The Increased Risk of Cancer in Obesity and Type 2 Diabetes: Potential Mechanisms

  • Emily J. GallagherEmail author
  • Brian A. Neel
  • Irini M. Antoniou
  • Shoshana Yakar
  • Derek LeRoith
Reference work entry


Theories on a connection between diabetes, obesity, and cancer have existed for over a century. In 1910, despite their elusive etiologies, Maynard hypothesized that a correlation between diabetes and cancer could exist, as both conditions were increasing in prevalence and had similar age distributions. In this chapter, we review the epidemiology linking obesity, diabetes, and cancer incidence and mortality and discuss some of the physiological changes that occur in obesity and type 2 diabetes that may contribute to cancer growth and metastases.


Diabetes Obesity Cancer Insulin Insulin-like growth factor Dyslipidemia 


  1. 1.
    Maynard GD. A statistical study in cancer death-rates. Biometrika 1910;7(3):276–304. doi:10.1093/biomet/7.3.276.Google Scholar
  2. 2.
    Kessler II. Cancer and diabetes mellitus. A review of the literature. J Chronic Dis. 1971;23(8):579–600.PubMedCrossRefGoogle Scholar
  3. 3.
    Sell C. Caloric restriction and insulin-like growth factors in aging and cancer. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2003;35(11–12):705–11. doi:10.1055/s-2004-814156.Google Scholar
  4. 4.
    Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625–38. doi:10.1056/NEJMoa021423.PubMedCrossRefGoogle Scholar
  5. 5.
    Campbell PT, Newton CC, Patel AV, Jacobs EJ, Gapstur SM. Diabetes and cause-specific mortality in a prospective cohort of one million U.S. adults. Diabetes Care. 2012;35(9):1835–44. doi:10.2337/dc12-0002.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Hjalgrim H, Frisch M, Ekbom A, Kyvik KO, Melbye M, Green A. Cancer and diabetes – a follow-up study of two population-based cohorts of diabetic patients. J Intern Med. 1997;241(6):471–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Stattin P, Bjor O, Ferrari P, Lukanova A, Lenner P, Lindahl B, et al. Prospective study of hyperglycemia and cancer risk. Diabetes Care. 2007;30(3):561–7. doi:10.2337/dc06-0922.PubMedCrossRefGoogle Scholar
  8. 8.
    Jee SH, Ohrr H, Sull JW, Yun JE, Ji M, Samet JM. Fasting serum glucose level and cancer risk in Korean men and women. JAMA. 2005;293(2):194–202. doi:10.1001/jama.293.2.194.PubMedCrossRefGoogle Scholar
  9. 9.
    Verlato G, Zoppini G, Bonora E, Muggeo M. Mortality from site-specific malignancies in type 2 diabetic patients from Verona. Diabetes Care. 2003;26(4):1047–51.PubMedCrossRefGoogle Scholar
  10. 10.
    Handelsman Y, Leroith D, Bloomgarden ZT, Dagogo-Jack S, Einhorn D, Garber AJ, et al. Diabetes and cancer – an AACE/ACE consensus statement. Endocr Pract. 2013;19(4):675–93. doi:10.4158/EP13248.CS.PubMedCrossRefGoogle Scholar
  11. 11.
    Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33(7):1674–85. doi:10.2337/dc10-0666.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Tancredi M, Rosengren A, Svensson AM, Kosiborod M, Pivodic A, Gudbjornsdottir S, et al. Excess mortality among persons with type 2 diabetes. N Engl J Med. 2015;373(18):1720–32. doi:10.1056/NEJMoa1504347.PubMedCrossRefGoogle Scholar
  13. 13.
    Harding JL, Shaw JE, Peeters A, Cartensen B, Magliano DJ. Cancer risk among people with type 1 and type 2 diabetes: disentangling true associations, detection bias, and reverse causation. Diabetes Care. 2015;38(2):264–70. doi:10.2337/dc14-1996.PubMedCrossRefGoogle Scholar
  14. 14.
    Hsu PC, Lin WH, Kuo TH, Lee HM, Kuo C, Li CY. A population-based cohort study of all-cause and site-specific cancer incidence among patients with type 1 diabetes mellitus in Taiwan. J Epidemiol/Jpn Epidemiol Assoc. 2015;25(9):567–73. doi:10.2188/jea.JE20140197.CrossRefGoogle Scholar
  15. 15.
    Zendehdel K, Nyren O, Ostenson CG, Adami HO, Ekbom A, Ye W. Cancer incidence in patients with type 1 diabetes mellitus: a population-based cohort study in Sweden. J Natl Cancer Inst. 2003;95(23):1797–800.PubMedCrossRefGoogle Scholar
  16. 16.
    Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA. 2014;311(8):806–14. doi:10.1001/jama.2014.732.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384(9945):766–81. doi:10.1016/S0140-6736(14)60460-8.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120(16):1640–5. doi:10.1161/CIRCULATIONAHA.109.192644.PubMedCrossRefGoogle Scholar
  19. 19.
    Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371(9612):569–78. doi:10.1016/S0140-6736(08)60269-X.PubMedCrossRefGoogle Scholar
  20. 20.
    Masters GA, Krilov L, Bailey HH, Brose MS, Burstein H, Diller LR, et al. Clinical cancer advances 2015: annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol. 2015;33(7):786–809. doi:10.1200/JCO.2014.59.9746.PubMedCrossRefGoogle Scholar
  21. 21.
    Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath Jr CW. Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med. 1999;341(15):1097–105. doi:10.1056/NEJM199910073411501.PubMedCrossRefGoogle Scholar
  22. 22.
    Gaudet MM, Carter BD, Patel AV, Teras LR, Jacobs EJ, Gapstur SM. Waist circumference, body mass index, and postmenopausal breast cancer incidence in the cancer prevention study-II nutrition cohort. Cancer Causes Control. 2014;25(6):737–45. doi:10.1007/s10552-014-0376-4.PubMedCrossRefGoogle Scholar
  23. 23.
