Metabolic Syndrome, Type 2 Diabetes, and Cancer: Epidemiology and Potential Mechanisms

  • Sarit Ben-Shmuel
  • Ran Rostoker
  • Eyal J. Scheinman
  • Derek LeRoithEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 233)


Obesity is associated with multiple metabolic disorders that drive cardiovascular disease, T2D and cancer. The doubling in the number of obese adults over the past 3 decades led to the recognition of obesity as a “disease”. With over 42 million children obese or overweight, this epidemic is rapidly growing worldwide. Obesity and T2D are both associated together and independently with an increased risk for cancer and a worse prognosis. Accumulating evidence from epidemiological studies revealed potential factors that may explain the association between obesity-linked metabolic disorders and cancer risk. Studies based on the insulin resistance MKR mice, highlighted the roe of the insulin receptor and its downstream signaling proteins in mediating hyperinsulinemia's mitogenic effects. Hypercholesterolemia was also shown to promote the formation of larger tumors and enhancement in metastasis. Furthermore, the conversion of cholesterol into 27-Hydroxycholesterol was found to link high fat diet-induced hypercholesterolemia with cancer pathophysiology. Alteration in circulating adipokines and cytokines are commonly found in obesity and T2D. Adipokines are involved in tumor growth through multiple mechanisms including mTOR, VEGF and cyclins. In addition, adipose tissues are known to recruit and alter macrophage phenotype; these macrophages can promote cancer progression by secreting inflammatory cytokines such as TNF-α and IL-6.

Better characterization on the above factors and their downstream effects is required in order to translate the current knowledge into the clinic, but more importantly is to understand which are the key factors that drive cancer in each patient. Until we reach this point, policies and activities toward healthy diets and physical activities remain the best medicine.


Cancer Hyperinsulinemia Obesity 


  1. Adams TD, Stroup AM, Gress RE, Adams KF, Calle EE, Smith SC, Halverson RC, Simper SC, Hopkins PN, Hunt SC (2009) Cancer incidence and mortality after gastric bypass surgery. Obesity (Silver Spring) 17:796–802CrossRefGoogle Scholar
  2. Algire C, Amrein L, Zakikhani M, Panasci L, Pollak M (2010) Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer 17:351–360PubMedCrossRefGoogle Scholar
  3. Alikhani N, Ferguson RD, Novosyadlyy R, Gallagher EJ, Scheinman EJ, Yakar S, LeRoith D (2013) Mammary tumor growth and pulmonary metastasis are enhanced in a hyperlipidemic mouse model. Oncogene 32:961–967PubMedPubMedCentralCrossRefGoogle Scholar
  4. Antalis CJ, Uchida A, Buhman KK, Siddiqui RA (2011) Migration of MDA-MB-231 breast cancer cells depends on the availability of exogenous lipids and cholesterol esterification. Clin Exp Metastasis 28:733–741PubMedCrossRefGoogle Scholar
  5. Arnlov J, Sundstrom J, Ingelsson E, Lind L (2011) Impact of BMI and the metabolic syndrome on the risk of diabetes in middle-aged men. Diabetes Care 34:61–65PubMedPubMedCentralCrossRefGoogle Scholar
  6. Berentzen TL, Gamborg M, Holst C, Sorensen TI, Baker JL (2014) Body mass index in childhood and adult risk of primary liver cancer. J Hepatol 60:325–330PubMedCrossRefGoogle Scholar
  7. Blando J, Moore T, Hursting S, Jiang G, Saha A, Beltran L, Shen J, Repass J, Strom S, DiGiovanni J (2011) Dietary energy balance modulates prostate cancer progression in Hi-Myc mice. Cancer Prev Res (Phila) 4:2002–2014CrossRefGoogle Scholar
