General Review Articles
Type 2 Diabetes and Cancer: What Is the Connection?
Dara Cannata,
Yvonne Fierz,
Archana Vijayakumar,
Derek LeRoith,
Archana Vijayakumar
Mount Sinai School of Medicine New York, NY
Search for more papers by this authorCorresponding Author
Derek LeRoith
Mount Sinai School of Medicine New York, NY
Mount Sinai School of Medicine New York, NYSearch for more papers by this author
Dara Cannata,
Yvonne Fierz,
Archana Vijayakumar,
Derek LeRoith,
Archana Vijayakumar
Mount Sinai School of Medicine New York, NY
Search for more papers by this authorCorresponding Author
Derek LeRoith
Mount Sinai School of Medicine New York, NY
Mount Sinai School of Medicine New York, NYSearch for more papers by this authorAbstract
Epidemiological studies have demonstrated an association between type 2 diabetes and cancer. Type 2 diabetes is characterized by insulin resistance and hyperinsulinemia. Hyperinsulinemia may lead to cancer through insulin's effect on its cognate receptor and the insulin-like growth factor system. The effects of insulin and insulin-like growth factor I on cancer development and progression have been demonstrated in animal and human studies. Type 2 diabetes has been positively associated with cancers of the breast, colon, and pancreas. An inverse relationship has been observed between type 2 diabetes and prostate cancer, and this may be due to lower testosterone levels in men with type 2 diabetes. Medications used to treat type 2 diabetes may affect cancer cells directly or indirectly by affecting serum insulin levels. Hyperinsulinemia may be an important risk factor for cancer as well as a target for cancer therapy. Mt Sinai J Med 77:197–213, 2010. © 2010 Mount Sinai School of Medicine
REFERENCES
- 1 Centers for Disease Control and Prevention. 2007; national diabetes fact sheet. http://www.cdc.gov/diabetes/pubs/estimates07.htm. Accessed January 2010.
- 2Kaaks R, Lukanova A. Energy balance and cancer: the role of insulin and insulin-like growth factor-I. Proc Nutr Soc 2001; 60: 91–106.
- 3Polednak AP. Trends in incidence rates for obesity-associated cancers in the US. Cancer Detect Prev 2003; 27: 415–421.
- 4Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 2004; 4: 579–591.
- 5Xue F, Michels KB. Diabetes, metabolic syndrome, and breast cancer: a review of the current evidence. Am J Clin Nutr 2007; 86: s823–s835.
- 6Vona-Davis L, Howard-McNatt M, Rose DP. Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer. Obes Rev 2007; 8: 395–408.
- 7Zendehdel K, Nyren O, Ostenson CG, et al. Cancer incidence in patients with type 1 diabetes mellitus: a population-based cohort study in Sweden. J Natl Cancer Inst 2003; 95: 1797–1800.
- 8LeRoith D, Werner H, Beitner-Johnson D, Roberts CT Jr. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 1995; 16: 143–163.
- 9Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 2007; 28: 20–47.
- 10Taha C, Klip A. The insulin signaling pathway. J Membr Biol 1999; 169: 1–12.
- 11Frasca F, Pandini G, Sciacca L, et al. The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch Physiol Biochem 2008; 114: 23–37.
- 12Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001; 414: 799–806.
- 13Fresno Vara JA, Casado E, de Castro J, et al. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 2004; 30: 193–204.
- 14Wolf I, Seger R. The mitogen-activated protein kinase signaling cascade: from bench to bedside. Isr Med Assoc J 2002; 4: 641–647.
- 15Belfiore A. The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer. Curr Pharm Des 2007; 13: 671–686.
- 16Mosthaf L, Grako K, Dull TJ, et al. Functionally distinct insulin receptors generated by tissue-specific alternative splicing. EMBO J 1990; 9: 2409–2413.
- 17Sciacca L, Prisco M, Wu A, et al. Signaling differences from the A and B isoforms of the insulin receptor (IR) in 32D cells in the presence or absence of IR substrate-1. Endocrinology 2003; 144: 2650–2658.
