Top

Published in:

01-09-2011 | Opinion Paper

Therapeutic effects of metformin in breast cancer: involvement of the immune system?

Authors: Sarah Schott, Angelika Bierhaus, Florian Schuetz, Philipp Beckhove, Andreas Schneeweiss, Christof Sohn, Christoph Domschke

Published in: Cancer Immunology, Immunotherapy | Issue 9/2011

Abstract

Breast cancer and associated diabetes mellitus have gained raising interest as an elevated risk of breast cancer prognosis resulting in increased mortality in diabetic patients. In this context, the long-acting insulin analog glargine and other antidiabetics have been discussed to promote tumorigenesis. In contrast, the biguanide class oral antidiabetic metformin has been shown capable of enhancing cell cycle arrest and inducing apoptosis as well as reducing growth factor signaling. Consequently, several studies are underway to evaluate a possible role of metformin in breast cancer treatment. Although mechanisms involved are not definitely clear yet, here, we discuss metformin’s anticancer effects including the potential impact of the immune system.

Anderson GF, Chu E (2007) Expanding priorities—confronting chronic disease in countries with low income. N Engl J Med 356:209–211PubMedCrossRef

Engelgau MM, Geiss LS, Saaddine JB, Boyle JP, Benjamin SM, Gregg EW, Tierney EF, Rios-Burrows N, Mokdad AH, Ford ES, Imperatore G, Narayan KM (2004) The evolving diabetes burden in the United States. Ann Intern Med 140:945–950PubMed

Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ (2006) Cancer statistics, 2006. CA Cancer J Clin 56:106–130PubMedCrossRef

Wolf I, Sadetzki S, Catane R, Karasik A, Kaufman B (2005) Diabetes mellitus and breast cancer. Lancet Oncol 6:103–111PubMedCrossRef

Erickson K, Patterson RE, Flatt SW, Natarajan L, Parker BA, Heath DD, Laughlin GA, Saquib N, Rock CL, Pierce JP (2011) Clinically defined type 2 diabetes mellitus and prognosis in early-stage breast cancer. J Clin Oncol 29:54–60PubMedCrossRef

Lipscombe LL, Goodwin PJ, Zinman B, McLaughlin JR, Hux JE (2008) The impact of diabetes on survival following breast cancer. Breast Cancer Res Treat 109:389–395PubMedCrossRef

Peairs KS, Barone BB, Snyder CF, Yeh HC, Stein KB, Derr RL, Brancati FL, Wolff AC (2011) Diabetes mellitus and breast cancer outcomes: a systematic review and meta-analysis. J Clin Oncol 29:40–46PubMedCrossRef

Novosyadlyy R, Lann DE, Vijayakumar A, Rowzee A, Lazzarino DA, Fierz Y, Carboni JM, Gottardis MM, Pennisi PA, Molinolo AA, Kurshan N, Mejia W, Santopietro S, Yakar S, Wood TL, LeRoith D (2010) Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res 70:741–751PubMedCrossRef

Hemkens LG, Grouven U, Bender R, Gunster C, Gutschmidt S, Selke GW, Sawicki PT (2009) Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 52:1732–1744PubMedCrossRef

10.

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

11.

Jonasson JM, Ljung R, Talback M, Haglund B, Gudbjornsdottir S, Steineck G (2009) Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden. Diabetologia 52:1745–1754PubMedCrossRef

12.

Colhoun HM (2009) Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 52:1755–1765PubMedCrossRef

13.

Home PD, Lagarenne P (2009) Combined randomised controlled trial experience of malignancies in studies using insulin glargine. Diabetologia 52:2499–2506PubMedCrossRef

14.

Idris I (2009) Observational registry database studies link insulin glargine with cancer risk. Diabetes Obes Metab 11:910–912PubMedCrossRef

15.

Hernandez-Diaz S, Adami HO (2010) Diabetes therapy and cancer risk: causal effects and other plausible explanations. Diabetologia 53:802–808PubMedCrossRef

16.

Zarich SW (2009) Antidiabetic agents and cardiovascular risk in type 2 diabetes. Nat Rev Endocrinol 5:500–506PubMedCrossRef

17.

Goodwin PJ, Stambolic V, Lemieux J, Chen BE, Parulekar WR, Gelmon KA, Hershman DL, Hobday TJ, Ligibel JA, Mayer IA, Pritchard KI, Whelan TJ, Rastogi P, Shepherd LE (2011) Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents. Breast Cancer Res Treat 126:215–220PubMedCrossRef

18.

Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304–1305PubMedCrossRef

19.

Bowker SL, Majumdar SR, Veugelers P, Johnson JA (2006) Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin: response to Farooki and Schneider. Diabetes Care 29:1990–1991PubMedCrossRef

20.

Monami M, Lamanna C, Balzi D, Marchionni N, Mannucci E (2009) Sulphonylureas and cancer: a case-control study. Acta Diabetol 46:279–284PubMedCrossRef

21.

Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32:1620–1625PubMedCrossRef

22.

Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ (2010) Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care 33:322–326PubMedCrossRef

23.

Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR (2010) Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care 33:1304–1308PubMedCrossRef

24.

Bosco JL, Antonsen S, Sorensen HT, Pedersen L, Lash TL (2011) Metformin and incident breast cancer among diabetic women: a population-based case-control study in Denmark. Cancer Epidemiol Biomarkers Prev 20:101–111PubMedCrossRef

25.

Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, Hsu L, Hung MC, Hortobagyi GN, Gonzalez-Angulo AM (2009) Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27:3297–3302PubMedCrossRef

26.

Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin-Castillo B, Menendez JA (2009) If mammalian target of metformin indirectly is mammalian target of rapamycin, then the insulin-like growth factor-1 receptor axis will audit the efficacy of metformin in cancer clinical trials. J Clin Oncol 27:e207–e209 author reply e210PubMedCrossRef

27.

Fierz Y, Novosyadlyy R, Vijayakumar A, Yakar S, LeRoith D (2010) Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression. Diabetes 59:686–693PubMedCrossRef

28.

Cazzaniga M, Bonanni B, Guerrieri-Gonzaga A, Decensi A (2009) Is it time to test metformin in breast cancer clinical trials? Cancer Epidemiol Biomarkers Prev 18:701–705PubMedCrossRef

29.

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

30.

Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Kovalenko IG, Poroshina TE, Semenchenko AV, Provinciali M, Re F, Franceschi C (2005) Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol 40:685–693PubMedCrossRef

31.

Liu B, Fan Z, Edgerton SM, Deng XS, Alimova IN, Lind SE, Thor AD (2009) Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle 8:2031–2040PubMedCrossRef

32.

Phoenix KN, Vumbaca F, Fox MM, Evans R, Claffey KP (2010) Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy. Breast Cancer Res Treat 123:333–344PubMedCrossRef

33.

Nguyen NP, Almeida FS, Chi A, Nguyen LM, Cohen D, Karlsson U, Vinh-Hung V (2010) Molecular biology of breast cancer stem cells: potential clinical applications. Cancer Treat Rev 36:485–491PubMedCrossRef

34.

Iliopoulos D, Hirsch HA, Wang G, Struhl K (2011) Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci USA 108:1397–1402PubMedCrossRef

35.

Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Del Barco S, Martin-Castillo B, Lopez-Bonet E, Menendez JA (2011) The anti-diabetic drug metformin suppresses the metastasis-associated protein CD24 in MDA-MB-468 triple-negative breast cancer cells. Oncol Rep 25:135–140PubMed

36.

Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K (2009) Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 69:7507–7511PubMedCrossRef

37.

Vazquez-Martin A, Oliveras-Ferraros C, Barco SD, Martin-Castillo B, Menendez JA (2011) The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat 126:355–364PubMedCrossRef

38.

Gonzalez-Angulo AM, Meric-Bernstam F (2010) Metformin: a therapeutic opportunity in breast cancer. Clin Cancer Res 16:1695–1700PubMedCrossRef

39.

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174PubMed

40.

Towler MC, Hardie DG (2007) AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 100:328–341PubMedCrossRef

41.

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 310:1642–1646PubMedCrossRef

42.

Jalving M, Gietema JA, Lefrandt JD, de Jong S, Reyners AK, Gans RO, de Vries EG (2010) Metformin: taking away the candy for cancer? Eur J Cancer 46:2369–2380PubMedCrossRef

43.

Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9–22PubMedCrossRef

44.

Morgensztern D, McLeod HL (2005) PI3 K/Akt/mTOR pathway as a target for cancer therapy. Anticancer Drug 16:797–803CrossRef

45.

Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA (2009) The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells. Cell Cycle 8:88–96PubMedCrossRef

46.

Phoenix KN, Vumbaca F, Claffey KP (2009) Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERalpha negative MDA-MB-435 breast cancer model. Breast Cancer Res Treat 113:101–111PubMedCrossRef

47.

Brown KA, Hunger NI, Docanto M, Simpson ER (2010) Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase. Breast Cancer Res Treat 123:591–596PubMedCrossRef

48.

Simpson ER, Misso M, Hewitt KN, Hill RA, Boon WC, Jones ME, Kovacic A, Zhou J, Clyne CD (2005) Estrogen—the good, the bad, and the unexpected. Endocr Rev 26:322–330PubMedCrossRef

49.

Dilman VM, Berstein LM, Ostroumova MN, Fedorov SN, Poroshina TE, Tsyrlina EV, Buslaeva VP, Semiglazov VF, Seleznev IK, Bobrov YuF, Vasilyeva IA, Kondratjev VB, Nemirovsky VS, Nikiforov YF (1982) Metabolic immunodepression and metabolic immunotherapy: an attempt of improvement in immunologic response in breast cancer patients by correction of metabolic disturbances. Oncology 39:13–19PubMedCrossRef

50.

Dilman VM, Anisimov VN (1979) Potentiation of antitumor effect of cyclophosphamide and hydrazine sulfate by treatment with the antidiabetic agent, 1-phenylethylbiguanide (phenformin). Cancer Lett 7:357–361PubMedCrossRef

51.

Prlic M, Williams MA, Bevan MJ (2007) Requirements for CD8 T-cell priming, memory generation and maintenance. Curr Opin Immunol 19:315–319PubMedCrossRef

52.

Harty JT, Badovinac VP (2008) Shaping and reshaping CD8+ T-cell memory. Nat Rev Immunol 8:107–119PubMedCrossRef

53.

Schirrmacher V, Feuerer M, Fournier P, Ahlert T, Umansky V, Beckhove P (2003) T-cell priming in bone marrow: the potential for long-lasting protective anti-tumor immunity. Trends Mol Med 9:526–534PubMedCrossRef

54.

Sommerfeldt N, Schutz F, Sohn C, Forster J, Schirrmacher V, Beckhove P (2006) The shaping of a polyvalent and highly individual T-cell repertoire in the bone marrow of breast cancer patients. Cancer Res 66:8258–8265PubMedCrossRef

55.

Garcia-Gil M, Bertini F, Pesi R, Voccoli V, Tozzi MG, Camici M (2006) 5′-Amino-4-imidazolecarboxamide riboside induces apoptosis in human neuroblastoma cells via the mitochondrial pathway. Nucleosides Nucleotides Nucleic Acids 25:1265–1270PubMedCrossRef

56.

Oliveras-Ferraros C, Cufi S, Vazquez-Martin A, Torres-Garcia VZ, Del Barco S, Martin-Castillo B, Menendez JA (2011) Micro(mi)RNA expression profile of breast cancer epithelial cells treated with the anti-diabetic drug metformin: Induction of the tumor suppressor miRNA let-7a and suppression of the TGFbeta-induced oncomiR miRNA-181a. Cell Cycle 10:1144–1151PubMedCrossRef

57.

Solano ME, Sander V, Wald MR, Motta AB (2008) Dehydroepiandrosterone and metformin regulate proliferation of murine T lymphocytes. Clin Exp Immunol 153:289–296PubMedCrossRef

58.

Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG, Choi Y (2009) Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460:103–107PubMedCrossRef

59.

Goodwin PJ, Ligibel JA, Stambolic V (2009) Metformin in breast cancer: time for action. J Clin Oncol 27:3271–3273PubMedCrossRef

Title: Therapeutic effects of metformin in breast cancer: involvement of the immune system?
Authors: Sarah Schott
Angelika Bierhaus
Florian Schuetz
Philipp Beckhove
Andreas Schneeweiss
Christof Sohn
Christoph Domschke
Publication date: 01-09-2011
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 9/2011
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-011-1062-y

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 9/2011

Gemcitabine enhances Wilms’ tumor gene WT1 expression and sensitizes human pancreatic cancer cells with WT1-specific T-cell-mediated antitumor immune response

Exploitation of differential homeostatic proliferation of T-cell subsets following chemotherapy to enhance the efficacy of vaccine-mediated antitumor responses

MAGE-A1, MAGE-A3, and NY-ESO-1 can be upregulated on neuroblastoma cells to facilitate cytotoxic T lymphocyte-mediated tumor cell killing

Increased PRAME antigen-specific killing of malignant cell lines by low avidity CTL clones, following treatment with 5-Aza-2′-Deoxycytidine

Immunotherapy eradicates metastases with reversible defects in MHC class I expression

CTL recognition of a novel HLA-A*0201-binding peptide derived from glioblastoma multiforme tumor cells

Keynote webinar | Spotlight on antibody–drug conjugates in cancer