  8. Bonovas S, Filioussi K, Tsantes A (2004) Diabetes mellitus and risk of prostate cancer: a meta-analysis. Diabetologia 47:1071–1078PubMedCrossRefGoogle Scholar
  9. Borowsky AD, Namba R, Young LJ, Hunter KW, Hodgson JG, Tepper CG, McGoldrick ET, Muller WJ, Cardiff RD, Gregg JP (2005) Syngeneic mouse mammary carcinoma cell lines: two closely related cell lines with divergent metastatic behavior. Clin Exp Metastasis 22:47–59PubMedCrossRefGoogle Scholar
  10. Bruning PF, Bonfrer JM, van Noord PA, Hart AA, de Jong-Bakker M, Nooijen WJ (1992) Insulin resistance and breast-cancer risk. Int J Cancer 52:511–516PubMedCrossRefGoogle Scholar
  11. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625–1638PubMedCrossRefGoogle Scholar
  12. Campbell MJ, Wollish WS, Lobo M, Esserman LJ (2002) Epithelial and fibroblast cell lines derived from a spontaneous mammary carcinoma in a MMTV/neu transgenic mouse. In Vitro Cell Dev Biol Anim 38:326–333PubMedCrossRefGoogle Scholar
  13. Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH (2003) Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988–1994. Arch Pediatr Adolesc Med 157:821–827PubMedCrossRefGoogle Scholar
  14. Cornier MA, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, Van Pelt RE, Wang H, Eckel RH (2008) The metabolic syndrome. Endocr Rev 29:777–822PubMedCrossRefGoogle Scholar
  15. Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ (2004) Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol 159:1160–1167PubMedCrossRefGoogle Scholar
  16. Crawford ED (2009) Understanding the epidemiology, natural history, and key pathways involved in prostate cancer. Urology 73:S4–S10PubMedCrossRefGoogle Scholar
  17. Del Prete A, Allavena P, Santoro G, Fumarulo R, Corsi MM, Mantovani A (2011) Molecular pathways in cancer-related inflammation. Biochem Med (Zagreb) 21:264–275CrossRefGoogle Scholar
  18. Djiogue S, Nwabo Kamdje AH, Vecchio L, Kipanyula MJ, Farahna M, Aldebasi Y, Seke Etet PF (2013) Insulin resistance and cancer: the role of insulin and IGFs. Endocr Relat Cancer 20:R1–R17PubMedCrossRefGoogle Scholar
  19. Dunlap SM, Chiao LJ, Nogueira L, Usary J, Perou CM, Varticovski L, Hursting SD (2012) Dietary energy balance modulates epithelial-to-mesenchymal transition and tumor progression in murine claudin-low and basal-like mammary tumor models. Cancer Prev Res (Phila) 5:930–942CrossRefGoogle Scholar
  20. Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA (2013) Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer 13:759–771PubMedCrossRefGoogle Scholar
  21. Ewens A, Mihich E, Ehrke MJ (2005) Distant metastasis from subcutaneously grown E0771 medullary breast adenocarcinoma. Anticancer Res 25:3905–3915PubMedGoogle Scholar
  22. Ferguson RD, Gallagher EJ, Scheinman EJ, Damouni R, LeRoith D (2013) The epidemiology and molecular mechanisms linking obesity, diabetes, and cancer. Vitam Horm 93:51–98PubMedCrossRefGoogle Scholar
  23. Fierz Y, Novosyadlyy R, Vijayakumar A, Yakar S, LeRoith D (2010a) Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression. Diabetes 59:686–693PubMedPubMedCentralCrossRefGoogle Scholar
  24. Fierz Y, Novosyadlyy R, Vijayakumar A, Yakar S, LeRoith D (2010b) Mammalian target of rapamycin inhibition abrogates insulin-mediated mammary tumor progression in type 2 diabetes. Endocr Relat Cancer 17:941–951PubMedPubMedCentralCrossRefGoogle Scholar
