Metformin Treatment for the Prevention and/or Treatment of Breast/Mammary Tumorigenesis

Current Pharmacology Reports

Volumn 1, Issue 5, 2015, Pages 312-323

  Grossmann, Michael E ^a,b   Yang, Da Qing ^a,b   Guo, Zhijun ^a,b   Potter, David A ^a,b   Cleary, Margot P ^a,b  

^a UNIVERSITY OF MINNESOTA   (United States)

^b UNIVERSITY OF MINNESOTA   (United States)

Author keywords

AMPK; Breast cancer; Chemoprevention; Humans; Metformin; Rodents

Indexed keywords

ADENYLATE KINASE; EPIDERMAL GROWTH FACTOR RECEPTOR 2; ESTROGEN RECEPTOR; METFORMIN; PLACEBO; STAT3 PROTEIN;

ANTINEOPLASTIC ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; BREAST CANCER; BREAST CARCINOGENESIS; CANCER GROWTH; CANCER INCIDENCE; CANCER MORTALITY; CELL PROLIFERATION; CHEMOPROPHYLAXIS; DISEASE FREE SURVIVAL; HUMAN; NEOADJUVANT THERAPY; NONHUMAN; PHASE 3 CLINICAL TRIAL (TOPIC); POLYMERASE CHAIN REACTION; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SIGNAL TRANSDUCTION;

EID: 85015411791     PISSN: None     EISSN: 2198641X     Source Type: Journal    
DOI: 10.1007/s40495-015-0032-z     Document Type: Review

References (81)