- 18Frasca F, Pandini G, Scalia P, et al. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol 1999; 19: 3278–3288.
- 19Sciacca L, Costantino A, Pandini G, et al. Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism. Oncogene 1999; 18: 2471–2479.
- 20Pandini G, Frasca F, Mineo R, et al. Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J Biol Chem 2002; 277: 39684–39695.
- 21Pandini G, Vigneri R, Costantino A, et al. Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: evidence for a second mechanism of IGF-I signaling. Clin Cancer Res 1999; 5: 1935–1944.
- 22Soos MA, Field CE, Siddle K. Purified hybrid insulin/insulin-like growth factor-I receptors bind insulin-like growth factor-I, but not insulin, with high affinity. Biochem J 1993; 290(pt 2): 419–426.
- 23Bailyes EM, Nave BT, Soos MA, et al. Insulin receptor/IGF-I receptor hybrids are widely distributed in mammalian tissues: quantification of individual receptor species by selective immunoprecipitation and immunoblotting. Biochem J 1997; 327(pt 1): 209–215.
- 24Papa V, Pezzino V, Costantino A, et al. Elevated insulin receptor content in human breast cancer. J Clin Invest 1990; 86: 1503–1510.
- 25Papa V, Gliozzo B, Clark GM, et al. Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer. Cancer Res 1993; 53: 3736–3740.
- 26Frittitta L, Sciacca L, Catalfamo R, et al. Functional insulin receptors are overexpressed in thyroid tumors: is this an early event in thyroid tumorigenesis? Cancer 1999; 85: 492–498.
10.1002/(SICI)1097-0142(19990115)85:2<492::AID-CNCR30>3.0.CO;2-I CASPubMedWeb of Science®Google Scholar
- 27Vella V, Pandini G, Sciacca L, et al. A novel autocrine loop involving IGF-II and the insulin receptor isoform-A stimulates growth of thyroid cancer. J Clin Endocrinol Metab 2002; 87: 245–254.
- 28Kuramoto H, Hongo A, Liu YX, et al. Immunohistochemical evaluation of insulin-like growth factor I receptor status in cervical cancer specimens. Acta Med Okayama 2008; 62: 251–259.
- 29Railo MJ, von Smitten K, Pekonen F. The prognostic value of insulin-like growth factor-I in breast cancer patients. Results of a follow-up study on 126 patients. Eur J Cancer 1994; 30A: 307–311.
- 30Matsubara J, Yamada Y, Hirashima Y, et al. Impact of insulin-like growth factor type 1 receptor, epidermal growth factor receptor, and HER2 expressions on outcomes of patients with gastric cancer. Clin Cancer Res 2008; 14: 3022–3029.
- 31Bentov I, Narla G, Schayek H, et al. Insulin-like growth factor-I regulates Kruppel-like factor-6 gene expression in a p53-dependent manner. Endocrinology 2008; 149: 1890–1897.
- 32Bruchim I, Attias Z, Werner H. Targeting the IGF1 axis in cancer proliferation. Expert Opin Ther Targets 2009; 13: 1179–1192.
- 33Sarfstein R, Werner H. The WT1 Wilms' tumor suppressor gene is a downstream target for insulin-like growth factor-I (IGF-I) action in PC12 cells. J Neurochem 2006; 99: 818–826.
- 34Webster NJ, Resnik JL, Reichart DB, et al. 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: 2781–2788.
- 35Frittitta L, Cerrato A, Sacco MG, et al. The insulin receptor content is increased in breast cancers initiated by three different oncogenes in transgenic mice. Breast Cancer Res Treat 1997; 45: 141–147.
- 36Mathieu MC, Clark GM, Allred DC, et al. Insulin receptor expression and clinical outcome in node-negative breast cancer. Proc Assoc Am Physicians 1997; 109: 565–571.
- 37Law JH, Habibi G, Hu K, et al. Phosphorylated insulin-like growth factor-I/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 2008; 68: 10238–10246.
- 38Sciacca L, Mineo R, Pandini G, et al. In IGF-I receptor-deficient leiomyosarcoma cells autocrine IGF-II induces cell invasion and protection from apoptosis via the insulin receptor isoform A. Oncogene 2002; 21: 8240–8250.
- 39Belfiore A, Pandini G, Vella V, et al. Insulin/IGF-I hybrid receptors play a major role in IGF-I signaling in thyroid cancer. Biochimie 1999; 81: 403–407.
- 40Vigneri P, Frasca F, Sciacca L, et al. Diabetes and cancer. Endocr Relat Cancer 2009; 16: 1103–1123.
- 41 2008 American Cancer Society Facts and Figures. Atlanta, GA: American Cancer Society; 2008.
- 42Key TJ, Verkasalo PK, Banks E. Epidemiology of breast cancer. Lancet Oncol 2001; 2: 133–140.
- 43Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer 2007; 121: 856–862.
- 44Ish-Shalom D, Christoffersen CT, Vorwerk P, et al. Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor. Diabetologia 1997; 40(suppl 2): S25–S31.
- 45Chappell J, Leitner JW, Solomon S, et al. Effect of insulin on cell cycle progression in MCF-7 breast cancer cells. Direct and potentiating influence. J Biol Chem 2001; 276: 38023–38028.
- 46Shafie SM, Hilf R. Insulin receptor levels and magnitude of insulin-induced responses in 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats. Cancer Res 1981; 41: 826–829.
- 47Heuson JC, Legros N, Heimann R. Influence of insulin administration on growth of the 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in intact, oophorectomized, and hypophysectomized rats. Cancer Res 1972; 32: 233–238.
- 48Nunez NP, Oh WJ, Rozenberg J, et al. Accelerated tumor formation in a fatless mouse with type 2 diabetes and inflammation. Cancer Res 2006; 66: 5469–5476.
- 49Novosyadlyy R, Lann DE, Vijayakumar A, et al. Insulin-mediated acceleration of breast cancer development and progression in a non-obese model of type 2 diabetes. Cancer Res 2010; 70: 741.
- 50Gunter MJ, Hoover DR, Yu H, et al. Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 2009; 101: 48–60.
- 51Michels KB, Solomon CG, Hu FB, et al. Type 2 diabetes and subsequent incidence of breast cancer in the Nurses' Health Study. Diabetes Care 2003; 26: 1752–1758.
- 52Yancik R, Wesley MN, Ries LA, et al. Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 2001; 285: 885–892.
- 53Verlato G, Zoppini G, Bonora E, Muggeo M. Mortality from site-specific malignancies in type 2 diabetic patients from Verona. Diabetes Care 2003; 26: 1047–1051.
- 54Coughlin SS, Calle EE, Teras LR, et al. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol 2004; 159: 1160–1167.
- 55Berrino F, Muti P, Micheli A, et al. Serum sex hormone levels after menopause and subsequent breast cancer. J Natl Cancer Inst 1996; 88: 291–296.
- 56Cauley JA, Lucas FL, Kuller LH, et al. Elevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer. Study of Osteoporotic Fractures Research Group. Ann Intern Med 1999; 130: 270–277.
- 57McTernan PG, Anwar A, Eggo MC, et al. Gender differences in the regulation of P450 aromatase expression and activity in human adipose tissue. Int J Obes Relat Metab Disord 2000; 24: 875–881.
- 58Singh A, Hamilton-Fairley D, Koistinen R, et al. Effect of insulin-like growth factor-type I (IGF-I) and insulin on the secretion of sex hormone binding globulin and IGF-I binding protein (IBP-I) by human hepatoma cells. J Endocrinol 1990; 124: R1–R3.
- 59Toniolo PG, Levitz M, Zeleniuch-Jacquotte A, et al. A prospective study of endogenous estrogens and breast cancer in postmenopausal women. J Natl Cancer Inst 1995; 87: 190–197.
- 60Key T, Appleby P, Barnes I, Reeves G. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 2002; 94: 606–616.
- 61Zeleniuch-Jacquotte A, Shore RE, Koenig KL, et al. Postmenopausal levels of oestrogen, androgen, and SHBG and breast cancer: long-term results of a prospective study. Br J Cancer 2004; 90: 153–159.
- 62Kaaks R, Rinaldi S, Key TJ, et al. Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr Relat Cancer 2005; 12: 1071–1082.
- 63 Endogenous Hormones and Breast Cancer Collaborative Group. Free estradiol and breast cancer risk in postmenopausal women: comparison of measured and calculated values. Cancer Epidemiol Biomarkers Prev 2003; 12: 1457–1461.
- 64Haffner SM, Laakso M, Miettinen H, et al. Low levels of sex hormone-binding globulin and testosterone are associated with smaller, denser low density lipoprotein in normoglycemic men. J Clin Endocrinol Metab 1996; 81: 3697–3701.
- 65Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst 2005; 97: 1679–1687.
- 66Will JC, Galuska DA, Vinicor F, Calle EE. Colorectal cancer: another complication of diabetes mellitus? Am J Epidemiol 1998; 147: 816–825.
- 67Giovannucci E. Insulin and colon cancer. Cancer Causes Control 1995; 6: 164–179.
- 68Tran TT, Medline A, Bruce WR. Insulin promotion of colon tumors in rats. Cancer Epidemiol Biomarkers Prev 1996; 5: 1013–1015.
- 69Koohestani N, Chia MC, Pham NA, et al. Aberrant crypt focus promotion and glucose intolerance: correlation in the rat across diets differing in fat, n-3 fatty acids and energy. Carcinogenesis 1998; 19: 1679–1684.
- 70Yakar S, Nunez NP, Pennisi P, et al. Increased tumor growth in mice with diet-induced obesity: impact of ovarian hormones. Endocrinology 2006; 147: 5826–5834.
- 71Hu FB, Manson JE, Liu S, et al. Prospective study of adult onset diabetes mellitus (type 2) and risk of colorectal cancer in women. J Natl Cancer Inst 1999; 91: 542–547.
- 72Yang YX, Hennessy S, Lewis JD. Type 2 diabetes mellitus and the risk of colorectal cancer. Clin Gastroenterol Hepatol 2005; 3: 587–594.
- 73Yang YX, Hennessy S, Lewis JD. Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology 2004; 127: 1044–1050.
- 74Vinikoor LC, Long MD, Keku TO, et al. The association between diabetes, insulin use, and colorectal cancer among whites and African Americans. Cancer Epidemiol Biomarkers Prev 2009; 18: 1239–1242.
- 75Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin 2009; 59: 225–249.
- 76Z'Graggen K, Warshaw AL, Werner J, et al. Promoting effect of a high-fat/high-protein diet in DMBA-induced ductal pancreatic cancer in rats. Ann Surg 2001; 233: 688–695.
- 77Pannala R, Leirness JB, Bamlet WR, et al. Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus. Gastroenterology 2008; 134: 981–987.
- 78Rousseau MC, Parent ME, Pollak MN, Siemiatycki J. Diabetes mellitus and cancer risk in a population-based case-control study among men from Montreal, Canada. Int J Cancer 2006; 118: 2105–2109.
- 79Kuriki 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: 83–89.
- 80Huxley R, Ansary-Moghaddam A, Berrington de Gonzalez A, et al. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer 2005; 92: 2076–2083.
- 81Ogunleye AA, Ogston SA, Morris AD, Evans JM. A cohort study of the risk of cancer associated with type 2 diabetes. Br J Cancer 2009; 101: 1199–1201.
- 82Silverman DT, Schiffman M, Everhart J, et al. Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer. Br J Cancer 1999; 80: 1830–1837.
- 83Fisher WE, Boros LG, Schirmer WJ. Insulin promotes pancreatic cancer: evidence for endocrine influence on exocrine pancreatic tumors. J Surg Res 1996; 63: 310–313.
- 84Williams JA, Goldfine ID. The insulin-pancreatic acinar axis. Diabetes 1985; 34: 980–986.
- 85Stevens RJ, Roddam AW, Beral V. Pancreatic cancer in type 1 and young-onset diabetes: systematic review and meta-analysis. Br J Cancer 2007; 96: 507–509.
- 86Permert J, Larsson J, Westermark GT, et al. Islet amyloid polypeptide in patients with pancreatic cancer and diabetes. N Engl J Med 1994; 330: 313–318.
- 87Isaksson B, Strommer L, Friess H, et al. Impaired insulin action on phosphatidylinositol 3-kinase activity and glucose transport in skeletal muscle of pancreatic cancer patients. Pancreas 2003; 26: 173–177.
- 88Gullo L, Pezzilli R, Morselli-Labate AM. Diabetes and the risk of pancreatic cancer. N Engl J Med 1994; 331: 81–84.
- 89Pannala R, Leibson CL, Rabe KG, et al. Temporal association of changes in fasting blood glucose and body mass index with diagnosis of pancreatic cancer. Am J Gastroenterol 2009; 104: 2318–2325.
- 90Bonovas S, Filioussi K, Tsantes A. Diabetes mellitus and risk of prostate cancer: a meta-analysis. Diabetologia 2004; 47: 1071–1078.
- 91Kasper JS, Giovannucci E. A meta-analysis of diabetes mellitus and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2006; 15: 2056–2062.
- 92Shaneyfelt T, Husein R, Bubley G, Mantzoros CS. Hormonal predictors of prostate cancer: a meta-analysis. J Clin Oncol 2000; 18: 847–853.
- 93Kalyani RR, Dobs AS. Androgen deficiency, diabetes, and the metabolic syndrome in men. Curr Opin Endocrinol Diabetes Obes 2007; 14: 226–234.
- 94Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595–1607.
- 95Grossmann M, Thomas MC, Panagiotopoulos S, et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab 2008; 93: 1834–1840.
- 96Stocks T, Lukanova A, Rinaldi S, et al. Insulin resistance is inversely related to prostate cancer: a prospective study in Northern Sweden. Int J Cancer 2007; 120: 2678–2686.
- 97Baradaran N, Ahmadi H, Salem S, et al. The protective effect of diabetes mellitus against prostate cancer: role of sex hormones. Prostate 2009; 69: 1744–1750.
- 98Ma J, Li H, Giovannucci E, et al. 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 2008; 9: 1039–1047.
- 99Aguilar-Bryan L, Nichols CG, Wechsler SW, et al. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 1995; 268: 423–426.
- 100Malhi H, Irani AN, Rajvanshi P, et al. KATP channels regulate mitogenically induced proliferation in primary rat hepatocytes and human liver cell lines. Implications for liver growth control and potential therapeutic targeting. J Biol Chem 2000; 275: 26050–26057.
- 101Wondergem R, Cregan M, Strickler L, et al. Membrane potassium channels and human bladder tumor cells: II. Growth properties. J Membr Biol 1998; 161: 257–262.
- 102Qian X, Li J, Ding J, et al. Glibenclamide exerts an antitumor activity through reactive oxygen species-c-jun NH2-terminal kinase pathway in human gastric cancer cell line MGC-803. Biochem Pharmacol 2008; 76: 1705–1715.
- 103Houghton PJ, Houghton JA. Antitumor diarylsulfonylureas: novel agents with unfulfilled promise. Invest New Drugs 1996; 14: 271–280.
- 104Lee CW, Hong DH, Han SB, et al. A novel stereo-selective sulfonylurea, 1-[1-(4-aminobenzoyl)-2, 3-dihydro-1H-indol-6-sulfonyl]− 4-phenyl-imidazolid in-2-one, has antitumor efficacy in in vitro and in vivo tumor models. Biochem Pharmacol 2002; 64: 473–480.
- 105Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 2006; 29: 254–258.
- 106Donadon V, Balbi M, Ghersetti M, et al. Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease. World J Gastroenterol 2009; 15: 2506–2511.
- 107Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009; 52: 1766–1777.
- 108Kurtzhals P, Schaffer L, Sorensen A, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000; 49: 999–1005.
- 109Mayer D, Shukla A, Enzmann H. Proliferative effects of insulin analogues on mammary epithelial cells. Arch Physiol Biochem 2008; 114: 38–44.
- 110Weinstein D, Simon M, Yehezkel E, et al. Insulin analogues display IGF-I-like mitogenic and anti-apoptotic activities in cultured cancer cells. Diabetes Metab Res Rev 2009; 25: 41–49.
- 111Stammberger I, Bube A, Durchfeld-Meyer B, et al. Evaluation of the carcinogenic potential of insulin glargine (LANTUS) in rats and mice. Int J Toxicol 2002; 21: 171–179.
- 112Hemkens LG, Grouven U, Bender R, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 2009; 52: 1732–1744.
- 113Colhoun HM. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 2009; 52: 1755–1765.
- 114Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000; 119: 1447–1453.
- 115Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108: 1167–1174.
- 116Hawley SA, Boudeau J, Reid JL, et al. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2003; 2: 28.
- 117Cazzaniga M, Bonanni B, Guerrieri-Gonzaga A, Decensi A. Is it time to test metformin in breast cancer clinical trials? Cancer Epidemiol Biomarkers Prev 2009; 18: 701–705.
- 118Zakikhani M, Dowling R, Fantus IG, et al. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 2006; 66: 10269–10273.
- 119Zakikhani M, Dowling RJ, Sonenberg N, Pollak MN. The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev Res 2008; 1: 369–375.
- 120Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 2009; 69: 7507–7511.
- 121Ben Sahra I, Laurent K, Loubat A, et al. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 2008; 27: 3576–3586.
- 122Anisimov VN, Berstein LM, Egormin PA, et al. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol 2005; 40: 685–693.
- 123Buzzai M, Jones RG, Amaravadi RK, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 2007; 67: 6745–6752.
- 124Algire C, Zakikhani M, Blouin MJ, et al. Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth. Endocr Relat Cancer 2008; 15: 833–839.
- 125Evans JM, Donnelly LA, Emslie-Smith AM, et al. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005; 330: 1304–1305.
- 126Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 2009; 27: 3297–3302.
- 127Saez E, Rosenfeld J, Livolsi A, et al. PPAR gamma signaling exacerbates mammary gland tumor development. Genes Dev 2004; 18: 528–540.
- 128Tontonoz P, Singer S, Forman BM, et al. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. Proc Natl Acad Sci U S A 1997; 94: 237–241.
- 129DuBois RN, Gupta R, Brockman J, et al. The nuclear eicosanoid receptor, PPARgamma, is aberrantly expressed in colonic cancers. Carcinogenesis 1998; 19: 49–53.
- 130Mueller E, Smith M, Sarraf P, et al. Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proc Natl Acad Sci U S A 2000; 97: 10990–10995.
- 131Sarraf P, Mueller E, Jones D, et al. Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nat Med 1998; 4: 1046–1052.
- 132Mueller E, Sarraf P, Tontonoz P, et al. Terminal differentiation of human breast cancer through PPAR gamma. Mol Cell 1998; 1: 465–470.
- 133Elstner E, Muller C, Koshizuka K, et al. Ligands for peroxisome proliferator-activated receptor gamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci U S A 1998; 95: 8806–8811.
- 134Lefebvre AM, Chen I, Desreumaux P, et al. Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. Nat Med 1998; 4: 1053–1057.
- 135Saez E, Tontonoz P, Nelson MC, et al. Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat Med 1998; 4: 1058–1061.
- 136Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (Prospective Pioglitazone Clinical Trial In Macrovascular Events): a randomised controlled trial. Lancet 2005; 366: 1279–1289.
- 137Govindarajan R, Ratnasinghe L, Simmons DL, et al. Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J Clin Oncol 2007; 25: 1476–1481.
- 138Burstein HJ, Demetri GD, Mueller E, et al. Use of the peroxisome proliferator-activated receptor (PPAR) gamma ligand troglitazone as treatment for refractory breast cancer: a phase II study. Breast Cancer Res Treat 2003; 79: 391–397.
- 139Blanquicett C, Roman J, Hart CM. Thiazolidinediones as anti-cancer agents. Cancer Ther 2008; 6: 25–34.