  25. Folsom AR, Anderson KE, Sweeney C, Jacobs DR Jr (2004) Diabetes as a risk factor for death following endometrial cancer. Gynecol Oncol 94:740–745PubMedCrossRefGoogle Scholar
  26. Ford NA, Nunez NP, Holcomb VB, Hursting SD (2013) IGF1 dependence of dietary energy balance effects on murine Met1 mammary tumor progression, epithelial-to-mesenchymal transition, and chemokine expression. Endocr Relat Cancer 20:39–51PubMedCrossRefGoogle Scholar
  27. Franzese A, Vajro P, Argenziano A, Puzziello A, Iannucci MP, Saviano MC, Brunetti F, Rubino A (1997) Liver involvement in obese children. Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population. Dig Dis Sci 42:1428–1432PubMedCrossRefGoogle Scholar
  28. Fujisawa T, Endo H, Tomimoto A, Sugiyama M, Takahashi H, Saito S, Inamori M, Nakajima N, Watanabe M, Kubota N, Yamauchi T, Kadowaki T, Wada K, Nakagama H, Nakajima A (2008) Adiponectin suppresses colorectal carcinogenesis under the high-fat diet condition. Gut 57:1531–1538PubMedPubMedCentralCrossRefGoogle Scholar
  29. Gallagher EJ, Fierz Y, Vijayakumar A, Haddad N, Yakar S, LeRoith D (2012) Inhibiting PI3K reduces mammary tumor growth and induces hyperglycemia in a mouse model of insulin resistance and hyperinsulinemia. Oncogene 31:3213–3222PubMedPubMedCentralCrossRefGoogle Scholar
  30. Gomez-Diaz RA, Talavera JO, Pool EC, Ortiz-Navarrete FV, Solorzano-Santos F, Mondragon-Gonzalez R, Valladares-Salgado A, Cruz M, Aguilar-Salinas CA, Wacher NH (2012) Metformin decreases plasma resistin concentrations in pediatric patients with impaired glucose tolerance: a placebo-controlled randomized clinical trial. Metabolism 61:1247–1255PubMedCrossRefGoogle Scholar
  31. Grossmann ME, Cleary MP (2012) The balance between leptin and adiponectin in the control of carcinogenesis - focus on mammary tumorigenesis. Biochimie 94:2164–2171PubMedPubMedCentralCrossRefGoogle Scholar
  32. Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Rohan TE, Manson JE, Li J, Ho GY, Xue X, Anderson GL, Kaplan RC, Harris TG, Howard BV, Wylie-Rosett J, Burk RD, Strickler HD (2009) Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 101:48–60PubMedPubMedCentralCrossRefGoogle Scholar
  33. Gunther EJ, Belka GK, Wertheim GB, Wang J, Hartman JL, Boxer RB, Chodosh LA (2002) A novel doxycycline-inducible system for the transgenic analysis of mammary gland biology. FASEB J 16:283–292PubMedCrossRefGoogle Scholar
  34. 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 12:954–961PubMedPubMedCentralCrossRefGoogle Scholar
  35. Hadsell DL, Greenberg NM, Fligger JM, Baumrucker CR, Rosen JM (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
  36. Haslam DW, James WP (2005) Obesity. Lancet 366:1197–1209PubMedCrossRefGoogle Scholar
  37. Howe LR, Subbaramaiah K, Hudis CA, Dannenberg AJ (2013) Molecular pathways: adipose inflammation as a mediator of obesity-associated cancer. Clin Cancer Res 19:6074–6083PubMedPubMedCentralCrossRefGoogle Scholar
  38. Huang Z, Willett WC, Colditz GA, Hunter DJ, Manson JE, Rosner B, Speizer FE, Hankinson SE (1999) Waist circumference, waist:hip ratio, and risk of breast cancer in the Nurses' Health Study. Am J Epidemiol 150:1316–1324PubMedCrossRefGoogle Scholar
  39. Imamura N, Yanagihara K, Kusunoki Y (1984) Tumor-associated antigen of spontaneous mammary tumor in rats. Oncology 41:206–209PubMedCrossRefGoogle Scholar
  40. Isaksson B, Strommer L, Friess H, Buchler MW, Herrington MK, Wang F, Zierath JR, Wallberg-Henriksson H, Larsson J, Permert J (2003) Impaired insulin action on phosphatidylinositol 3-kinase activity and glucose transport in skeletal muscle of pancreatic cancer patients. Pancreas 26:173–177PubMedCrossRefGoogle Scholar
