Skip to main content
SpringerLink
Log in

Potential Mechanisms Linking Insulin to Cancer

  • Chapter
  • First Online:
Insulin Resistance and Cancer

Part of the book series: Energy Balance and Cancer ((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).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801

    CAS  PubMed  Google Scholar 

  2. Alberti KG, Zimmet P, Shaw J, IDF Epidemiology Task Force Consensus (2005) The metabolic syndrome: a new worldwide definition. Lancet 366:1059–1062

    PubMed  Google Scholar 

  3. Belfiore A (2007) The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer. Curr Pharm Des 13:671–686

    CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 13:1163–1172

    CAS  PubMed  Google Scholar 

  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 29:254–258

    PubMed  Google Scholar 

  7. Brown JR, DuBois RN (2005) Cox-2: a molecular target for colorectal cancer prevention. J Clin Oncol 23:2840–2855

    CAS  PubMed  Google Scholar 

  8. Brown KA, Simpson ER (2010) Obesity and breast cancer: progress to understanding the relationship. Cancer Res 70:4–7

    CAS  PubMed  Google Scholar 

  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 79:391–397

    CAS  PubMed  Google Scholar 

  10. Calle EE, Kaaks R (2004) Overweight, obesity, and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4:579–591

    CAS  PubMed  Google Scholar 

  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 348:1625–1638

    PubMed  Google Scholar 

  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–R579

    PubMed  PubMed Central  Google Scholar 

  13. Carroll KK, Braden LM (1984) Dietary fat and mammary carcinogenesis. Nutr Cancer 6:254–259

    CAS  PubMed  Google Scholar 

  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 43:3559–3562

    CAS  PubMed  Google Scholar 

  15. Casey PJ (1995) Protein lipidation in cell signaling. Science 268:221–225

    CAS  PubMed  Google Scholar 

  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 18:701–705

    CAS  Google Scholar 

  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 15:707–719

    PubMed  Google Scholar 

  18. Chappell J, Golovchenko I, Wall K et al (2000) Potentiation of Rho-A-mediated lysophosphatidic acid activity by hyperinsulinemia. J Biol Chem 275:31792–31797

    CAS  PubMed  Google Scholar 

  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 276:38023–38028

    CAS  PubMed  Google Scholar 

  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 216:28–43

    CAS  PubMed  Google Scholar 

  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 28:956–962

    CAS  PubMed  Google Scholar 

  22. Clemons M, Goss P (2001) Estrogen and the risk of breast cancer. N Engl J Med 344:276–285

    CAS  PubMed  Google Scholar 

  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 52:1755–1765

    Google Scholar 

  24. Cowey S, Hardy RW (2006) The metabolic syndrome: A high-risk state for cancer? Am J Pathol 169:1505–1522

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Currie CJ, Poole CD, Gale EAM (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52:1766–1777

    CAS  PubMed  Google Scholar 

  26. DeBerardinis RJ, Lum JJ, Hatzivassiliou G et al (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7:11–20

    CAS  PubMed  Google Scholar 

  27. Del Giudice ME, Fantus IG, Ezzat S et al (1998) Insulin and related factors in premenopausal breast cancer risk. Breast Cancer Res Treat 47:111–120

    PubMed  Google Scholar 

  28. Despres JP (2001) Health consequences of visceral obesity. Ann Med 33:534–541

    CAS  PubMed  Google Scholar 

  29. DiCristofanoA PPP (2000) The multiple roles of PTEN in tumor suppression. Cell 100:387–390

    Google Scholar 

  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 345:271–279

    CAS  PubMed  Google Scholar 

  31. Ding VW, Chen RH, McCormick F (2000) Differential regulation of glycogen synthase kinase 3B by insulin and Wnt signaling. J Biol Chem 275:32475–32481