1. Evans JMM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Meformin and reduced risk of cancer in diabetic patients. Brit Med J. 2005;330:1304–5.
2. Bowker SL, Veugelers PJ, Majumdar SR, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care. 2006;29:254–8.
3. Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JMM. New users of metformin are at low risk of incident cancer. A cohort study among people with type 2 diabetes. Diabetes Care. 2009;32:1620–5.
4. Goodwin PJ, Pritchard KI, Ennis M, Clemons M, Graham M, Fantus IG. Insulin-lowering effects of metformin in women with early breast cancer. Clin Breast Cancer. 2008;8:501–5.
5. Noto H, Goto A, Tsujimoto T, Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS One. 2012;7:e33411.
6. Franciosi M, Lucisano G, Laprice E, Strippoli GFM, Pellegrini F, Nicolucci A. Metformin therapy and risk of cancer inpatients with type 2 diabetes: systematic review. PLoS One. 2013;8:e71583.
7. Bo S, Ciccone G, Rosato R, Villois P, Appendino G, Ghigo E, et al. Cancer mortality reduction and metformin: a retrospective cohort study in type 2 diabetic patients. Diabetes Obes Metab. 2012;14:23–9.
8. Zhang P, Li H, Tan X, Chen L, Wang S. Association of metformin use with cancer incidence and mortality: a meta-analysis. Cancer Epidemiol. 2013;37:207–18.
9. Malek M, Aghili R, Emani Z, Khamseh ME. Risk of cancer in diabetes: the effect of metformin. ISRN Endocrinol. 2013;article ID 636927.
10. Jiralerspong S, Palla SL, Girdano SH, Meric-Bernstam F, Liedtke C, Barnett CM, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009;27:3297–302.
11. Tseng C-H. Metformin may reduce breast cancer risk in Taiwanese women with type 2 diabetes. Breast Cancer Res Treat. 2014;145:785–90.
12. Aksoy S, Sendur MAN, Altundag K. Demographic and clinico-pathological characteristics in patients with invasive breast cancer receiving metformin. Med Oncol. 2013;30:560.
13. Qiu H, Rhoads GG, Berlin JA, Marcella SW, Demissie K. Initial metformin or sulphonylurea exposure and cancer occurrence among patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2013;15:349–57.
14. Simó R, Plana-Ripoli O, Puente D, Morros R, Mundet X, Vilca LM, et al. Impact of glucose-lowering agents on the risk of cancer in type 2 diabetic patients. The Barcelona Case–control Study. PLoS One. 2013;8:e79968.
15. Niraula S, Dowling RJO, Ennis M, Chang MC, Done SJ, Hood N, et al. Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res Treat. 2012;135:821–30.
16. Bonanni B, Puntoni M, Cazzaniga M, Pruneri G, Serrano D, Guerrieri-Gongaga A, et al. Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J Clin Oncol. 2012;30:2593–600.
17. Hadad S, Iwamoto T, Jordan L, Purdie C, Bray S, Baker L, et al. Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Res Treat. 2011;128:783–94.
18. Gail MH, Brinton LA, Byar DP, Green SB, Shairir C, Mulvhihill JJ. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81:1879–86.
19. Martin LJ, Boyd NF. Potential mechanisms of breast cancer risk associated with mammaographic density: hypothesis based on epidemiological evidence. Breast Cancer Res. 2008;10:201.
20. Santen RJ, Boyd NF, Chlebowski RT, Cummings S, Cuzik J, Dowsett M, et al. Critical assessment of new risk factors for breast cancer: considerations for development of an improved risk prediction model. Endocrine-Relat Cancer. 2007;14:169–87.
21. Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 2006;66:10269–73.
22. Dowling RJO, Zakikhani M, Fantus IG, Pollack M, Sonenberg N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 2007;67:10804–12.
23. Cipl. J Mol Signal. 2008;3:1–11.
24. Liu B, Fan Z, Edgerton SM, Deng X-S, Alimova IN, Lind SE, et al. Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle. 2009;8:2031–40.
25. Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T, Lind SE, et al. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle. 2009;8:909–15.
26. Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. The antidiabetic drug metformin supprresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells. Cell Cycle. 2009;8:88–96.
27. Zakikhani M, Blouin M-J, Piura E, Pollack MN. Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells. Breast Cancer Res Treat. 2010;213:271–9.
28. Jung J-W, Park S-B, Lee S-J, Seo M-S, Trosko JE, Kang K-S. Metformin represses self-renewal of the human breast carcinoma stem cells via inhibition of estrogen receptor-mediated OCT4 expression. PLos One 2011;e28068.
29. Zhu Z, Jiang W, Thompson MD, McGinley JN, Thompson HJ. Metformin as an energy restriction mimetic agent for breast cancer prevention. J Carcinog. 2011;10:17.
30. Liu B, Fan Z, Edgerton SM, Yang X, Lind SE, Thor AD. Potent anti-proliferative effects of metformin on trastuzamab-resistant breast cancer cells via inhibition of ErbB2/IGF-1 receptor interactions. Cell Cycle. 2011;10:2959–66.
31. -/low cells is sufficient to overcome primary resistance to trastuzumab in HER2+ human breast cancer xenografts. Oncotarget. 2012;3:395–8.
32. Williams CC, Singleton BA, Llopis SD, Skiripnikova EV. Metformin induces a senescence-associated gene signature in breast cancer cells. J Health Care Poor Underserved. 2013;24:93–103.
33. Zhu P, Davis M, Blackweider AJ, Backman N, Liu B, Edgerton S, et al. Metformin selectively targets tumor-initiating cells in ErbB2-overexpressing breast cancer models. Cancer Prev Res. 2014;7:199–210. This paper presents details of the effects of metformin both in vitro and in vivo on HER2/neu/ErbB2 overexpressing breast cancer.
34. Du Y, Zheng H, Wang J, Ren Y, Li M, Gong C, et al. Metformin inhibits histone H2B monoubiquitination and downstream gene transcription in human breast cancer cells. Oncol Lett. 2014;8:809–12.
35. Choi YW, Lim IK. Sensitization of metformin-cytotoxicity by dichloroacetate via reprogramming glucose metabolism in cancer cells. Cancer Lett. 2014;346:300–8.
36. Phoenix K, Vumbaca F, Claffey KP. Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERα negative MDA-MB-435 breast cancer model. Breast Cancer Res Treat. 2009;113:101–11.
37. Hirsch 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;69:7507–11.
38. Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res. 2011;71:3196–201. This manuscript presents the effects of metformin treatment in xenograft experiments as well as work with potential effects of metformin on breast cancer stem cells.
39. Cheong J-H, Park ES, Liang J, Dennison JB, Tsavachiidou D, Nguyen-Charles C, et al. Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinial cancer models. Mol Cancer Ther. 2011;10:2350–62.
40. Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci U S A. 2013;110:972–7.
41. Orecchioi S, Reggiani F, Talarico G, Mancusco P, Calleri A, Gregato G, et al. The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells. Int J Cancer. 2015;136:534–44. Results presented comparing metformin to phenformin and show that metformin can have direct activity against breast cancer cells and also has anti-angiogenic activity against white adipose tissue progenitor cells.
42. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinksi MA, 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;40:685–93. Long-term treatment study indicating prevention of mammary tumor development in HER-2/neu transgenic mice.
43. Anisimov VN, Egormin PA, Piskunova TS, Popovich IG, Tyndyk ML, Yurova MV, et al. Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo. Cell Cycle. 2010;9:188–97.
44. Bojková B, Orendas P, Kassayova M, Kutna V, Ahlersová E, Ahlers I. Metformin in chemically-induced mammary carcinogenesis in rats. Neoplasma. 2009;56:269–74.
45. Giles ED, Wellberg EA, Astling DP, Anderson SM, Thor AD, Jindal S, et al. Obesity and overfeeding affecting both tumor and systemic metabolism activates the progesterone receptor to contribute to postmenopausal breast cancer. Cancer Res. 2012;72:6490–501.
46. Hadad SM, Appleyard V, Thompson AM. Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERα negative MDA-MB-435 breast cancer model. Breast Cancer Res Treat. 2009;114:391.
47. Ross DT, Scherf U, Eisen MB, Perou CM, Rees C, Spellman P, et al. Systematic variation in gene expression patterns of human cancer cell lines. Nat Genet. 2000;24:227–35.
48. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinksi MA, et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008;7:2769–73.
49. Dilman VM, Berstein LM, Zabezhinksi MA, Alexandrov VA, Bobrov YF, Pliss GB. Inhibition of DMBA-induced carcinogenesis by phenformin in the mammary gland of rats. Arch Geschwulstforsc. 1978;48:1–8.
50. Dilman VM, Anisimov VN. Effect of treatment with phenformin, diphenylhydantoin or L-dopa on life span and tumour incidence in C3H/Sn mice. Gerontology. 1980;26:241–6.
51. Hardie DG, Hawley SA. AMP-activated protein kinase: the energy charge hypothesis revisited. BioEssays. 2001;23:1112–9.
52. Carling D. The AMP-activated protein kinase cascade—a unifying system for energy control. Trends Biochem Sci. 2004;29:18–24.
53. Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 2013;17:113–24. This paper provides data supporting a link between AMPK and HIF-1α activities.
54. Choi YH, Lee MG. Pharmacokinetic and pharmacodynamic interaction between nifedine and metformin in rats: competitive inhibition for metabolism of nifedine and metformin by each other via CYP isozymes. Xenobiotica. 2012;42:483–95.
55. Hahn-Windgassen A, Nogueira V, Chen C-C, Skeen JE, Sonenberg N, Hay N. AKT activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J Biol Chem. 2005;280:32081–9.
56. Sun S-Y, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005;65:7052–8.
57. Ratten R, Giri S, Singh AK, Singh I. 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase. J Biol Chem. 2005;280:39582–93.
58. Sakamoto K, Gõransson O, Hardie DG, Alessi DR. Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR. Am J Physiol. 2004;287:E310–7.
59. Fernandes N, Sun Y, Chen S, Paul P, Shaw RJ, Cantley LC, et al. DNA damage-induced association of ATM with its target proteins requires a protein interaction domain in the N terminas of ATM. J Biol Chem. 2005;280:15158–64.
60. 366) on LKB1/STK11, the protein kinase mutated in Peutz-Jeghers cancer syndrome. Biochem J. 2002;362:481–90.
61. Sun Y, Connors KE, Yang D-Q. AICAR induces phosphorylation of AMPK in an ATM-dependent LKB1-independent manner. Mol Cell Biochem. 2007;306:239–45. This is the first report documenting that AMPK can be phosphorylated/activated in an ATM-dependent manner.
62. UKPDS, GoDarts Diabetes Pharmacogenetic Study Group. The Welcome Trust Case Control Consortium 2. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet. 2011;43:117–20. This is the first GWAS study that links genetic variances of ATM with type 2 diabetes patients’ response to metformin treatment.
63. Yang D-Q, Halaby M-J, Li Y, Hibma JC, Burn P. Cytoplasmic ATM protein kinase: an emerging therapeutic target for diabetes, cancer and neuronal degeneration. Drug Dis Today. 2011;16:332–8. This is a comprehensive review that details ATM’s connection with insulin resistance and type 2 diabetes.
64. DeBerardinis RJ, Lum JJ, Hatzivassilou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7:11–20.
65. Chen JQ, Russo J. Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells. Biochim Biophys Acta. 1826;2012:370–84.
66. Storozhuk Y, Hopmans SN, Sanli T, Barron C, Tsiani E, Cutz J-C, et al. Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK. Brit J Cancer. 2013;108:2021–32.
67. Yi G, He Z, Zhou Y, Xian L, Yuan T, Jia X, et al. Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway. Int J Oncol. 2013;43:1503–10.
68. Jones RG, Plas DR, Kubek S, Buzzai MJ, Mu J, Xu Y, et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell. 1994;18:283–93.
69. Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Menendez JA. Metformin activates an ataxia telengiectasia mutated (ATM)/Chk2-regulated DNA damage-like response. Cell Cycle. 2011;10:1499–501.
70. Del Barco S, Vazquez-Martin A, Cufi S, Oliveras-Ferraros C, Bosch-Barrera B, Joven J, et al. Metformin: multi-faceted protection against cancer. Oncotarget. 2011;2:896–917.
71. Liu X, Chhipa RR, Pooya S, Wortman M, Yachyshin S, Chow LML, et al. Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK. Proc Natl Acad Sci USA 2014.
72. Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, et al. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 2008;27:3576–86.
73. Ben Sahra I, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, et al. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 2011;71:4366–72.
74. Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin-Castillo B, Menendez JA. The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat. 2011;126:355–64.
75. Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin-Castillo B, Menendez JA. Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status. Cell Cycle. 2010;18:3807–14.
76. Pollak M. The insulin receptor/insulin-like growth factor receptor family as a therapeutic target in oncology. Clin Cancer Res. 2012;18:40–50.
77. Deng X-S, Wang S, Deng A, Liu B, Edgerton SM, Lind SE, et al. Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. Cell Cycle. 2012;11:367–76.
78. Zhang Q, Raje V, Yakovlev VA, Yacoub A, Szczepanek K, Meier J, et al. Mitochondrial localized Stat3 promotes breast cancer growth via phosphorylation of serin 727. J Biol Chem. 2013;288:31280–8.
79. Macias E, Rao D, Carbajal S, Kiguchi K, DiGiovanni J. Stat3 binds to mtDNA and regulates mitochondrial gene expression in keratinocytes. J Invest Derm. 2014;134:1971–80.
80. Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, et al. Metformin inhibits mitochondrial complex 1 of cancer cells to reduce tumorigenesis. eLife. 2014;3:e02242.
81. El-Mir M-Y, Nogueria V, Fontaine E, Avéret N, Rigoulet M, Leserve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000;275:223–8.