  41. Jaggers JR, Sui X, Hooker SP, LaMonte MJ, Matthews CE, Hand GA, Blair SN (2009) Metabolic syndrome and risk of cancer mortality in men. Eur J Cancer 45:1831–1838PubMedPubMedCentralCrossRefGoogle Scholar
  42. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66PubMedCrossRefGoogle Scholar
  43. Kasper JS, Giovannucci E (2006) A meta-analysis of diabetes mellitus and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 15:2056–2062PubMedCrossRefGoogle Scholar
  44. Kawashima Y, Chen J, Sun H, Lann D, Hajjar RJ, Yakar S, Leroith D (2009) Apolipoprotein E deficiency abrogates insulin resistance in a mouse model of type 2 diabetes mellitus. Diabetologia 52:1434–1441PubMedCrossRefGoogle Scholar
  45. Kelesidis I, Kelesidis T, Mantzoros CS (2006) Adiponectin and cancer: a systematic review. Br J Cancer 94:1221–1225PubMedPubMedCentralCrossRefGoogle Scholar
  46. Kim H, Pennisi PA, Gavrilova O, Pack S, Jou W, Setser-Portas J, East-Palmer J, Tang Y, Manganiello VC, Leroith D (2006) Effect of adipocyte beta3-adrenergic receptor activation on the type 2 diabetic MKR mice. Am J Physiol Endocrinol Metab 290:E1227–E1236PubMedCrossRefGoogle Scholar
  47. Körner A, Kratzsch J, Kiess W (2006) Effect of adiponectin on proliferation of breast cancer cells. Exp Clin Endocrinol Diabetes 114:P03_043Google Scholar
  48. Kushiro K, Nunez NP (2011) Ob/ob serum promotes a mesenchymal cell phenotype in B16BL6 melanoma cells. Clin Exp Metastasis 28:877–886PubMedCrossRefGoogle Scholar
  49. Lanari C, Lamb CA, Fabris VT, Helguero LA, Soldati R, Bottino MC, Giulianelli S, Cerliani JP, Wargon V, Molinolo A (2009) The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer. Endocr Relat Cancer 16:333–350PubMedCrossRefGoogle Scholar
  50. Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA (2014) Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res 2014:149185PubMedPubMedCentralCrossRefGoogle Scholar
  51. Larsson O, Morita M, Topisirovic I, Alain T, Blouin MJ, Pollak M, Sonenberg N (2012) Distinct perturbation of the translatome by the antidiabetic drug metformin. Proc Natl Acad Sci U S A 109:8977–8982PubMedPubMedCentralCrossRefGoogle Scholar
  52. Lashinger LM, Harrison LM, Rasmussen AJ, Logsdon CD, Fischer SM, McArthur MJ, Hursting SD (2013) Dietary energy balance modulation of Kras- and Ink4a/Arf+/–driven pancreatic cancer: the role of insulin-like growth factor-I. Cancer Prev Res (Phila) 6:1046–1055CrossRefGoogle Scholar
  53. Lee AV, Yee D (1995) Insulin-like growth factors and breast cancer. Biomed Pharmacother 49:415–421PubMedCrossRefGoogle Scholar
  54. Levine AJ, Feng Z, Mak TW, You H, Jin S (2006) Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev 20:267–275PubMedCrossRefGoogle Scholar
  55. Liu J, Xu A, Lam KS, Wong NS, Chen J, Shepherd PR, Wang Y (2013) Cholesterol-induced mammary tumorigenesis is enhanced by adiponectin deficiency: role of LDL receptor upregulation. Oncotarget 4:1804–1818PubMedPubMedCentralCrossRefGoogle Scholar
  56. Ma J, Li H, Giovannucci E, Mucci L, Qiu W, Nguyen PL, Gaziano JM, Pollak M, Stampfer MJ (2008) Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis. Lancet Oncol 9:1039–1047PubMedPubMedCentralCrossRefGoogle Scholar
  57. McHenry PR, Sears JC, Herrick MP, Chang P, Heckman-Stoddard BM, Rybarczyk M, Chodosh LA, Gunther EJ, Hilsenbeck SG, Rosen JM, Vargo-Gogola T (2010) P190B RhoGAP has pro-tumorigenic functions during MMTV-Neu mammary tumorigenesis and metastasis. Breast Cancer Res 12:R73PubMedPubMedCentralCrossRefGoogle Scholar