    Harvie M, Hooper L, Howell AH. Central obesity and breast cancer risk: a systematic review. Obes Rev. 2003;4(3):157–73.PubMedCrossRefGoogle Scholar
  24. 24.
    Moghaddam AA, Woodward M, Huxley R. Obesity and risk of colorectal cancer: a meta-analysis of 31 studies with 70,000 events. Cancer Epidemiol Biomarkers Prev. 2007;16(12):2533–47. doi:10.1158/1055-9965.EPI-07-0708.PubMedCrossRefGoogle Scholar
  25. 25.
    Sjostrom L, Gummesson A, Sjostrom CD, Narbro K, Peltonen M, Wedel H, et al. Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol. 2009;10(7):653–62. doi:10.1016/S1470-2045(09)70159-7.PubMedCrossRefGoogle Scholar
  26. 26.
    Adams TD, Stroup AM, Gress RE, Adams KF, Calle EE, Smith SC, et al. Cancer incidence and mortality after gastric bypass surgery. Obesity. 2009;17(4):796–802. doi:10.1038/oby.2008.610.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Michels KB, Solomon CG, Hu FB, Rosner BA, Hankinson SE, Colditz GA, et al. Type 2 diabetes and subsequent incidence of breast cancer in the Nurses’ Health Study. Diabetes Care. 2003;26(6):1752–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Davis AA, Kaklamani VG. Metabolic syndrome and triple-negative breast cancer: a new paradigm. Int J Breast Cancer. 2012;2012:809291. doi:10.1155/2012/809291.PubMedCrossRefGoogle Scholar
  29. 29.
    Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer. 2007;121(4):856–62. doi:10.1002/ijc.22717.PubMedCrossRefGoogle Scholar
  30. 30.
    Petrelli JM, Calle EE, Rodriguez C, Thun MJ. Body mass index, height, and postmenopausal breast cancer mortality in a prospective cohort of US women. Cancer Causes Control. 2002;13(4):325–32.PubMedCrossRefGoogle Scholar
  31. 31.
    Aune D, Navarro Rosenblatt DA, Chan DS, Vingeliene S, Abar L, Vieira AR, et al. Anthropometric factors and endometrial cancer risk: a systematic review and dose–response meta-analysis of prospective studies. Ann Oncol/ESMO. 2015;26(8):1635–48. doi:10.1093/annonc/mdv142.CrossRefGoogle Scholar
  32. 32.
    Crosbie EJ, Zwahlen M, Kitchener HC, Egger M, Renehan AG. Body mass index, hormone replacement therapy, and endometrial cancer risk: a meta-analysis. Cancer Epidemiol Biomark Prev. 2010;19(12):3119–30. doi:10.1158/1055-9965.EPI-10-0832.CrossRefGoogle Scholar
  33. 33.
    Adams TD, Hunt SC. Cancer and obesity: effect of bariatric surgery. World J Surg. 2009;33(10):2028–33. doi:10.1007/s00268-009-0169-1.PubMedCrossRefGoogle Scholar
  34. 34.
    Saltzman BS, Doherty JA, Hill DA, Beresford SA, Voigt LF, Chen C, et al. Diabetes and endometrial cancer: an evaluation of the modifying effects of other known risk factors. Am J Epidemiol. 2008;167(5):607–14. doi:10.1093/aje/kwm333.PubMedCrossRefGoogle Scholar
  35. 35.
    Olsen CM, Nagle CM, Whiteman DC, Ness R, Pearce CL, Pike MC, et al. Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium. Endocr Relat Cancer. 2013;20(2):251–62. doi:10.1530/ERC-12-0395.PubMedCrossRefGoogle Scholar
  36. 36.
    Pavelka JC, Brown RS, Karlan BY, Cass I, Leuchter RS, Lagasse LD, et al. Effect of obesity on survival in epithelial ovarian cancer. Cancer. 2006;107(7):1520–4. doi:10.1002/cncr.22194.PubMedCrossRefGoogle Scholar
  37. 37.
    Gapstur SM, Patel AV, Diver WR, Hildebrand JS, Gaudet MM, Jacobs EJ, et al. Type II diabetes mellitus and the incidence of epithelial ovarian cancer in the cancer prevention study-II nutrition cohort. Cancer Epidemiol Biomarkers Prev. 2012;21(11):2000–5. doi:10.1158/1055-9965.EPI-12-0867.PubMedCrossRefGoogle Scholar
  38. 38.
    Shah MM, Erickson BK, Matin T, McGwin Jr G, Martin JY, Daily LB, et al. Diabetes mellitus and ovarian cancer: more complex than just increasing risk. Gynecol Oncol. 2014;135(2):273–7. doi:10.1016/j.ygyno.2014.09.004.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Inoue M, Iwasaki M, Otani T, Sasazuki S, Noda M, Tsugane S. Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan. Arch Intern Med. 2006;166(17):1871–7. doi:10.1001/archinte.166.17.1871.PubMedCrossRefGoogle Scholar
  40. 40.
    Weiderpass E, Ye W, Vainio H, Kaaks R, Adami HO. Diabetes mellitus and ovarian cancer (Sweden). Cancer Causes Control. 2002;13(8):759–64.PubMedCrossRefGoogle Scholar
  41. 41.
    Swerdlow AJ, Laing SP, Qiao Z, Slater SD, Burden AC, Botha JL, et al. Cancer incidence and mortality in patients with insulin-treated diabetes: a UK cohort study. Br J Cancer. 2005;92(11):2070–5. doi:10.1038/sj.bjc.6602611.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Ulmer H, Bjorge T, Concin H, Lukanova A, Manjer J, Hallmans G, et al. Metabolic risk factors and cervical cancer in the metabolic syndrome and cancer project (Me-Can). Gynecol Oncol. 2012;125(2):330–5. doi:10.1016/j.ygyno.2012.01.052.PubMedCrossRefGoogle Scholar
  43. 43.