    CAS  PubMed  Google Scholar 

  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 67:10804–10812

    CAS  PubMed  Google Scholar 

  33. Eckel RH, Grundy SM, Zimmet PZ (2005) The metabolic syndrome. Lancet 365:1415–1428

    CAS  PubMed  Google Scholar 

  34. Evans JM, Donnelly LA, Emslie-Smith AM et al (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304–1305

    PubMed  PubMed Central  Google Scholar 

  35. Fierz Y, Novosyadlyy R, Vijayakumar A et al (2010) Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression. Diabetes 59:686–693

    CAS  PubMed  Google Scholar 

  36. Firth SM, Baxter RC (2002) Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 23:824–854

    CAS  PubMed  Google Scholar 

  37. Flegal KM, Carroll MD, Ogden CL et al (2010) Prevalence and trends in obesity among US adults, 1999–2008. JAMA 303:235–241

    CAS  PubMed  Google Scholar 

  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 19:3278–3288

    CAS  PubMed  PubMed Central  Google Scholar 

  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 45:141–147

    CAS  PubMed  Google Scholar 

  40. Gallagher EJ, LeRoith D (2010) The proliferating role of insulin and insulin-like growth ­factors in cancer. Trends Endocrinol Metab 21:610–618

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Gerstein HC (2010) Does insulin therapy promote, reduce or have a neutral effect on cancers. JAMA 303:446–447

    CAS  PubMed  Google Scholar 

  42. Giovannucci E, Harlan DM, Archer MC et al (2010) Diabetes and cancer: A consensus report. Diabetes Care 33:1674–1685

    PubMed  PubMed Central  Google Scholar 

  43. Giovanucci E (2001) Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutri 131:3109S–3120S

    Google Scholar 

  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 273:23892–23896

    CAS  PubMed  Google Scholar 

  45. Goalstone ML, Leitner JW, Golovchenko I et al (1999) Insulin promotes phosphorylation and activation of geranyulgeranyltransferase II. J Biol Chem 274:2880–2884

    CAS  PubMed  Google Scholar 

  46. Goalstone ML, Leitner JW, Berhanu P et al (2001) Insulin signals to prenyltransferases via the Shc branch of intracellular signaling. J Biol Chem 276:12805–12812

    CAS  PubMed  Google Scholar 

  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 20:42–51

    CAS  PubMed  Google Scholar 

  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 23:6037–6042

    CAS  PubMed  Google Scholar 

  49. Gruber CJ, Tschugguel W, Schneeberger C et al (2002) Production and actions of estrogens. N Engl J Med 346:340–352

    CAS  PubMed  Google Scholar 

  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 118:2609–2619

    CAS  PubMed  PubMed Central  Google Scholar 

  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 101:48–60

    CAS  PubMed  PubMed Central  Google Scholar 

  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 12:954–961

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Hall JM, Couse JF, Korach KS (2001) The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem 276:36869–36872

    CAS  PubMed  Google Scholar 

  54. Hamelers IHL, Steenbergh PH (2003) Interactions between estrogen and insulin-like growth factor signaling pathways in human breast tumor cells. Endocr Relat Cancer 10:331–345

    CAS  PubMed  Google Scholar 

  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 60:6353–6358

    CAS  PubMed  Google Scholar 

  56. Hatsell S, Rowlands T, Hiremath M et al (2003) B-catenin and Tcfs in mammary development and cancer. J Mammary Gland Biol Neoplasia 8:145–158

    PubMed  Google Scholar 

  57. Heiden MG, Cantley CC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033

    Google Scholar 

  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 52:1732–1744

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5:341–354

    CAS  PubMed  Google Scholar 

  60. Ishikawa M, Kitayaama J, Kazama S et al (2005) Plasma adiponectin and gastric cancer. Clin Cancer Res 11:466–472

    CAS  PubMed  Google Scholar 

  61. Iyer A, Fairlie DP, Prins JB et al (2010) Inflammatory lipid mediators in adipocytes function and obesity. Nat Rev Endocrinol 5:71–82

