Exp Clin Endocrinol Diabetes 2010; 118(10): 673-677
DOI: 10.1055/s-0030-1254116
Review

© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Breast Cancer and Diabetes Mellitus

S. Schott1 , A. Schneeweiss1 , C. Sohn1
  • 1University Hospital Heidelberg, Department of Gynecology and Obstetrics within the National Center for Tumor Diseases, Heidelberg
Further Information

Publication History

received 27.04.2010 first decision 27.04.2010

accepted 27.04.2010

Publication Date:
08 June 2010 (online)

Abstract

Breast cancer is the leading neoplastic malignancy among females worldwide. Another major health problem in industrial countries is diabetes mellitus type 2, both with a raising tendency. Up to 16% of the elderly breast cancer patients additionally suffer from diabetes. Epidemiologic studies suggest that type 2 diabetes increases breast cancer risk and goes along with an increased mortality however, there has been limited experimental evidence supporting this association. In the present review we summarized epidemiological data on a correlation between diabetes and breast cancer. Further, the diverse hypothesized molecular investigations and purposed mechanisms are recapitulated. The latest discussions on insulin and its enhancement of cancer rates among patients with diabetes have also toughed the breast cancer sector. In contrary, recent data indicate a benefit of breast cancer treatment due to metformin therapy. A large amount of literature is available and provides concepts for future research that is needed to rule out possible overlapping pathomechanism, prognostic factors, therapy interactions as well as possible synergistic or additive or even controversial interaction of chemotherapy and diabetes medication.