  58. McNamara KM, Sasano H (2015) The intracrinology of breast cancer. J Steroid Biochem Mol Biol. Ahead of print 145:172–178Google Scholar
  59. Michels KB, Solomon CG, Hu FB, Rosner BA, Hankinson SE, Colditz GA, Manson JE, Nurses’ Health S (2003) Type 2 diabetes and subsequent incidence of breast cancer in the Nurses’ Health Study. Diabetes Care 26:1752–1758Google Scholar
  60. Middleton PJ (1965) The histogenesis of mammary tumours induced in the rat by chemical carcinogens. Br J Cancer 19:830–839PubMedPubMedCentralCrossRefGoogle Scholar
  61. Moon HS, Liu X, Nagel JM, Chamberland JP, Diakopoulos KN, Brinkoetter MT, Hatziapostolou M, Wu Y, Robson SC, Iliopoulos D, Mantzoros CS (2013) Salutary effects of adiponectin on colon cancer: in vivo and in vitro studies in mice. Gut 62:561–570PubMedCrossRefGoogle Scholar
  62. Moore T, Beltran L, Carbajal S, Hursting SD, DiGiovanni J (2012) Energy balance modulates mouse skin tumor promotion through altered IGF-1R and EGFR crosstalk. Cancer Prev Res (Phila) 5:1236–1246CrossRefGoogle Scholar
  63. Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P (1988) Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54:105–115PubMedCrossRefGoogle Scholar
  64. Nalabolu MR, Palasamudram K, Jamil K (2014) Adiponectin and leptin molecular actions and clinical significance in breast cancer. Int J Hematol Oncol Stem Cell Res 8:31–40PubMedPubMedCentralGoogle Scholar
  65. Nelson ER, Wardell SE, Jasper JS, Park S, Suchindran S, Howe MK, Carver NJ, Pillai RV, Sullivan PM, Sondhi V, Umetani M, Geradts J, McDonnell DP (2013) 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 342:1094–1098PubMedPubMedCentralCrossRefGoogle Scholar
  66. Nielsen SF, Nordestgaard BG, Bojesen SE (2012) Statin use and reduced cancer-related mortality. N Engl J Med 367:1792–1802PubMedCrossRefGoogle Scholar
  67. Noto H, Goto A, Tsujimoto T, Osame K, Noda M (2013) Latest insights into the risk of cancer in diabetes. J Diabetes Investig 4:225–232PubMedPubMedCentralCrossRefGoogle Scholar
  68. Novosyadlyy R, LeRoith D (2010) Hyperinsulinemia and type 2 diabetes: impact on cancer. Cell Cycle 9:1449–1450PubMedCrossRefGoogle Scholar
  69. Ntikoudi E, Kiagia M, Boura P, Syrigos KN (2014) Hormones of adipose tissue and their biologic role in lung cancer. Cancer Treat Rev 40:22–30PubMedCrossRefGoogle Scholar
  70. Olivo-Marston SE, Hursting SD, Perkins SN, Schetter A, Khan M, Croce C, Harris CC, Lavigne J (2014) Effects of calorie restriction and diet-induced obesity on murine colon carcinogenesis, growth and inflammatory factors, and microRNA expression. PLoS One 9:e94765PubMedPubMedCentralCrossRefGoogle Scholar
  71. Park J, Scherer PE (2011) Leptin and cancer: from cancer stem cells to metastasis. Endocr Relat Cancer 18:C25–C29PubMedPubMedCentralCrossRefGoogle Scholar
  72. Park MH, Falconer C, Viner RM, Kinra S (2012) The impact of childhood obesity on morbidity and mortality in adulthood: a systematic review. Obes Rev 13:985–1000PubMedCrossRefGoogle Scholar
  73. Pei XF, Noble MS, Davoli MA, Rosfjord E, Tilli MT, Furth PA, Russell R, Johnson MD, Dickson RB (2004) Explant-cell culture of primary mammary tumors from MMTV-c-Myc transgenic mice. In Vitro Cell Dev Biol Anim 40:14–21PubMedCrossRefGoogle Scholar
  74. Pelton K, Freeman MR, Solomon KR (2012) Cholesterol and prostate cancer. Curr Opin Pharmacol 12:751–759PubMedPubMedCentralCrossRefGoogle Scholar