    Google Scholar 

  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 59:1254–1260

    Google Scholar 

  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 104:447–457

    CAS  PubMed  PubMed Central  Google Scholar 

  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 13:485–498

    PubMed  Google Scholar 

  65. Jogie-Brahim S, Feldman D, Oh Y (2009) Unraveling insulin-like growth factor binding protein-3 actions in human disease. Endocr Rev 30:417–437

    CAS  PubMed  PubMed Central  Google Scholar 

  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 52:1745–1754

    CAS  PubMed  Google Scholar 

  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 11:793–814

    CAS  PubMed  Google Scholar 

  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–S51

    CAS  PubMed  Google Scholar 

  69. Kadowaki T, Yamauchi T (2005) Adiponectin and adiponectin receptors. Endocr Rev 26:439–451

    CAS  PubMed  Google Scholar 

  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 6:22–31

    CAS  PubMed  Google Scholar 

  71. Karim R, Tse G, Putti T et al (2004) The significance of the Wnt pathway in the pathology of human cancers. Pathology 36:120–128

    CAS  PubMed  Google Scholar 

  72. Kato S (2001) Estrogen receptor-mediated cross-talk with growth factor signaling pathways. Breast Cancer 8:3–9

    CAS  PubMed  Google Scholar 

  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 122:647–659

    PubMed  Google Scholar 

  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 106:3354–3359

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Kim JK (2006) Fat uses a TOLL-road to connect inflammation and diabetes. Cell Metab 4:417–419

    CAS  PubMed  Google Scholar 

  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 100:1589–1596

    CAS  PubMed  Google Scholar 

  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 111:79–91

    CAS  PubMed  Google Scholar 

  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 49:999–1005

    CAS  PubMed  Google Scholar 

  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 15:267–275

    PubMed  Google Scholar 

  80. Lee MM, Lin SS (2000) Dietary fat and breast cancer. Annu Rev Nutr 20:221–248

    CAS  PubMed  Google Scholar 

  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 23:3281–3282

    Google Scholar 

  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 87:4262–4266

    Google Scholar 

  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 163:2113–2126

    PubMed  PubMed Central  Google Scholar 

  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 98:303–309

    PubMed  Google Scholar 

  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 98:349–356

    PubMed  Google Scholar 

  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 10:33–42

    CAS  PubMed  Google Scholar 

  87. Mantzoros C, Petridou E, Dessypris N et al (2004) Adiponectin and breast cancer risk. J Clin Endocrinol Metab 89:1102–1107

    CAS  PubMed  Google Scholar 

  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 109:565–571

    CAS  PubMed  Google Scholar 

  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 729:161–173

    Google Scholar 

  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 70:685–696

    CAS  PubMed  PubMed Central  Google Scholar 

  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 16:359–371

    CAS  PubMed  Google Scholar 

  92. Michaelson JS, Leder P (2001) B-catenin is a downstream effector of Wnt-mediated tumorigenesis in the mammary gland. Oncogene 20:5093–5099

    CAS  PubMed  Google Scholar 

  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 26:1752–1758

    PubMed  Google Scholar 

  94. Milazzo G, Giorgino MG, Damante G et al (1992) Insulin receptor expression and function in human breast cancer cell lines. Cancer Res 52:3924–3930

    CAS  PubMed  Google Scholar 

  95. Miyoshi K, Hennighausen L (2003) B-catenin: a transforming actor on many stages. Breast Cancer Res 5:63–68

    CAS  PubMed  Google Scholar 

  96. Monami M, Lamanna C, Marchionni N et al (2008) Rosiglitazone and risk of cancer: a meta-analysis of randomized clinical trials. Diabetes Care 31:1455–1460

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Monami M, Lamanna C, Balzi D et al (2009) Sulphonylureas and cancer: a case-control study. Acta Diabetol 46:279–284