    Frumovitz M, Jhingran A, Soliman PT, Klopp AH, Schmeler KM, Eifel PJ. Morbid obesity as an independent risk factor for disease-specific mortality in women with cervical cancer. Obstet Gynecol. 2014;124(6):1098–104. doi:10.1097/AOG.0000000000000558.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Bergstrom A, Pisani P, Tenet V, Wolk A, Adami HO. Overweight as an avoidable cause of cancer in Europe. Int J Cancer. 2001;91(3):421–30.PubMedCrossRefGoogle Scholar
  45. 45.
    Zhang X, Zhou G, Sun B, Zhao G, Liu D, Sun J, et al. Impact of obesity upon prostate cancer-associated mortality: a meta-analysis of 17 cohort studies. Oncol lett. 2015;9(3):1307–12. doi:10.3892/ol.2014.2841.PubMedGoogle Scholar
  46. 46.
    Cai H, Xu Z, Xu T, Yu B, Zou Q. Diabetes mellitus is associated with elevated risk of mortality amongst patients with prostate cancer: a meta-analysis of 11 cohort studies. Diabetes Metab Res Rev. 2014. doi:10.1002/dmrr.2582.Google Scholar
  47. 47.
    Kasper JS, Giovannucci E. A meta-analysis of diabetes mellitus and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2006;15(11):2056–62. doi:10.1158/1055-9965.EPI-06-0410.PubMedCrossRefGoogle Scholar
  48. 48.
    Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4(8):579–91. doi:10.1038/nrc1408.PubMedCrossRefGoogle Scholar
  49. 49.
    Rieken M, Xylinas E, Kluth L, Crivelli JJ, Chrystal J, Faison T, et al. Association of diabetes mellitus and metformin use with oncological outcomes of patients with non-muscle-invasive bladder cancer. BJU Int. 2013;112(8):1105–12. doi:10.1111/bju.12448.PubMedCrossRefGoogle Scholar
  50. 50.
    Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst. 2005;97(22):1679–87. doi:10.1093/jnci/dji375.PubMedCrossRefGoogle Scholar
  51. 51.
    Hu FB, Manson JE, Liu S, Hunter D, Colditz GA, Michels KB, et al. Prospective study of adult onset diabetes mellitus (type 2) and risk of colorectal cancer in women. J Natl Cancer Inst. 1999;91(6):542–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Aleksandrova K, Boeing H, Jenab M, Bas Bueno-de-Mesquita H, Jansen E, van Duijnhoven FJ, et al. Metabolic syndrome and risks of colon and rectal cancer: the European prospective investigation into cancer and nutrition study. Cancer Prev Res. 2011;4(11):1873–83. doi:10.1158/1940-6207.CAPR-11-0218.CrossRefGoogle Scholar
  53. 53.
    Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, Hubbell FA, Ascensao J, Rodabough RJ, et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med. 2004;350(10):991–1004. doi:10.1056/NEJMoa032071.PubMedCrossRefGoogle Scholar
  54. 54.
    Cronin KA, Krebs-Smith SM, Feuer EJ, Troiano RP, Ballard-Barbash R. Evaluating the impact of population changes in diet, physical activity, and weight status on population risk for colon cancer (United States). Cancer Causes control. 2001;12(4):305–16.PubMedCrossRefGoogle Scholar
  55. 55.
    Jafri SH, Mills G. Lifestyle modification in colorectal cancer patients: an integrative oncology approach. Future Oncol. 2013;9(2):207–18. doi:10.2217/fon.12.184.PubMedCrossRefGoogle Scholar
  56. 56.
    Devesa SS, Blot WJ, Fraumeni Jr JF. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer. 1998;83(10):2049–53.PubMedCrossRefGoogle Scholar
  57. 57.
    Kubo A, Corley DA. Body mass index and adenocarcinomas of the esophagus or gastric cardia: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2006;15(5):872–8. doi:10.1158/1055-9965.EPI-05-0860.PubMedCrossRefGoogle Scholar
  58. 58.
    Mayne ST, Navarro SA. Diet, obesity and reflux in the etiology of adenocarcinomas of the esophagus and gastric cardia in humans. J Nutr. 2002;132(11 Suppl):3467S–70S.PubMedGoogle Scholar
  59. 59.
    Ji BT, Chow WH, Yang G, McLaughlin JK, Gao RN, Zheng W, et al. Body mass index and the risk of cancers of the gastric cardia and distal stomach in Shanghai, China. Cancer Epidemiol Biomarkers Prev. 1997;6(7):481–5.PubMedGoogle Scholar
  60. 60.
    Dixon JL, Copeland LA, Zeber JE, MacCarthy AA, Reznik SI, Smythe WR, et al. Association between diabetes and esophageal cancer, independent of obesity, in the United States Veterans Affairs population. Dis Esophagus. 2015. doi:10.1111/dote.12402.PubMedGoogle Scholar
  61. 61.
    Showalter SL, Rosato EL, Anne PR, Scott W, Mitchell E, Berger AC. Does diabetes mellitus influence pathologic complete response and tumor downstaging after neoadjuvant chemoradiation for esophageal and gastroesophageal cancer? A two-institution report. J Surg Oncol. 2010;101(1):43–6. doi:10.1002/jso.21418.PubMedCrossRefGoogle Scholar
  62. 62.
    Bell ET. Carcinoma of the pancreas. I. A clinical and pathologic study of 609 necropsied cases. II. The relation of carcinoma of the pancreas to diabetes mellitus. Am J Pathol. 1957;33(3):499–523.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Magruder JT, Elahi D, Andersen DK. Diabetes and pancreatic cancer: chicken or egg? Pancreas. 2011;40(3):339–51. doi:10.1097/MPA.0b013e318209e05d.PubMedCrossRefGoogle Scholar
  64. 64.
    Wang F, Herrington M, Larsson J, Permert J. The relationship between diabetes and pancreatic cancer. Mol Cancer. 2003;2:4.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Patel AV, Rodriguez C, Bernstein L, Chao A, Thun MJ, Calle EE. Obesity, recreational physical activity, and risk of pancreatic cancer in a large U.S. Cohort. Cancer Epidemiol Biomarkers Prev. 2005;14(2):459–66. doi:10.1158/1055-9965.EPI-04-0583.PubMedCrossRefGoogle Scholar
  66. 66.