  75. Permert J, Larsson J, Westermark GT, Herrington MK, Christmanson L, Pour PM, Westermark P, Adrian TE (1994) Islet amyloid polypeptide in patients with pancreatic cancer and diabetes. N Engl J Med 330:313–318PubMedCrossRefGoogle Scholar
  76. Petrelli JM, Calle EE, Rodriguez C, Thun MJ (2002) Body mass index, height, and postmenopausal breast cancer mortality in a prospective cohort of US women. Cancer Causes Control 13:325–332PubMedCrossRefGoogle Scholar
  77. Pierobon M, Frankenfeld CL (2013) Obesity as a risk factor for triple-negative breast cancers: a systematic review and meta-analysis. Breast Cancer Res Treat 137:307–314PubMedCrossRefGoogle Scholar
  78. Pisani P (2008) Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem 114:63–70PubMedCrossRefGoogle Scholar
  79. Pothiwala P, Jain SK, Yaturu S (2009) Metabolic syndrome and cancer. Metab Syndr Relat Disord 7:279–288PubMedPubMedCentralCrossRefGoogle Scholar
  80. Prentice RL, Caan B, Chlebowski RT, Patterson R, Kuller LH, Ockene JK, Margolis KL, Limacher MC, Manson JE, Parker LM, Paskett E, Phillips L, Robbins J, Rossouw JE, Sarto GE, Shikany JM, Stefanick ML, Thomson CA, Van Horn L, Vitolins MZ, Wactawski-Wende J, Wallace RB, Wassertheil-Smoller S, Whitlock E, Yano K, Adams-Campbell L, Anderson GL, Assaf AR, Beresford SA, Black HR, Brunner RL, Brzyski RG, Ford L, Gass M, Hays J, Heber D, Heiss G, Hendrix SL, Hsia J, Hubbell FA, Jackson RD, Johnson KC, Kotchen JM, LaCroix AZ, Lane DS, Langer RD, Lasser NL, Henderson MM (2006) Low-fat dietary pattern and risk of invasive breast cancer: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 295:629–642PubMedCrossRefGoogle Scholar
  81. Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D, Million Women Study C (2007) Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. BMJ 335:1134CrossRefGoogle Scholar
  82. Rizner TL (2013) Estrogen biosynthesis, phase I and phase II metabolism, and action in endometrial cancer. Mol Cell Endocrinol 381:124–139PubMedCrossRefGoogle Scholar
  83. Robinson WR, Tse CK, Olshan AF, Troester MA (2014) Body size across the life course and risk of premenopausal and postmenopausal breast cancer in Black women, the Carolina Breast Cancer Study, 1993–2001. Cancer Causes Control. Ahead of print 25(9):1101–1117Google Scholar
  84. Rondini EA, Harvey AE, Steibel JP, Hursting SD, Fenton JI (2011) Energy balance modulates colon tumor growth: Interactive roles of insulin and estrogen. Mol Carcinog 50:370–382PubMedPubMedCentralCrossRefGoogle Scholar
  85. Rostoker R, Bitton-Worms K, Caspi A, Shen-Orr Z, LeRoith D (2013) Investigating new therapeutic strategies targeting hyperinsulinemia’s mitogenic effects in a female mouse breast cancer model. Endocrinology 154:1701–1710PubMedCrossRefGoogle Scholar
  86. Rousseau MC, Parent ME, Pollak MN, Siemiatycki J (2006) Diabetes mellitus and cancer risk in a population-based case-control study among men from Montreal, Canada. Int J Cancer 118:2105–2109PubMedCrossRefGoogle Scholar
  87. Rudling MJ, Stahle L, Peterson CO, Skoog L (1986) Content of low density lipoprotein receptors in breast cancer tissue related to survival of patients. Br Med J (Clin Res Ed) 292:580–582CrossRefGoogle Scholar
  88. Sandgren EP, Schroeder JA, Qui TH, Palmiter RD, Brinster RL, Lee DC (1995) Inhibition of mammary gland involution is associated with transforming growth factor alpha but not c-myc-induced tumorigenesis in transgenic mice. Cancer Res 55:3915–3927PubMedGoogle Scholar