    CAS  PubMed  Google Scholar 

  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 574:63–71

    CAS  PubMed  PubMed Central  Google Scholar 

  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 106:39–47

    CAS  PubMed  Google Scholar 

  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 65:11118–11128

    CAS  PubMed  Google Scholar 

  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 353:2643–2653

    Google Scholar 

  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 28:3477–3486

    CAS  PubMed  PubMed Central  Google Scholar 

  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 70:741–751

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Olefsky JM, Kolterman OG (1981) Mechanisms of insulin resistance in obesity and noninsulin-dependent (type II) diabetes. Am J Med 70:151–168

    CAS  PubMed  Google Scholar 

  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 38:94–102

    CAS  PubMed  Google Scholar 

  106. Papa V, Belfiore A (1996) Insulin receptors in breast cancer: biological and clinical role. J Endocrinol Invest 19:324–333

    CAS  PubMed  Google Scholar 

  107. Papa V, PezzinoV CA et al (1990) Elevated insulin receptor content in human breast cancer. J Clin Invest 86:1503–1510

    CAS  PubMed  PubMed Central  Google Scholar 

  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 140:197–208

    CAS  PubMed  PubMed Central  Google Scholar 

  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 116:247–255

    CAS  PubMed  Google Scholar 

  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 266:18868–18876

    CAS  PubMed  Google Scholar 

  111. Prentice AM, Jebb SA (2003) Fast foods, energy density and obesity: a possible mechanistic link. Obes Rev 4:187–194

    CAS  PubMed  Google Scholar 

  112. Rajala MW, Scherer PE (2003) Mini review: The adipocytes at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 144:3765–3773

    CAS  PubMed  Google Scholar 

  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 899–915

    Google Scholar 

  114. Reed MJ, Purohit A (2001) Aromatase regulation and breast cancer. Clin Endocrinol (Oxf) 54:563–571

    CAS  Google Scholar 

  115. Renehan AG, Frystyk J, Flyvbjerg A (2006) Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol Metab 17:328–336

    CAS  PubMed  Google Scholar 

  116. Ridley AJ (1996) Rho: theme and variations. Curr Biol 6:1256–1264

    CAS  PubMed  Google Scholar 

  117. Rose DP, Connolly JM (2000) Regulation of tumor angiogenesis by dietary fatty acids and eicosanoids. Nutr Cancer 37:119–127

    CAS  PubMed  Google Scholar 

  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 53:4686–4690

    CAS  PubMed  Google Scholar 

  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 52:1971–1973

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Rubenstrunk A, Hanf R, Hum DW et al (2007) Safety issues and prospects for future generations of PPAR modulators. Biochim Biophys Acta 1771:1065–1081

    CAS  PubMed  Google Scholar 

  121. Shao D, Lazar MA (1999) Modulating nuclear receptor function: may the phos be with you. J Clin Invest 103:1617–1618

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Shaw RJ, Lamia KA, Vasquez D et al (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310:1642–1646

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Shi H, Kokoeva V, Inouye K et al (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116:3015–3025

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Sinagra D, Amato C, Scarpilta AM et al (2002) Metabolic syndrome and breast cancer risk. Eur Rev Med Pharmacol Sci 6:55–59

    CAS  PubMed  Google Scholar 

  125. Smith U, Gale EAM (2009) Does diabetes therapy influence the risk of cancer? Diabetologia 52:1699–1708

    CAS  PubMed  Google Scholar 

  126. Somasundar P, McFadden DW, Hileman SM et al (2004) Leptin as a growth factor in cancer. J Surg Res 116:337–349

    CAS  PubMed  Google Scholar 

  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 95:29–39

    CAS  PubMed  Google Scholar 

  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 28:3132–3144

    CAS  PubMed  Google Scholar 

  129. Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signaling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7:85–96