    Hammerstad SS, Grock SF, Lee HJ, Hasham A, Sundaram N, Tomer Y. Diabetes and hepatitis C: a two-way association. Front Endocrinol. 2015;6:134. doi:10.3389/fendo.2015.00134.CrossRefGoogle Scholar
  67. 67.
    Shaib YH, El-Serag HB, Davila JA, Morgan R, McGlynn KA. Risk factors of intrahepatic cholangiocarcinoma in the United States: a case–control study. Gastroenterology. 2005;128(3):620–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Larsson SC, Wolk A. Body mass index and risk of multiple myeloma: a meta-analysis. Int J Cancer. 2007;121(11):2512–6. doi:10.1002/ijc.22968.PubMedCrossRefGoogle Scholar
  69. 69.
    Larsson SC, Wolk A. Obesity and risk of non-Hodgkin’s lymphoma: a meta-analysis. Int J Cancer. 2007;121(7):1564–70. doi:10.1002/ijc.22762.PubMedCrossRefGoogle Scholar
  70. 70.
    Birmann BM, Giovannucci E, Rosner B, Anderson KC, Colditz GA. Body mass index, physical activity, and risk of multiple myeloma. Cancer Epidemiol Biomarkers Prev. 2007;16(7):1474–8. doi:10.1158/1055-9965.EPI-07-0143.PubMedCrossRefGoogle Scholar
  71. 71.
    Khan AE, Gallo V, Linseisen J, Kaaks R, Rohrmann S, Raaschou-Nielsen O, et al. Diabetes and the risk of non-Hodgkin’s lymphoma and multiple myeloma in the European prospective investigation into cancer and nutrition. Haematologica. 2008;93(6):842–50. doi:10.3324/haematol.12297.PubMedCrossRefGoogle Scholar
  72. 72.
    Wu W, Merriman K, Nabaah A, Seval N, Seval D, Lin H, et al. The association of diabetes and anti-diabetic medications with clinical outcomes in multiple myeloma. Br J Cancer. 2014;111(3):628–36. doi:10.1038/bjc.2014.307.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Olson JE, Yang P, Schmitz K, Vierkant RA, Cerhan JR, Sellers TA. Differential association of body mass index and fat distribution with three major histologic types of lung cancer: evidence from a cohort of older women. Am J Epidemiol. 2002;156(7):606–15.PubMedCrossRefGoogle Scholar
  74. 74.
    Kuriki K, Hirose K, Tajima K. Diabetes and cancer risk for all and specific sites among Japanese men and women. Eur J Cancer Prev. 2007;16(1):83–9. doi:10.1097/01.cej.0000228404.37858.40.PubMedCrossRefGoogle Scholar
  75. 75.
    Renehan AG, Frystyk J, Flyvbjerg A. Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol Metab. 2006;17(8):328–36. doi:10.1016/j.tem.2006.08.006.PubMedCrossRefGoogle Scholar
  76. 76.
    LeRoith D, Roberts Jr CT. The insulin-like growth factor system and cancer. Cancer Lett. 2003;195(2):127–37.PubMedCrossRefGoogle Scholar
  77. 77.
    Morris PG, Hudis CA, Giri D, Morrow M, Falcone DJ, Zhou XK, et al. Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev Res. 2011;4(7):1021–9. doi:10.1158/1940-6207.CAPR-11-0110.CrossRefGoogle Scholar
  78. 78.
    Dankner R, Shanik MH, Keinan-Boker L, Cohen C, Chetrit A. Effect of elevated basal insulin on cancer incidence and mortality in cancer incident patients: the Israel GOH 29-year follow-up study. Diabetes Care. 2012;35(7):1538–43. doi:10.2337/dc11-1513.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madarnas Y, et al. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clinical Oncol. 2002;20(1):42–51.CrossRefGoogle Scholar
  80. 80.
    Stocks T, Lukanova A, Rinaldi S, Biessy C, Dossus L, Lindahl B, et al. Insulin resistance is inversely related to prostate cancer: a prospective study in Northern Sweden. Int J Cancer. 2007;120(12):2678–86. doi:10.1002/ijc.22587.PubMedCrossRefGoogle Scholar
  81. 81.
    Baxter RC. Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. Am J Physiol Endocrinol Metab. 2000;278(6):E967–76.PubMedGoogle Scholar
  82. 82.
    Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab. 1994;79(3):872–8. doi:10.1210/jcem.79.3.7521354.PubMedGoogle Scholar
  83. 83.
    Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 2011;3(70):70ra13. doi:10.1126/scitranslmed.3001845.Google Scholar
  84. 84.
    Schernhammer ES, Holly JM, Hunter DJ, Pollak MN, Hankinson SE. Insulin-like growth factor-I, its binding proteins (IGFBP-1 and IGFBP-3), and growth hormone and breast cancer risk in The Nurses Health Study II. Endocr Relat Cancer. 2006;13(2):583–92. doi:10.1677/erc.1.01149.PubMedCrossRefGoogle Scholar
  85. 85.
    Cao Y, Nimptsch K, Shui IM, Platz EA, Wu K, Pollak MN, et al. Prediagnostic plasma IGFBP-1, IGF-1 and risk of prostate cancer. Int J Cancer. 2015;136(10):2418–26. doi:10.1002/ijc.29295.PubMedCrossRefGoogle Scholar
  86. 86.
    Crowe FL, Key TJ, Allen NE, Appleby PN, Overvad K, Gronbaek H, et al. A cross-sectional analysis of the associations between adult height, BMI and serum concentrations of IGF-I and IGFBP-1 -2 and −3 in the European Prospective Investigation into Cancer and Nutrition (EPIC). Ann Hum Biol. 2011;38(2):194–202. doi:10.3109/03014460.2010.507221.PubMedCrossRefGoogle Scholar
  87. 87.
    Galli G, Pinchera A, Piaggi P, Fierabracci P, Giannetti M, Querci G, et al. Serum insulin-like growth factor-1 concentrations are reduced in severely obese women and raise after weight loss induced by laparoscopic adjustable gastric banding. Obes Surg. 2012;22(8):1276–80. doi:10.1007/s11695-012-0669-1.PubMedCrossRefGoogle Scholar
  88. 88.
    Novosyadlyy R, LeRoith D. Hyperinsulinemia and type 2 diabetes: impact on cancer. Cell Cycle. 2010;9(8):1449–50.PubMedCrossRefGoogle Scholar
  89. 89.
    Ferguson RD, Gallagher EJ, Cohen D, Tobin-Hess A, Alikhani N, Novosyadlyy R, et al. Hyperinsulinemia promotes metastasis to the lung in a mouse model of Her2-mediated breast cancer. Endocr Relat Cancer. 2013;20(3):391–401. doi:10.1530/ERC-12-0333.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Fierz Y, Novosyadlyy R, Vijayakumar A, Yakar S, LeRoith D. Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression. Diabetes. 2010;59(3):686–93. doi:10.2337/db09-1291.PubMedCrossRefGoogle Scholar
  91. 91.
    Bol DK, Kiguchi K, Gimenez-Conti I, Rupp T, DiGiovanni J. Overexpression of insulin-like growth factor-1 induces hyperplasia, dermal abnormalities, and spontaneous tumor formation in transgenic mice. Oncogene. 1997;14(14):1725–34. doi:10.1038/sj.onc.1201011.PubMedCrossRefGoogle Scholar
  92. 92.
    Pollak M, Blouin MJ, Zhang JC, Kopchick JJ. Reduced mammary gland carcinogenesis in transgenic mice expressing a growth hormone antagonist. Br J Cancer. 2001;85(3):428–30. doi:10.1054/bjoc.2001.1895.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Gallagher EJ, Alikhani N, Tobin-Hess A, Blank J, Buffin NJ, Zelenko Z, et al. Insulin receptor phosphorylation by endogenous insulin or the insulin analog AspB10 promotes mammary tumor growth independent of the IGF-I receptor. Diabetes. 2013;62(10):3553–60. doi:10.2337/db13-0249.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Wu Y, Yakar S, Zhao L, Hennighausen L, LeRoith D. Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res. 2002;62(4):1030–5.PubMedGoogle Scholar
  95. 95.
    Dunn SE, Kari FW, French J, Leininger JR, Travlos G, Wilson R, et al. Dietary restriction reduces insulin-like growth factor I levels, which modulates apoptosis, cell proliferation, and tumor progression in p53-deficient mice. Cancer Res. 1997;57(21):4667–72.PubMedGoogle Scholar
  96. 96.
    Wu Y, Cui K, Miyoshi K, Hennighausen L, Green JE, Setser J, et al. Reduced circulating insulin-like growth factor I levels delay the onset of chemically and genetically induced mammary tumors. Cancer Res. 2003;63(15):4384–8.PubMedGoogle Scholar
  97. 97.
    De Meyts P, Palsgaard J, Sajid W, Theede AM, Aladdin H. Structural biology of insulin and IGF-1 receptors. Novartis Found Symp. 2004;262:160–71. discussion 71–6, 265–8.PubMedCrossRefGoogle Scholar
  98. 98.
    LeRoith D, Werner H, Beitner-Johnson D, Roberts Jr CT. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev. 1995;16(2):143–63. doi:10.1210/edrv-16-2-143.PubMedCrossRefGoogle Scholar
  99. 99.
    Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev. 2009;30(6):586–623. doi:10.1210/er.2008-0047.PubMedCrossRefGoogle Scholar
  100. 100.
    Harrington SC, Weroha SJ, Reynolds C, Suman VJ, Lingle WL, Haluska P. Quantifying insulin receptor isoform expression in FFPE breast tumors. Growth Horm IGF Res. 2012;22(3–4):108–15. doi:10.1016/j.ghir.2012.04.001.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Yakar S, Leroith D, Brodt P. The role of the growth hormone/insulin-like growth factor axis in tumor growth and progression: lessons from animal models. Cytokine Growth Factor Rev. 2005;16(4–5):407–20. doi:10.1016/j.cytogfr.2005.01.010.PubMedCrossRefGoogle Scholar
  102. 102.
    Webster NJ, Resnik JL, Reichart DB, Strauss B, Haas M, Seely BL. Repression of the insulin receptor promoter by the tumor suppressor gene product p53: a possible mechanism for receptor overexpression in breast cancer. Cancer Res. 1996;56(12):2781–8.PubMedGoogle Scholar
  103. 103.
    Frittitta L, Cerrato A, Sacco MG, Weidner N, Goldfine ID, Vigneri R. The insulin receptor content is increased in breast cancers initiated by three different oncogenes in transgenic mice. Breast Cancer Res Treat. 1997;45(2):141–7.PubMedCrossRefGoogle Scholar
  104. 104.
    King H, Aleksic T, Haluska P, Macaulay VM. Can we unlock the potential of IGF-1R inhibition in cancer therapy? Cancer Treat Rev. 2014;40(9):1096–105. doi:10.1016/j.ctrv.2014.07.004.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Ulanet DB, Ludwig DL, Kahn CR, Hanahan D. Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy. Proc Natl Acad Sci U S A. 2010;107(24):10791–8. doi:10.1073/pnas.0914076107.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330(7503):1304–5. doi:10.1136/bmj.38415.708634.F7.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–74. doi:10.1172/JCI13505.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Kim SY, Kang JW, Song X, Kim BK, Yoo YD, Kwon YT, et al. Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells. Cell Signal. 2013;25(4):961–9. doi:10.1016/j.cellsig.2013.01.007.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Jeong SH, Lee YJ, Cho BI, Ha WS, Choi SK, Jung EJ, et al. OCT-1 overexpression is associated with poor prognosis in patients with well-differentiated gastric cancer. Tumour Biol. 2014;35(6):5501–9. doi:10.1007/s13277-014-1724-4.PubMedCrossRefGoogle Scholar
  110. 110.
    Advani AS, Lim K, Gibson S, Shadman M, Jin T, Copelan E, et al. OCT-2 expression and OCT-2/BOB.1 co-expression predict prognosis in patients with newly diagnosed acute myeloid leukemia. Leuk Lymphoma. 2010;51(4):606–12. doi:10.3109/10428191003592735.PubMedCrossRefGoogle Scholar
  111. 111.
    El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000;275(1):223–8.PubMedCrossRefGoogle Scholar
  112. 112.
    Levine AJ, Feng Z, Mak TW, You H, Jin S. Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev. 2006;20(3):267–75. doi:10.1101/gad.1363206.PubMedCrossRefGoogle Scholar
  113. 113.
    Adekola K, Rosen ST, Shanmugam M. Glucose transporters in cancer metabolism. Curr Opin Oncol. 2012;24(6):650–4. doi:10.1097/CCO.0b013e328356da72.PubMedCrossRefGoogle Scholar
  114. 114.
    Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol. 2005;202(3):654–62. doi:10.1002/jcp.20166.PubMedCrossRefGoogle Scholar
  115. 115.
    Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33. doi:10.1126/science.1160809.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Scafoglio C, Hirayama BA, Kepe V, Liu J, Ghezzi C, Satyamurthy N, et al. Functional expression of sodium-glucose transporters in cancer. Proc Natl Acad Sci U S A. 2015;112(30):E4111–9. doi:10.1073/pnas.1511698112.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    de Beer JC, Liebenberg L. Does cancer risk increase with HbA1c, independent of diabetes? Br J Cancer. 2014;110(9):2361–8. doi:10.1038/bjc.2014.150.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Bell Jr RH, McCullough PJ, Pour PM. Influence of diabetes on susceptibility to experimental pancreatic cancer. Am J Surg. 1988;155(1):159–64.PubMedCrossRefGoogle Scholar
  119. 119.
    Cocca C, Martin G, Rivera E, Davio C, Cricco G, Lemos B, et al. An experimental model of diabetes and cancer in rats. Eur J Cancer. 1998;34(6):889–94.PubMedCrossRefGoogle Scholar
  120. 120.
    Shafie SM, Grantham FH. Role of hormones in the growth and regression of human breast cancer cells (MCF-7) transplanted into athymic nude mice. J Natl Cancer Inst. 1981;67(1):51–6.PubMedGoogle Scholar
  121. 121.
    Barbosa-Desongles A, Hernandez C, De Torres I, Munell F, Poupon MF, Simo R, et al. Diabetes protects from prostate cancer by downregulating androgen receptor: new insights from LNCaP cells and PAC120 mouse model. PLoS One. 2013;8(9), e74179. doi:10.1371/journal.pone.0074179.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Chahil TJ, Ginsberg HN. Diabetic dyslipidemia. Endocrinol Metab Clin North Am. 2006;35(3):491–510. doi:10.1016/j.ecl.2006.06.002. vii-viii.PubMedCrossRefGoogle Scholar
  123. 123.
    Nelson ER, Chang CY, McDonnell DP. Cholesterol and breast cancer pathophysiology. Trends Endocrinol Metab. 2014;25(12):649–55. doi:10.1016/j.tem.2014.10.001.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Mainous 3rd AG, Wells BJ, Koopman RJ, Everett CJ, Gill JM. Iron, lipids, and risk of cancer in the Framingham Offspring cohort. Am J Epidemiol. 2005;161(12):1115–22. doi:10.1093/aje/kwi131.PubMedCrossRefGoogle Scholar
  125. 125.
    Melvin JC, Holmberg L, Rohrmann S, Loda M, Van Hemelrijck M. Serum lipid profiles and cancer risk in the context of obesity: four meta-analyses. J Cancer Epidemiol. 2013;2013:823849. doi:10.1155/2013/823849.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Hsu MC, Lee KT, Hsiao WC, Wu CH, Sun HY, Lin IL, et al. The dyslipidemia-associated SNP on the APOA1/C3/A5 gene cluster predicts post-surgery poor outcome in Taiwanese breast cancer patients: a 10-year follow-up study. BMC Cancer. 2013;13:330. doi:10.1186/1471-2407-13-330.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Chang NW, Chen DR, Wu CT, Aouizerat BE, Chen FN, Hung SJ, et al. Influences of apolipoprotein E polymorphism on the risk for breast cancer and HER2/neu status in Taiwan. Breast Cancer Res Treat. 2005;90(3):257–61. doi:10.1007/s10549-004-4656-7.PubMedCrossRefGoogle Scholar
  128. 128.
    Moysich KB, Freudenheim JL, Baker JA, Ambrosone CB, Bowman ED, Schisterman EF, et al. Apolipoprotein E genetic polymorphism, serum lipoproteins, and breast cancer risk. Mol Carcinog. 2000;27(1):2–9. doi:10.1002/(SICI)1098-2744(200001)27:1<2::AID-MC2>3.0.CO;2-W [pii].PubMedCrossRefGoogle Scholar
  129. 129.
    Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med. 2012;367(19):1792–802. doi:10.1056/NEJMoa1201735.PubMedCrossRefGoogle Scholar
  130. 130.
    Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology. 2013;144(2):323–32. doi:10.1053/j.gastro.2012.10.005.PubMedCrossRefGoogle Scholar
  131. 131.
    Yu O, Eberg M, Benayoun S, Aprikian A, Batist G, Suissa S, et al. Use of statins and the risk of death in patients with prostate cancer. J Clin Oncol. 2014;32(1):5–11. doi:10.1200/JCO.2013.49.4757.PubMedCrossRefGoogle Scholar
  132. 132.
    Ahern TP, Pedersen L, Tarp M, Cronin-Fenton DP, Garne JP, Silliman RA, et al. Statin prescriptions and breast cancer recurrence risk: a Danish nationwide prospective cohort study. J Natl Cancer Inst. 2011;103(19):1461–8. doi:10.1093/jnci/djr291.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Zhang XL, Liu M, Qian J, Zheng JH, Zhang XP, Guo CC, et al. Statin use and risk of kidney cancer: a meta-analysis of observational studies and randomized trials. Br J Clin Pharmacol. 2014;77(3):458–65. doi:10.1111/bcp.12210.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Tan M, Song X, Zhang G, Peng A, Li X, Li M, et al. Statins and the risk of lung cancer: a meta-analysis. PLoS One. 2013;8(2), e57349. doi:10.1371/journal.pone.0057349.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Zhang XL, Geng J, Zhang XP, Peng B, Che JP, Yan Y, et al. Statin use and risk of bladder cancer: a meta-analysis. Cancer Causes Control. 2013;24(4):769–76. doi:10.1007/s10552-013-0159-3.PubMedCrossRefGoogle Scholar
  136. 136.
    Cui X, Xie Y, Chen M, Li J, Liao X, Shen J, et al. Statin use and risk of pancreatic cancer: a meta-analysis. Cancer Causes Control. 2012;23(7):1099–111. doi:10.1007/s10552-012-9979-9.PubMedCrossRefGoogle Scholar
  137. 137.
    Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences. Clin Pharmacokinet. 1997;32(5):403–25. doi:10.2165/00003088-199732050-00005.PubMedCrossRefGoogle Scholar
  138. 138.
    Woditschka S, Habel LA, Udaltsova N, Friedman GD, Sieh W. Lipophilic statin use and risk of breast cancer subtypes. Cancer Epidemiol Biomarkers Prev. 2010;19(10):2479–87. doi:10.1158/1055-9965.EPI-10-0524.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Dansky HM, Shu P, Donavan M, Montagno J, Nagle DL, Smutko JS, et al. A phenotype-sensitizing Apoe-deficient genetic background reveals novel atherosclerosis predisposition loci in the mouse. Genetics. 2002;160(4):1599–608.PubMedPubMedCentralGoogle Scholar
  140. 140.
    Alikhani N, Ferguson RD, Novosyadlyy R, Gallagher EJ, Scheinman EJ, Yakar S, et al. Mammary tumor growth and pulmonary metastasis are enhanced in a hyperlipidemic mouse model. Oncogene. 2013;32(8):961–7. doi:10.1038/onc.2012.113.PubMedCrossRefGoogle Scholar
  141. 141.
    Llaverias G, Danilo C, Mercier I, Daumer K, Capozza F, Williams TM, et al. Role of cholesterol in the development and progression of breast cancer. Am J Pathol. 2011;178(1):402–12. doi:10.1016/j.ajpath.2010.11.005.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Llaverias G, Danilo C, Wang Y, Witkiewicz AK, Daumer K, Lisanti MP, et al. A Western-type diet accelerates tumor progression in an autochthonous mouse model of prostate cancer. Am J Pathol. 2010;177(6):3180–91. doi:10.2353/ajpath.2010.100568.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Nelson ER, Wardell SE, Jasper JS, Park S, Suchindran S, Howe MK, et al. 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science. 2013;342(6162):1094–8. doi:10.1126/science.1241908.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Pelton K, Coticchia CM, Curatolo AS, Schaffner CP, Zurakowski D, Solomon KR, et al. Hypercholesterolemia induces angiogenesis and accelerates growth of breast tumors in vivo. Am J Pathol. 2014;184(7):2099–110. doi:10.1016/j.ajpath.2014.03.006.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Zhuang L, Lin J, Lu ML, Solomon KR, Freeman MR. Cholesterol-rich lipid rafts mediate akt-regulated survival in prostate cancer cells. Cancer Res. 2002;62(8):2227–31.PubMedGoogle Scholar
  146. 146.
    Scheinman EJ, Rostoker R, Leroith D. Cholesterol affects gene expression of the Jun family in colon carcinoma cells using different signaling pathways. Mol Cell Endocrinol. 2013;374(1–2):101–7. doi:10.1016/j.mce.2013.04.011.PubMedCrossRefGoogle Scholar
  147. 147.
    Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447–54. doi:10.1158/0008-5472.CAN-08-0249.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Pelton K, Freeman MR, Solomon KR. Cholesterol and prostate cancer. Curr Opin Pharmacol. 2012;12(6):751–9. doi:10.1016/j.coph.2012.07.006.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    de Medina P, Paillasse MR, Segala G, Voisin M, Mhamdi L, Dalenc F, et al. Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties. Nat Commun. 2013;4:1840. doi:10.1038/ncomms2835.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Harford KA, Reynolds CM, McGillicuddy FC, Roche HM. Fats, inflammation and insulin resistance: insights to the role of macrophage and T-cell accumulation in adipose tissue. Proc Nutr Soc. 2011;70(4):408–17. doi:10.1017/S0029665111000565.PubMedCrossRefGoogle Scholar
  151. 151.
    Marette A. Mediators of cytokine-induced insulin resistance in obesity and other inflammatory settings. Curr Opin Clin Nutr Metab Care. 2002;5(4):377–83.PubMedCrossRefGoogle Scholar
  152. 152.
    Onuma M, Bub JD, Rummel TL, Iwamoto Y. Prostate cancer cell-adipocyte interaction: leptin mediates androgen-independent prostate cancer cell proliferation through c-Jun NH2-terminal kinase. J Biol Chem. 2003;278(43):42660–7. doi:10.1074/jbc.M304984200.PubMedCrossRefGoogle Scholar
  153. 153.
    Rose DP, Komninou D, Stephenson GD. Obesity, adipocytokines, and insulin resistance in breast cancer. Obes Rev. 2004;5(3):153–65. doi:10.1111/j.1467-789X.2004.00142.x.PubMedCrossRefGoogle Scholar
  154. 154.
    Gonullu G, Ersoy C, Ersoy A, Evrensel T, Basturk B, Kurt E, et al. Relation between insulin resistance and serum concentrations of IL-6 and TNF-alpha in overweight or obese women with early stage breast cancer. Cytokine. 2005;31(4):264–9. doi:10.1016/j.cyto.2005.05.003.PubMedCrossRefGoogle Scholar
  155. 155.
    Rosean TR, Tompkins VS, Tricot G, Holman CJ, Olivier AK, Zhan F, et al. Preclinical validation of interleukin 6 as a therapeutic target in multiple myeloma. Immunol Res. 2014;59(1–3):188–202. doi:10.1007/s12026-014-8528-x.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Cozen W, Gebregziabher M, Conti DV, Van Den Berg DJ, Coetzee GA, Wang SS, et al. Interleukin-6-related genotypes, body mass index, and risk of multiple myeloma and plasmacytoma. Cancer Epidemiol Biomarkers Prev. 2006;15(11):2285–91. doi:10.1158/1055-9965.EPI-06-0446.PubMedCrossRefGoogle Scholar
  157. 157.
    Plaisance I, Morandi C, Murigande C, Brink M. TNF-alpha increases protein content in C2C12 and primary myotubes by enhancing protein translation via the TNF-R1, PI3K, and MEK. Am J Physiol Endocrinol Metab. 2008;294(2):E241–50. doi:10.1152/ajpendo.00129.2007.PubMedCrossRefGoogle Scholar
  158. 158.
    Zinman B, Hanley AJ, Harris SB, Kwan J, Fantus IG. Circulating tumor necrosis factor-alpha concentrations in a native Canadian population with high rates of type 2 diabetes mellitus. J Clin Endocrinol Metab. 1999;84(1):272–8. doi:10.1210/jcem.84.1.5405.PubMedGoogle Scholar
  159. 159.
    Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 1997;389(6651):610–4. doi:10.1038/39335.PubMedCrossRefGoogle Scholar
  160. 160.
    Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425–32. doi:10.1038/372425a0.PubMedCrossRefGoogle Scholar
  161. 161.
    Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999;341(12):879–84. doi:10.1056/NEJM199909163411204.PubMedCrossRefGoogle Scholar
  162. 162.
    Maffei M, Fei H, Lee GH, Dani C, Leroy P, Zhang Y, et al. Increased expression in adipocytes of ob RNA in mice with lesions of the hypothalamus and with mutations at the db locus. Proc Natl Acad Sci U S A. 1995;92(15):6957–60.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Vona-Davis L, Howard-McNatt M, Rose DP. Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer. Obes Rev. 2007;8(5):395–408. doi:10.1111/j.1467-789X.2007.00396.x.PubMedCrossRefGoogle Scholar
  164. 164.
    Surmacz E. Leptin and adiponectin: emerging therapeutic targets in breast cancer. J Mammary Gland Biol Neoplasia. 2013;18(3–4):321–32. doi:10.1007/s10911-013-9302-8.PubMedCrossRefGoogle Scholar
  165. 165.
    Hardwick JC, Van Den Brink GR, Offerhaus GJ, Van Deventer SJ, Peppelenbosch MP. Leptin is a growth factor for colonic epithelial cells. Gastroenterology. 2001;121(1):79–90.PubMedCrossRefGoogle Scholar
  166. 166.
    Khan S, Shukla S, Sinha S, Meeran SM. Role of adipokines and cytokines in obesity-associated breast cancer: therapeutic targets. Cytokine Growth Factor Rev. 2013;24(6):503–13. doi:10.1016/j.cytogfr.2013.10.001.PubMedCrossRefGoogle Scholar
  167. 167.
    Vansaun MN. Molecular pathways: adiponectin and leptin signaling in cancer. Clin Cancer Res. 2013;19(8):1926–32. doi:10.1158/1078-0432.CCR-12-0930.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Ishikawa M, Kitayama J, Yamauchi T, Kadowaki T, Maki T, Miyato H, et al. Adiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specific membrane receptors AdipoR1 and AdipoR2. Cancer Sci. 2007;98(7):1120–7. doi:10.1111/j.1349-7006.2007.00486.x.PubMedCrossRefGoogle Scholar
  169. 169.
    Hebbard L, Ranscht B. Multifaceted roles of adiponectin in cancer. Best Pract Res Clin Endocrinol Metab. 2014;28(1):59–69. doi:10.1016/j.beem.2013.11.005.PubMedCrossRefGoogle Scholar
  170. 170.
    Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature. 2001;409(6818):307–12. doi:10.1038/35053000.PubMedCrossRefGoogle Scholar
  171. 171.
    Zhang J, Wu Y, Zhang Y, Leroith D, Bernlohr DA, Chen X. The role of lipocalin 2 in the regulation of inflammation in adipocytes and macrophages. Mol Endocrinol. 2008;22(6):1416–26. doi:10.1210/me.2007-0420.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Hursting SD, Nunez NP, Varticovski L, Vinson C. The obesity-cancer link: lessons learned from a fatless mouse. Cancer Res. 2007;67(6):2391–3. doi:10.1158/0008-5472.CAN-06-4237.PubMedCrossRefGoogle Scholar
  173. 173.
    Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF, Longcope C, et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst. 2003;95(16):1218–26.PubMedCrossRefGoogle Scholar
  174. 174.
    Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev. 2002;11(12):1531–43.PubMedGoogle Scholar
  175. 175.
    Slattery ML, Potter JD, Curtin K, Edwards S, Ma KN, Anderson K, et al. Estrogens reduce and withdrawal of estrogens increase risk of microsatellite instability-positive colon cancer. Cancer Res. 2001;61(1):126–30.PubMedGoogle Scholar
  176. 176.
    Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ. Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst. 1996;88(16):1118–26.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Emily J. Gallagher
    • 1
    Email author
  • Brian A. Neel
    • 1
  • Irini M. Antoniou
    • 2
  • Shoshana Yakar
    • 1
  • Derek LeRoith
    • 1
  1. 1.Division of Endocrinology, Diabetes and Bone Disease, Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkUSA
  2. 2.Division of Endocrinology, Diabetes and Bone Disease, Department of MedicineMount Sinai School of MedicineNew YorkUSA

Personalised recommendations