  89. Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C (2006) Prevalence of fatty liver in children and adolescents. Pediatrics 118:1388–1393PubMedCrossRefGoogle Scholar
  90. Sciacca L, Vigneri R, Tumminia A, Frasca F, Squatrito S, Frittitta L, Vigneri P (2013) Clinical and molecular mechanisms favoring cancer initiation and progression in diabetic patients. Nutr Metab Cardiovasc Dis 23:808–815PubMedCrossRefGoogle Scholar
  91. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310:1642–1646PubMedPubMedCentralCrossRefGoogle Scholar
  92. Singh S, Akhtar N, Ahmad J (2012) Plasma adiponectin levels in women with polycystic ovary syndrome: impact of metformin treatment in a case-control study. Diabetes Metab Syndr 6:207–211PubMedCrossRefGoogle Scholar
  93. Sinn E, Muller W, Pattengale P, Tepler I, Wallace R, Leder P (1987) Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell 49:465–475PubMedCrossRefGoogle Scholar
  94. Sirotnak FM, DeGraw JI, Schmid FA, Goutas LJ, Moccio DM (1984) New folate analogs of the 10-deaza-aminopterin series. Further evidence for markedly increased antitumor efficacy compared with methotrexate in ascitic and solid murine tumor models. Cancer Chemother Pharmacol 12:26–30PubMedGoogle Scholar
  95. Sjostrom L, Gummesson A, Sjostrom CD, Narbro K, Peltonen M, Wedel H, Bengtsson C, Bouchard C, Carlsson B, Dahlgren S, Jacobson P, Karason K, Karlsson J, Larsson B, Lindroos AK, Lonroth H, Naslund I, Olbers T, Stenlof K, Torgerson J, Carlsson LM (2009) Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol 10:653–662PubMedCrossRefGoogle Scholar
  96. Somasundar P, Yu AK, Vona-Davis L, McFadden DW (2003) Differential effects of leptin on cancer in vitro. J Surg Res 113:50–55PubMedCrossRefGoogle Scholar
  97. Stewart TA, Pattengale PK, Leder P (1984) Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell 38:627–637PubMedCrossRefGoogle Scholar
  98. Sturmer T, Buring JE, Lee IM, Gaziano JM, Glynn RJ (2006) Metabolic abnormalities and risk for colorectal cancer in the physicians’ health study. Cancer Epidemiol Biomarkers Prev 15:2391–2397PubMedPubMedCentralCrossRefGoogle Scholar
  99. Tseng CH, Tseng FH (2014) Diabetes and gastric cancer: the potential links. World J Gastroenterol 20:1701–1711PubMedPubMedCentralCrossRefGoogle Scholar
  100. Tsukamoto AS, Grosschedl R, Guzman RC, Parslow T, Varmus HE (1988) Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 55:619–625PubMedCrossRefGoogle Scholar
  101. Tzeng YJ, Guhl E, Graessmann M, Graessmann A (1993) Breast cancer formation in transgenic animals induced by the whey acidic protein SV40 T antigen (WAP-SV-T) hybrid gene. Oncogene 8:1965–1971PubMedGoogle Scholar
  102. Uddin S, Hussain AR, Khan OS, Al-Kuraya KS (2014) Role of dysregulated expression of leptin and leptin receptors in colorectal carcinogenesis. Tumour Biol 35:871–879PubMedCrossRefGoogle Scholar
  103. Van Itallie TB (1985) Health implications of overweight and obesity in the United States. Ann Intern Med 103:983–988PubMedCrossRefGoogle Scholar
  104. Vansaun MN (2013) Molecular pathways: adiponectin and leptin signaling in cancer. Clin Cancer Res 19:1926–1932PubMedPubMedCentralCrossRefGoogle Scholar