    CAS  PubMed  Google Scholar 

  130. Thompson JE, Thompson CB (2004) Putting the rap on Akt. J Clin Oncol 22:4217–4226

    CAS  PubMed  Google Scholar 

  131. Tlsty TD, Coussens LM (2006) Tumor stroma and regulation of cancer development. Annu Rev Pathol 1:119–150

    CAS  PubMed  Google Scholar 

  132. Trayhum P, Woods IS (2004) Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 92:347–355

    Google Scholar 

  133. Trimboli AJ, Cantemir-Stone CZ, Li F et al (2009) PTEN in stromal fibroblasts suppresses mammary epithelial tumours. Nature 461:1084–1091

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Uauy R, Diaz E (2005) Consequences of food energy excess and positive energy balance. Public Health Nutr 8:1077–1099

    PubMed  Google Scholar 

  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 107:10791–10798

    Google Scholar 

  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 119:659–667

    CAS  PubMed  Google Scholar 

  137. Vigneri P, Frasca F, Sciacca L et al (2009) Diabetes and Cancer. Endocr Relat Cancer 16:1103–1123

    CAS  PubMed  Google Scholar 

  138. Virkamaki A, Ueki K, Kahn CR (1999) Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest 103:931–943

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Vona-Davis L, Rose DP (2007) Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Relat Cancer 14:189–206

    CAS  PubMed  Google Scholar 

  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 21:2785–2796

    CAS  PubMed  Google Scholar 

  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 66:11462–11470

    CAS  PubMed  Google Scholar 

  142. Wang Y, Lam KS, Xu A (2007) Adiponectin as a negative regulator in obesity-related ­mammary carcinogenesis. Cell Res 17:280–282

    CAS  PubMed  Google Scholar 

  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. 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 5:16–23

    CAS  PubMed  Google Scholar 

  145. Weiderpass E, Gridley G, Persson I et al (1997) Risk of endometrial and breast cancer in patients with diabetes mellitus. Int J Cancer 71:360–363

    CAS  PubMed  Google Scholar 

  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 25:41–49

    CAS  PubMed  Google Scholar 

  147. Wellen KE, Hotamisligil GS (2003) Obesity-induced inflammatory changes in adipose tissue. J Clin Invest 112:1785–1788

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Yee D, Lee AV (2000) Crosstalk between the insulin-like growth factors and estrogens in breast cancer. J Mammary Gland Biol Neoplasia 5:107–115

    CAS  PubMed  Google Scholar 

  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 149:2341–2351

    CAS  PubMed  Google Scholar 

  150. Yu H, Pardoll D, Jove R (2009) Stats in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Zakikhani M, Dowling R, Fantus IG et al (2006) Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 66:10269–10273

    CAS  PubMed  Google Scholar 

  152. Zhang H, Fagan DH, Zeng X et al (2010) Inhibition of cancer cell proliferation and metastasis by insulin receptor downregulation. Oncogene 29:2517l–2527l

    Google Scholar 

  153. Zhou G, Myers R, Li Y et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network and Banting and Best Diabetes Centre, Toronto, ON, Canada

    Yael Babichev, Sarah Khalid & I. George Fantus

  2. Centre for Modeling Human Disease, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada

    Yael Babichev & I. George Fantus

  3. Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada

    Sarah Khalid & I. George Fantus

Authors
  1. Yael Babichev
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarah Khalid
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. George Fantus
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I. George Fantus .

Editor information

Editors and Affiliations

  1. Mount Sinai Hospital, Dept. Medicine, University of Toronto, Murray St. 60, Toronto, M5T 3L9, Ontario, Canada

    I. George Fantus

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Babichev, Y., Khalid, S., Fantus, I.G. (2011). Potential Mechanisms Linking Insulin to Cancer. In: Fantus, I. (eds) Insulin Resistance and Cancer. Energy Balance and Cancer, vol 1. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9911-5_7

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-9911-5_7

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4419-9910-8

  • Online ISBN: 978-1-4419-9911-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation