  48. 48.
    Goodwin PJ, Ennis M, Fantus IG et al (2005) Is leptin a mediator of adverse prognostic effects of obesity in breast cancer? J Clin Oncol 23:6037–6042PubMedGoogle Scholar
  49. 49.
    Gruber CJ, Tschugguel W, Schneeberger C et al (2002) Production and actions of estrogens. N Engl J Med 346:340–352PubMedGoogle Scholar
  50. 50.
    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 118:2609–2619PubMedPubMedCentralGoogle Scholar
  51. 51.
    Gunter MJ, Hoover DR, Yu H et al (2009) Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 101:48–60PubMedPubMedCentralGoogle Scholar
  52. 52.
    Guy CT, Cardiff RD, Muller WJ (1992) Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol 12:954–961PubMedPubMedCentralGoogle Scholar
  53. 53.
    Hall JM, Couse JF, Korach KS (2001) The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem 276:36869–36872PubMedGoogle Scholar
  54. 54.
    Hamelers IHL, Steenbergh PH (2003) Interactions between estrogen and insulin-like growth factor signaling pathways in human breast tumor cells. Endocr Relat Cancer 10:331–345PubMedGoogle Scholar
  55. 55.
    Hardy S, Langelier Y, Prentki M (2000) Oleate activates phosphatidylinositol 3-kinase and promotes proliferation and reduces apoptosis of MDA-MB-231 breast cancer cells, whereas palmitate has opposite effects. Cancer Res 60:6353–6358PubMedGoogle Scholar
  56. 56.
    Hatsell S, Rowlands T, Hiremath M et al (2003) B-catenin and Tcfs in mammary development and cancer. J Mammary Gland Biol Neoplasia 8:145–158PubMedGoogle Scholar
  57. 57.
    Heiden MG, Cantley CC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033Google Scholar
  58. 58.
    Hemkens LG, Grouven U, Bender R et al (2009) Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 52:1732–1744PubMedPubMedCentralGoogle Scholar
  59. 59.
    Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5:341–354PubMedGoogle Scholar
  60. 60.
    Ishikawa M, Kitayaama J, Kazama S et al (2005) Plasma adiponectin and gastric cancer. Clin Cancer Res 11:466–472PubMedGoogle Scholar
  61. 61.
    Iyer A, Fairlie DP, Prins JB et al (2010) Inflammatory lipid mediators in adipocytes function and obesity. Nat Rev Endocrinol 5:71–82Google Scholar
  62. 62.
    Jee SH, Ohrr H, Sull JW et al (2010) Associations of hyperglycemia and insulin usage with the risk of cancer in type 2 diabetes: the Hong Kong Diabetes Registry. Diabetes 59:1254–1260Google Scholar
  63. 63.
    Jiang ZY, Lin YW, Clemont A et al (1999) Characterization of selective resistance to insulin signaling in the vasculative of obese Zucker (fa/fa) rats. J Clin Invest 104:447–457PubMedPubMedCentralGoogle Scholar
  64. 64.
    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 13:485–498PubMedGoogle Scholar
  65. 65.
    Jogie-Brahim S, Feldman D, Oh Y (2009) Unraveling insulin-like growth factor binding protein-3 actions in human disease. Endocr Rev 30:417–437PubMedPubMedCentralGoogle Scholar
  66. 66.
    Jonasson JM, Ljung R, Talback M et al (2009) Insulin glargine use and short-term incidence of malignancies – a population-based follow-up study in Sweden. Diabetologia 52:1745–1754PubMedGoogle Scholar
  67. 67.
    Jones HE, Goddard L, Gee JM et al (2004) Insulin-like growth factor-I receptor signaling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr Relat Cancer 11:793–814PubMedGoogle Scholar
  68. 68.
    Jones HE, Gee JM, Hutchenson IR et al (2006) Growth factor receptor interplay and resistance in cancer. Endocr Relat Cancer 13(Suppl 1):S45–S51PubMedGoogle Scholar
  69. 69.
    Kadowaki T, Yamauchi T (2005) Adiponectin and adiponectin receptors. Endocr Rev 26:439–451PubMedGoogle Scholar
  70. 70.
    Kalamegham R, Carroll KK (1984) Reversal of the promotional effect of high-fat diet on mammary tumorigenesis by subsequent lowering of dietary fat. Nutr Cancer 6:22–31PubMedGoogle Scholar
  71. 71.
    Karim R, Tse G, Putti T et al (2004) The significance of the Wnt pathway in the pathology of human cancers. Pathology 36:120–128PubMedGoogle Scholar
  72. 72.
    Kato S (2001) Estrogen receptor-mediated cross-talk with growth factor signaling pathways. Breast Cancer 8:3–9PubMedGoogle Scholar
  73. 73.
    Khalid S, Hwang D, Babichev Y et al (2009) Evidence for a tumor promoting effect of high-fat diet independent of insulin resistance in HER2/Neu mammary carcinogenesis. Breast Cancer Res Treat 122:647–659PubMedGoogle Scholar
  74. 74.
    Khasawneh J, Schulz MD, Walch A et al (2009) Inflammation and mitochondrial fatty acid beta-oxidation link obesity to early tumor promotion. Proc Natl Acad Sci USA 106:3354–3359PubMedGoogle Scholar
  75. 75.
    Kim JK (2006) Fat uses a TOLL-road to connect inflammation and diabetes. Cell Metab 4:417–419PubMedGoogle Scholar
  76. 76.
    Kim F, Pham M, Luttrell I et al (2007) Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res 100:1589–1596PubMedGoogle Scholar
  77. 77.
    Knowlden JM, Jones JE, Barrow D et al (2008) Insulin receptor substrate-1 involvement in epidermal growth factor and insulin-like growth factor receptor signaling: implication for Getitinib (Iressa) response and resistance. Breast Cancer Res Treat 111:79–91PubMedGoogle Scholar
  78. 78.
    Kurtzhals P, Schaffer L, Sorensen A et al (2000) Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed form clinical use. Diabetes 49:999–1005PubMedGoogle Scholar
  79. 79.
    Lawlor DA, Smith GD, Ebrahim S (2004) Hyperinsulinaemia and increased risk of breast cancer: findings from the British Women’s Heart and Health Study. Cancer Causes Control 15:267–275PubMedGoogle Scholar
  80. 80.
    Lee MM, Lin SS (2000) Dietary fat and breast cancer. Annu Rev Nutr 20:221–248PubMedGoogle Scholar
  81. 81.
    Li S, Brown MS, Goldstein JL (2010) Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc Natl Acad Sci USA 23:3281–3282Google Scholar
  82. 82.
    Lin SY, Xia W, Wang TC et al (2000) B-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci USA 87:4262–4266Google Scholar
  83. 83.
    Lin EY, Jones JG, Li P et al (2003) Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol 163:2113–2126PubMedPubMedCentralGoogle Scholar
  84. 84.
    Lipscombe LL, Goodwin PJ, Zinman B et al (2006) Increased prevalence of prior breast cancer in women with newly diagnosed diabetes. Breast Cancer Res Treat 98:303–309PubMedGoogle Scholar
  85. 85.
    Lipscombe LL, Goodwin PJ, Zinman B et al (2006) Diabetes mellitus and breast cancer: a retrospective population-based cohort study. Breast Cancer Res Treat 98:349–356PubMedGoogle Scholar
  86. 86.
    Manjer J, Kaaks R, Riboli E et al (2001) Risk of breast cancer in relation to anthropometry, blood pressure, blood lipids and glucose metabolism: a prospective study within the Malmo Preventive Project. Eur J Cancer Prev 10:33–42PubMedGoogle Scholar
  87. 87.
    Mantzoros C, Petridou E, Dessypris N et al (2004) Adiponectin and breast cancer risk. J Clin Endocrinol Metab 89:1102–1107PubMedGoogle Scholar
  88. 88.
    Mathieu MC, Clark GM, Allred DC et al (1997) Insulin receptor expression and clinical outcome in node-negative breast cancer. Proc Assoc Am Physicians 109:565–571PubMedPubMedCentralGoogle Scholar
  89. 89.
    Mawson A, Lai A, Carroll JS et al (2005) Estrogen and insulin/IGF/1 cooperatively stimulates cell cycle progression in MCF-7 breast cancer cells through differential regulation of c-cyc and cyclin D1. Mol Cell Endocrinol 729:161–173Google Scholar
  90. 90.
    McCune K et al (2010) Prognosis of hormone-dependent breast cancers: implications of the presence of dysfunctional transcriptional networks activated by insulin via the immune transcription factor T-bet. Cancer Res 70:685–696PubMedPubMedCentralGoogle Scholar
  91. 91.
    Menendez JA, Vellon L, Colomer R et al (2005) Oleic acid, the main monounsaturated fatty acid of olive oil, suppresses Her-2/neu (erbB-2) expression and synergistically enhances the growth inhibitory effects of trastuzumab (Herceptin) in breast cancer cells with Her-2/neu oncogene amplification. Ann Oncol 16:359–371PubMedGoogle Scholar
  92. 92.
    Michaelson JS, Leder P (2001) B-catenin is a downstream effector of Wnt-mediated tumorigenesis in the mammary gland. Oncogene 20:5093–5099PubMedGoogle Scholar
  93. 93.
    Michels KB, Solomon CG, Hu FB et al (2003) Type 2 Diabetes and subsequent incidence of breast cancer in the nurses’ health study. Diabetes Care 26:1752–1758PubMedGoogle Scholar
  94. 94.
    Milazzo G, Giorgino MG, Damante G et al (1992) Insulin receptor expression and function in human breast cancer cell lines. Cancer Res 52:3924–3930PubMedGoogle Scholar
  95. 95.
    Miyoshi K, Hennighausen L (2003) B-catenin: a transforming actor on many stages. Breast Cancer Res 5:63–68PubMedGoogle Scholar
  96. 96.
    Monami M, Lamanna C, Marchionni N et al (2008) Rosiglitazone and risk of cancer: a meta-analysis of randomized clinical trials. Diabetes Care 31:1455–1460PubMedPubMedCentralGoogle Scholar
  97. 97.
    Monami M, Lamanna C, Balzi D et al (2009) Sulphonylureas and cancer: a case-control study. Acta Diabetol 46:279–284PubMedGoogle Scholar
  98. 98.
    Motoshima H, Goldstein BJ, Igata M et al (2006) AMPK and cell proliferation–AMPK as a therapeutic target for atherosclerosis and cancer. J Physiol 574:63–71PubMedPubMedCentralGoogle Scholar
  99. 99.
    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 106:39–47PubMedPubMedCentralGoogle Scholar
  100. 100.
    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 65:11118–11128Google Scholar
  101. 101.
    Nathan DM, Cleary PA, Backlund BJ et al Diabetes Control and Complications Trial/Epidermiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group (2005) Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353:2643–2653Google Scholar
  102. 102.
    Novosyadlyy R, Vijayakumar A, Lann D et al (2009) Physical and functional interaction between polyoma virus middle T antigen and insulin and IGF-I receptors is required for oncogene activation and tumour initiation. Oncogene 28:3477–3486PubMedPubMedCentralGoogle Scholar
  103. 103.
    Novosyadlyy R, Lann DE, Vijayakumar A et al (2010) Insulin-mediated acceleration of breast cancer development and progeression in a nonobese model of type 2 diabetes. Cancer Res 70:741–751PubMedPubMedCentralGoogle Scholar
  104. 104.
    Olefsky JM, Kolterman OG (1981) Mechanisms of insulin resistance in obesity and noninsulin-dependent (type II) diabetes. Am J Med 70:151–168PubMedGoogle Scholar
  105. 105.
    Osborne CK, Monaco ME, Lippman ME et al (1978) Correlation among insulin binding, degradation, and biological activity in human breast cancer cells in long-term tissue culture. Cancer Res 38:94–102PubMedGoogle Scholar
  106. 106.
    Papa V, Belfiore A (1996) Insulin receptors in breast cancer: biological and clinical role. J Endocrinol Invest 19:324–333PubMedGoogle Scholar
  107. 107.
    Papa V, PezzinoV CA et al (1990) Elevated insulin receptor content in human breast cancer. J Clin Invest 86:1503–1510PubMedPubMedCentralGoogle Scholar
  108. 108.
    Park EJ, Lee JH, Yu GY et al (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing Il-6 and TNF expression. Cell 140:197–208PubMedPubMedCentralGoogle Scholar
  109. 109.
    Pontiggia O, Rodriguez V, Fabris V et al (2009) Establishment of an in vitro estrogen-­dependent mouse mammary tumor model: a new tool to understand estrogen responsiveness and development of tamoxifen resistance in the context of stromal-epithelial interactions. Breast Cancer Res Treat 116:247–255PubMedGoogle Scholar
  110. 110.
    Powell DR, Suwanichkul A, Cubbage ML et al (1991) Insulin inhibits transcription of the human gene for insulin-like growth factor-binding protein-1. J Biol Chem 266:18868–18876PubMedGoogle Scholar
  111. 111.
    Prentice AM, Jebb SA (2003) Fast foods, energy density and obesity: a possible mechanistic link. Obes Rev 4:187–194PubMedGoogle Scholar
  112. 112.
    Rajala MW, Scherer PE (2003) Mini review: The adipocytes at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 144:3765–3773PubMedGoogle Scholar
  113. 113.
    Reaven GM (2004) Insulin resistance and its consequences. In: LeRoith D, Taylor SI (eds) Diabetes mellitus: a fundamental and clinical text. Lippincott, Williams & Wilkins, Philadelphia, pp 899–915Google Scholar
  114. 114.
    Reed MJ, Purohit A (2001) Aromatase regulation and breast cancer. Clin Endocrinol (Oxf) 54:563–571Google Scholar
  115. 115.
    Renehan AG, Frystyk J, Flyvbjerg A (2006) Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol Metab 17:328–336PubMedGoogle Scholar
  116. 116.
    Ridley AJ (1996) Rho: theme and variations. Curr Biol 6:1256–1264PubMedGoogle Scholar
  117. 117.
    Rose DP, Connolly JM (2000) Regulation of tumor angiogenesis by dietary fatty acids and eicosanoids. Nutr Cancer 37:119–127PubMedGoogle Scholar
  118. 118.
    Rose DP, Hatala MA, Connolly JM et al (1993) Effect of diets containing different levels of linoleic acid on human breast cancer growth and lung metastasis in nude mice. Cancer Res 53:4686–4690PubMedGoogle Scholar
  119. 119.
    Rosenstock J, Fonseca V, McGill JB et al (2009) Similar risk of malignancy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: ­findings from a 5 year randomized, open-label study. Diabetologia 52:1971–1973PubMedPubMedCentralGoogle Scholar
  120. 120.
    Rubenstrunk A, Hanf R, Hum DW et al (2007) Safety issues and prospects for future generations of PPAR modulators. Biochim Biophys Acta 1771:1065–1081PubMedGoogle Scholar
  121. 121.
    Shao D, Lazar MA (1999) Modulating nuclear receptor function: may the phos be with you. J Clin Invest 103:1617–1618PubMedPubMedCentralGoogle Scholar
  122. 122.
    Shaw RJ, Lamia KA, Vasquez D et al (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310:1642–1646PubMedPubMedCentralGoogle Scholar
  123. 123.
    Shi H, Kokoeva V, Inouye K et al (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116:3015–3025PubMedPubMedCentralGoogle Scholar
  124. 124.
    Sinagra D, Amato C, Scarpilta AM et al (2002) Metabolic syndrome and breast cancer risk. Eur Rev Med Pharmacol Sci 6:55–59PubMedGoogle Scholar
  125. 125.
    Smith U, Gale EAM (2009) Does diabetes therapy influence the risk of cancer? Diabetologia 52:1699–1708PubMedGoogle Scholar
  126. 126.
    Somasundar P, McFadden DW, Hileman SM et al (2004) Leptin as a growth factor in cancer. J Surg Res 116:337–349PubMedGoogle Scholar
  127. 127.
    Stambolic V, Suzuki A, de la Pompa JL et al (1998) Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95:29–39PubMedGoogle Scholar
  128. 128.
    Sun J, Khalid S, Rozakis-Adcock M et al (2009) p-21 activated protein kinase-1 function as a linker between insulin and Wnt signaling pathways in the intestine. Oncogene 28:3132–3144PubMedGoogle Scholar
  129. 129.
    Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signaling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7:85–96PubMedPubMedCentralGoogle Scholar
  130. 130.
    Thompson JE, Thompson CB (2004) Putting the rap on Akt. J Clin Oncol 22:4217–4226PubMedGoogle Scholar
  131. 131.
    Tlsty TD, Coussens LM (2006) Tumor stroma and regulation of cancer development. Annu Rev Pathol 1:119–150PubMedGoogle Scholar
  132. 132.
    Trayhum P, Woods IS (2004) Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 92:347–355Google Scholar
  133. 133.
    Trimboli AJ, Cantemir-Stone CZ, Li F et al (2009) PTEN in stromal fibroblasts suppresses mammary epithelial tumours. Nature 461:1084–1091PubMedPubMedCentralGoogle Scholar
  134. 134.
    Uauy R, Diaz E (2005) Consequences of food energy excess and positive energy balance. Public Health Nutr 8:1077–1099PubMedGoogle Scholar
  135. 135.
    Ulanet DB, Ludwig DL, Kahn CR et al (2009) Insulin receptor functionally enhances ­multistage tumor progression and conveys instrinsic resistance to IGF-R targeted therapy. Proc Natl Acad Sci USA 107:10791–10798Google Scholar
  136. 136.
    Verheus M, Peeters PH, Rinaldi S et al (2006) Serum C-peptide levels and breast cancer risk: results from the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer 119:659–667PubMedGoogle Scholar
  137. 137.