  105. Verheus M, Peeters PH, Rinaldi S, Dossus L, Biessy C, Olsen A, Tjonneland A, Overvad K, Jeppesen M, Clavel-Chapelon F, Tehard B, Nagel G, Linseisen J, Boeing H, Lahmann PH, Arvaniti A, Psaltopoulou T, Trichopoulou A, Palli D, Tumino R, Panico S, Sacerdote C, Sieri S, van Gils CH, Bueno-de-Mesquita BH, Gonzalez CA, Ardanaz E, Larranaga N, Garcia CM, Navarro C, Quiros JR, Key T, Allen N, Bingham S, Khaw KT, Slimani N, Riboli E, Kaaks R (2006) Serum C-peptide levels and breast cancer risk: results from the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer 119:659–667PubMedCrossRefGoogle Scholar
  106. Verlato G, Zoppini G, Bonora E, Muggeo M (2003) Mortality from site-specific malignancies in type 2 diabetic patients from Verona. Diabetes Care 26:1047–1051PubMedCrossRefGoogle Scholar
  107. Wang L, Di LJ (2014) BRCA1 and estrogen/estrogen receptor in breast cancer: where they interact? Int J Biol Sci 10:563–573Google Scholar
  108. Wang Z, Lai ST, Xie L, Zhao JD, Ma NY, Zhu J, Ren ZG, Jiang GL (2014) Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Res Clin Pract 106(1):19–26Google Scholar
  109. Warburg O (1956) On the origin of cancer cells. Science 123:309–314PubMedCrossRefGoogle Scholar
  110. Weiderpass E, Gridley G, Persson I, Nyren O, Ekbom A, Adami HO (1997) Risk of endometrial and breast cancer in patients with diabetes mellitus. Int J Cancer 71:360–363PubMedCrossRefGoogle Scholar
  111. Weiss R, Dziura J, Burgert TS, Tamborlane WV, Taksali SE, Yeckel CW, Allen K, Lopes M, Savoye M, Morrison J, Sherwin RS, Caprio S (2004) Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 350:2362–2374PubMedCrossRefGoogle Scholar
  112. Williams JC, Gusterson B, Humphreys J, Monaghan P, Coombes RC, Rudland P, Neville AM (1981) N-methyl-N-nitrosourea-induced rat mammary tumors. Hormone responsiveness but lack of spontaneous metastasis. J Natl Cancer Inst 66:147–155PubMedGoogle Scholar
  113. Xu CX, Zhu HH, Zhu YM (2014) Diabetes and cancer: associations, mechanisms, and implications for medical practice. World J Diabetes 5:372–380PubMedPubMedCentralCrossRefGoogle Scholar
  114. Yakar S, Nunez NP, Pennisi P, Brodt P, Sun H, Fallavollita L, Zhao H, Scavo L, Novosyadlyy R, Kurshan N, Stannard B, East-Palmer J, Smith NC, Perkins SN, Fuchs-Young R, Barrett JC, Hursting SD, LeRoith D (2006) Increased tumor growth in mice with diet-induced obesity: impact of ovarian hormones. Endocrinology 147:5826–5834PubMedCrossRefGoogle Scholar
  115. Yancik R, Ganz PA, Varricchio CG, Conley B (2001a) Perspectives on comorbidity and cancer in older patients: approaches to expand the knowledge base. J Clin Oncol 19:1147–1151PubMedGoogle Scholar
  116. Yancik R, Wesley MN, Ries LA, Havlik RJ, Edwards BK, Yates JW (2001b) Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 285:885–892PubMedCrossRefGoogle Scholar
  117. Yang YX, Hennessy S, Lewis JD (2005) Type 2 diabetes mellitus and the risk of colorectal cancer. Clin Gastroenterol Hepatol 3:587–594PubMedCrossRefGoogle Scholar
  118. Zhang P, Li H, Tan X, Chen L, Wang S (2013) Association of metformin use with cancer incidence and mortality: a meta-analysis. Cancer Epidemiol 37:207–218PubMedCrossRefGoogle Scholar
  119. Zhu P, Davis M, Blackwelder AJ, Bachman N, Liu B, Edgerton S, Williams LL, Thor AD, Yang X (2014) Metformin selectively targets tumor-initiating cells in ErbB2-overexpressing breast cancer models. Cancer Prev Res (Phila) 7:199–210CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Sarit Ben-Shmuel
    • 1
  • Ran Rostoker
    • 1
  • Eyal J. Scheinman
    • 1
  • Derek LeRoith
    • 1
    Email author
  1. 1.Clinical Research Institute at Rambam (CRIR), Diabetes and Metabolism Clinical Research Center of ExcellenceHaifaIsrael

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