References

  • 1 Ahn J, Schatzkin A, Lacey JV. et al . Adiposity, adult weight change, and postmenopausal breast cancer risk.  Arch Intern Med. 2007;  167 2091-2102
  • 2 Anisimov 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
  • 3 Baron JA, Weiderpass E, Newcomb PA. et al . Metabolic disorders and breast cancer risk (United States).  Cancer Causes Control. 2001;  12 875-880
  • 4 Barone BB, Yeh HC, Snyder CF. et al . Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis.  JAMA. 2008;  300 2754-2764
  • 5 Ben 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
  • 6 Bianchini F, Kaaks R, Vainio H. Overweight, obesity, and cancer risk.  Lancet Oncol. 2002;  3 565-574
  • 7 Blonde L. Current antihyperglycemic treatment guidelines and algorithms for patients with type 2 diabetes mellitus.  Am J Med. 2010;  123 S12-S18
  • 8 Bodmer M, Meier C, Krahenbuhl S. et al . Long-term metformin use is associated with decreased risk of breast cancer.  Diabetes Care. 2010; 
  • 9 Brown KA, Hunger NI, Docanto M. et al . Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase.  Breast Cancer Res Treat. 2010; 
  • 10 Buzzai 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
  • 11 Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms.  Nat Rev Cancer. 2004;  4 579-591
  • 12 Calle EE, Rodriguez C, Walker-Thurmond K. et al . Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.  N Engl J Med. 2003;  348 1625-1638
  • 13 Colhoun 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
  • 14 Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes.  Diabetologia. 2009;  52 1766-1777
  • 15 Eliassen AH, Colditz GA, Rosner B. et al . Adult weight change and risk of postmenopausal breast cancer.  JAMA. 2006;  296 193-201
  • 16 Engelgau MM, Geiss LS, Saaddine JB. et al . The evolving diabetes burden in the United States.  Ann Intern Med. 2004;  140 945-950
  • 17 Fierz Y, Novosyadlyy R, Vijayakumar A. et al . Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression.  Diabetes. 2010;  59 686-693
  • 18 Frankenberry KA, Skinner H, Somasundar P. et al . Leptin receptor expression and cell signaling in breast cancer.  Int J Oncol. 2006;  28 985-993
  • 19 Fresno Vara JA, Casado E, de Castro J. et al . PI3K/Akt signalling pathway and cancer.  Cancer Treat Rev. 2004;  30 193-204
  • 20 Frittitta 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
  • 21 Frittitta L, Vigneri R, Stampfer MR. et al . Insulin receptor overexpression in 184B5 human mammary epithelial cells induces a ligand-dependent transformed phenotype.  J Cell Biochem. 1995;  57 666-669
  • 22 Frystyk J, Skjaerbaek C, Vestbo E. et al . Circulating levels of free insulin-like growth factors in obese subjects: the impact of type 2 diabetes.  Diabetes Metab Res Rev. 1999;  15 314-322
  • 23 Gonzalez-Angulo AM, Meric-Bernstam F. Metformin: a therapeutic opportunity in breast cancer.  Clin Cancer Res. 2010;  16 1695-1700
  • 24 Goodwin PJ. Insulin in the adjuvant breast cancer setting: a novel therapeutic target for lifestyle and pharmacologic interventions?.  J Clin Oncol. 2008;  26 833-834
  • 25 Goodwin PJ, Ligibel JA, Stambolic V. Metformin in breast cancer: time for action.  J Clin Oncol. 2009;  27 3271-3273
  • 26 Grote VA, Becker S, Kaaks R. Diabetes mellitus type 2 - an independent risk factor for cancer?.  Exp Clin Endocrinol Diabetes. 2010;  118 4-8
  • 27 Gunter MJ, Hoover DR, Yu H. et al . Insulin, insulin-like growth factor-I, endogenous estradiol, and risk of colorectal cancer in postmenopausal women.  Cancer Res. 2008;  68 329-337
  • 28 Hancke K, Grubeck D, Hauser N. et al . Adipocyte fatty acid-binding protein as a novel prognostic factor in obese breast cancer patients.  Breast Cancer Res Treat. 2010;  119 367
  • 29 Hemkens 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
  • 30 Hernandez-Diaz S, Adami HO. Diabetes therapy and cancer risk: causal effects and other plausible explanations.  Diabetologia. 2010; 
  • 31 Hjalgrim H, Frisch M, Ekbom A. et al . Cancer and diabetes – a follow-up study of two population-based cohorts of diabetic patients.  J Intern Med. 1997;  241 471-475
  • 32 Home PD, Lagarenne P. Combined randomised controlled trial experience of malignancies in studies using insulin glargine.  Diabetologia. 2009;  52 2499-2506
  • 33 Ibrahim EM, Al-Homaidh A. Physical activity and survival after breast cancer diagnosis: meta-analysis of published studies.  Med Oncol. 2010; 
  • 34 Idris I. Observational registry database studies link insulin glargine with cancer risk.  Diabetes Obes Metab. 2009;  11 910-912
  • 35 Inoue M, Iwasaki M, Otani T. et al . Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan.  Arch Intern Med. 2006;  166 1871-1877
  • 36 Jemal A, Siegel R, Ward E. et al . Cancer statistics, 2006.  CA Cancer J Clin. 2006;  56 106-130
  • 37 Jiralerspong 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
  • 38 Jonasson JM, Ljung R, Talback M. et al . Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden.  Diabetologia. 2009;  52 1745-1754
  • 39 Key T, Appleby P, Barnes I. et al . Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies.  J Natl Cancer Inst. 2002;  94 606-616
  • 40 Kusmic C, L’Abbate A, Sambuceti G. et al . Improved myocardial perfusion in chronic diabetic mice by the up-regulation of pLKB1 and AMPK signaling.  J Cell Biochem. 2010;  109 1033-1044
  • 41 Lahmann PH, Hoffmann K, Allen N. et al . Body size and breast cancer risk: findings from the European Prospective Investigation into Cancer And Nutrition (EPIC).  Int J Cancer. 2004;  111 762-771
  • 42 Lai A, Sarcevic B, Prall OW. et al . Insulin/insulin-like growth factor-I and estrogen cooperate to stimulate cyclin E-Cdk2 activation and cell Cycle progression in MCF-7 breast cancer cells through differential regulation of cyclin E and p21(WAF1/Cip1).  J Biol Chem. 2001;  276 25823-25833
  • 43 Landman GW, Kleefstra N, van Hateren KJ. et al . Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16.  Diabetes Care. 2010;  33 322-326
  • 44 Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis.  Int J Cancer. 2007;  121 856-862
  • 45 Lipscombe LL, Goodwin PJ, Zinman B. et al . Diabetes mellitus and breast cancer: a retrospective population-based cohort study.  Breast Cancer Res Treat. 2006;  98 349-356
  • 46 Lipscombe LL, Goodwin PJ, Zinman B. et al . The impact of diabetes on survival following breast cancer.  Breast Cancer Res Treat. 2008;  109 389-395
  • 47 Liu B, Fan Z, Edgerton SM. et al . Metformin induces unique biological and molecular responses in triple negative breast cancer cells.  Cell Cycle. 2009;  8 2031-2040
  • 48 Maccio A, Madeddu C, Gramignano G. et al . Correlation of body mass index and leptin with tumor size and stage of disease in hormone-dependent postmenopausal breast cancer: preliminary results and therapeutic implications.  J Mol Med. 2010; 
  • 49 Meyerhardt JA, Catalano PJ, Haller DG. et al . Impact of diabetes mellitus on outcomes in patients with colon cancer.  J Clin Oncol. 2003;  21 433-440
  • 50 Michels 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
  • 51 Milazzo G, Giorgino F, Damante G. et al . Insulin receptor expression and function in human breast cancer cell lines.  Cancer Res. 1992;  52 3924-3930
  • 52 Morimoto LM, White E, Chen Z. et al . Obesity, body size, and risk of postmenopausal breast cancer: the Women's Health Initiative (United States).  Cancer Causes Control. 2002;  13 741-751
  • 53 Mussig K, Haring HU. Insulin Signal Transduction in Normal Cells and its Role in Carcinogenesis.  Exp Clin Endocrinol Diabetes. 2010; 
  • 54 Nardon E, Buda I, Stanta G. et al . Insulin-like growth factor system gene expression in women with type 2 diabetes and breast cancer.  J Clin Pathol. 2003;  56 599-604
  • 55 Nguyen NP, Almeida FS, Chi A. et al . Molecular biology of breast cancer stem cells: Potential clinical applications.  Cancer Treat Rev. 2010; 
  • 56 Novosyadlyy R, Lann DE, Vijayakumar A. et al . Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes.  Cancer Res. 2010;  70 741-751
  • 57 Nyholm H, Djursing H, Hagen C. et al . Androgens and estrogens in postmenopausal insulin-treated diabetic women.  J Clin Endocrinol Metab. 1989;  69 946-949
  • 58 Papa V, Pezzino V, Costantino A. et al . Elevated insulin receptor content in human breast cancer.  J Clin Invest. 1990;  86 1503-1510
  • 59 Pinhas-Hamiel O, Zeitler P. The global spread of type 2 diabetes mellitus in children and adolescents.  J Pediatr. 2005;  146 693-700
  • 60 Ray A, Cleary MP. Leptin as a potential therapeutic target for breast cancer prevention and treatment.  Expert Opin Ther Targets. 2010;  14 443-451
  • 61 Renehan AG, Tyson M, Egger M. et al . Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies.  Lancet. 2008;  371 569-578
  • 62 Renehan AG, Zwahlen M, Minder C. et al . Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis.  Lancet. 2004;  363 1346-1353
  • 63 Rose DP, Komninou D, Stephenson GD. Obesity, adipocytokines, and insulin resistance in breast cancer.  Obes Rev. 2004;  5 153-165
  • 64 Sachdev D, Yee D. The IGF system and breast cancer.  Endocr Relat Cancer. 2001;  8 197-209
  • 65 Saltiel AR. New perspectives into the molecular pathogenesis and treatment of type 2 diabetes.  Cell. 2001;  104 517-529
  • 66 Siddle K, Urso B, Niesler CA. et al . Specificity in ligand binding and intracellular signalling by insulin and insulin-like growth factor receptors.  Biochem Soc Trans. 2001;  29 513-525
  • 67 Stumvoll M, Nawroth PP. The insulin glargine dilemma: an opportunity for the diabetes community?.  Diabetologia. 2009;  52 1987-1989
  • 68 Sullivan PW, Morrato EH, Ghushchyan V. et al . Obesity, inactivity, and the prevalence of diabetes and diabetes-related cardiovascular comorbidities in the U.S, 2000–2002.  Diabetes Care. 2005;  28 1599-1603
  • 69 Taha C, Klip A. The insulin signaling pathway.  J Membr Biol. 1999;  169 1-12
  • 70 Taunk NK, Goyal S, Moran MS. et al . Prognostic significance of IGF-1R expression in patients treated with breast-conserving surgery and radiation therapy.  Radiother Oncol. 2010; 
  • 71 Tsugane S, Inoue M. Insulin resistance and cancer: Epidemiological evidence.  Cancer Sci. 2010; 
  • 72 van den Brandt PA, Spiegelman D, Yaun SS. et al . Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk.  Am J Epidemiol. 2000;  152 514-527
  • 73 von Eynatten M, Liu D, Hock C. et al . Urinary adiponectin excretion: a novel marker for vascular damage in type 2 diabetes.  Diabetes. 2009;  58 2093-2099
  • 74 Vona-Davis L, Howard-McNatt M, Rose DP. Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer.  Obes Rev. 2007;  8 395-408
  • 75 Webster 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
  • 76 Weiss HA, Brinton LA, Potischman NA. et al . Breast cancer risk in young women and history of selected medical conditions.  Int J Epidemiol. 1999;  28 816-823
  • 77 Wolf I, Sadetzki S, Catane R. et al . Diabetes mellitus and breast cancer.  Lancet Oncol. 2005;  6 103-111
  • 78 Wolf I, Seger R. The mitogen-activated protein kinase signaling cascade: from bench to bedside.  Isr Med Assoc J. 2002;  4 641-647
  • 79 http://www.cancer.org
  • 80 Xue F, Michels KB. Diabetes, metabolic syndrome, and breast cancer: a review of the current evidence.  Am J Clin Nutr. 2007;  86 s823-s835
  • 81 Zarich SW. Antidiabetic agents and cardiovascular risk in type 2 diabetes.  Nat Rev Endocrinol. 2009;  5 500-506
  • 82 Zhou 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

Correspondence

S. Scho1ttMD 

Voßstraße 9

69115 Heidelberg

Germany

Phone: +49/06221/56 7856

Email: sarah.schott@med.uni-heidelberg.de

    >