    Vigneri P, Frasca F, Sciacca L et al (2009) Diabetes and Cancer. Endocr Relat Cancer 16:1103–1123PubMedGoogle Scholar
  138. 138.
    Virkamaki A, Ueki K, Kahn CR (1999) Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest 103:931–943PubMedPubMedCentralGoogle Scholar
  139. 139.
    Vona-Davis L, Rose DP (2007) Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Relat Cancer 14:189–206PubMedGoogle Scholar
  140. 140.
    Wang D, Patel S, Li W et al (2002) Activation of the TGF-alpha autocrine loop in downstream of IGF-1 receptor activation during mitogenesis in growth factor dependent human colon ­carcinoma cells. Oncogene 21:2785–2796PubMedGoogle Scholar
  141. 141.
    Wang Y, Lam JB, Lam KSL et al (2006) Adiponectin modulates the glycogen synthase kinase-3beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice. Cancer Res 66:11462–11470PubMedGoogle Scholar
  142. 142.
    Wang Y, Lam KS, Xu A (2007) Adiponectin as a negative regulator in obesity-related ­mammary carcinogenesis. Cell Res 17:280–282PubMedGoogle Scholar
  143. 143.
    WCRF/AICR. Food, nutrition, physical activity, and the prevention of cancer: a global ­perspective (report online). World Cancer Research Fund, American Institute for Cancer Research, London. http://www.dietandcancerreport.org
  144. 144.
    Wei M, Gaskill SP, Haffner SM et al (1997) Waist circumference as the best predictor of noninsulin dependent diabetes mellitus (NIDDM) compared to body mass index, waist/hip ratio and other anthropometric measurements in Mexican Americans – a 7-year prospective study. Obes Res 5:16–23PubMedGoogle Scholar
  145. 145.
    Weiderpass E, Gridley G, Persson I et al (1997) Risk of endometrial and breast cancer in patients with diabetes mellitus. Int J Cancer 71:360–363PubMedGoogle Scholar
  146. 146.
    Weinstein D, Simon M, Yehezkel E et al (2009) Insulin analogues display IGFD-1-like ­mitogenic and anti-apoptotic activities in cultured cancer cells. Diabetes Metab Res Rev 25:41–49PubMedGoogle Scholar
  147. 147.
    Wellen KE, Hotamisligil GS (2003) Obesity-induced inflammatory changes in adipose tissue. J Clin Invest 112:1785–1788PubMedPubMedCentralGoogle Scholar
  148. 148.
    Yee D, Lee AV (2000) Crosstalk between the insulin-like growth factors and estrogens in breast cancer. J Mammary Gland Biol Neoplasia 5:107–115PubMedGoogle Scholar
  149. 149.
    Yi F, Sun J, Lim GE et al (2008) Crosst6alk between the insulin and Wnt signaling pathways: evidence from intestinal endocrine L cells. Endocrinology 149:2341–2351PubMedGoogle Scholar
  150. 150.
    Yu H, Pardoll D, Jove R (2009) Stats in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809PubMedPubMedCentralGoogle Scholar
  151. 151.
    Zakikhani M, Dowling R, Fantus IG et al (2006) Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 66:10269–10273PubMedGoogle Scholar
  152. 152.
    Zhang H, Fagan DH, Zeng X et al (2010) Inhibition of cancer cell proliferation and metastasis by insulin receptor downregulation. Oncogene 29:2517l–2527lGoogle Scholar
  153. 153.
    Zhou G, Myers R, Li Y et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174PubMedPubMedCentralGoogle Scholar
  154. 154.
    Zhuang Y, Miskimins WK (2008) Cell cycle arrest in metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1. J Mol Signal 3:18. doi: 10.1186/1750-2187-3-18 CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Zielinski R, Przytycki PF, Zheng J et al (2009) The crosstalk between EGF, IGF, and Insulin cell signaling pathways – computational and experimental analysis. BMC Syst Biol 3:88. doi: 10.1186/1752-0509-3-88 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Yael Babichev
    • 1
    • 2
  • Sarah Khalid
    • 1
    • 3
  • I. George Fantus
    • 1
    • 2
    • 3
    Email author
  1. 1.Division of Cellular and Molecular Biology, Toronto General Research InstituteUniversity Health Network and Banting and Best Diabetes CentreTorontoCanada
  2. 2.Centre for Modeling Human DiseaseSamuel Lunenfeld Research Institute, Mount Sinai HospitalTorontoCanada
  3. 3.Departments of Medicine and PhysiologyUniversity of TorontoTorontoCanada

Personalised recommendations