Anticancer effects of metformin and its potential use as a therapeutic agent for breast cancer

Papers of special note have been highlighted as:   of interest

Bibliography

• 1  Rothwell PM: Treating individuals 2. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. Lancet365(9454),176–186 (2005).
  MedlineGoogle Scholar
• 2  Goodwin PJ, Stambolic V, Lemieux J et al.: 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(1),215–220 (2011).
  Medline CASGoogle Scholar
• 3  Maki RG: Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer. J. Clin. Oncol.28(33),4985–4995 (2010).
  Medline CASGoogle Scholar
• 4  Wolf I, Sadetzki S, Catane R, Karasik A, Kaufman B: Diabetes mellitus and breast cancer. Lancet Oncol.6(2),103–111 (2005).
  Medline CASGoogle Scholar
• 5  Larsson SC, Mantzoros CS, Wolk A: Diabetes mellitus and risk of breast cancer: a meta-analysis. Int. J. Cancer121(4),856–862 (2007).
  Medline CASGoogle Scholar
• 6  Del Giudice ME, Fantus IG, Ezzat S, Mckeown-Eyssen G, Page D, Goodwin PJ: Insulin and related factors in premenopausal breast cancer risk. Breast Cancer Res. Treat.47(2),111–120 (1998).
  Medline CASGoogle Scholar
• 7  Goodwin PJ, Ennis M, Pritchard KI et al.: Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J. Clin. Oncol.20(1),42–51 (2002).
  Medline CASGoogle Scholar
• 8  Pollak M: Insulin resistance, estimated by C-peptide level, is associated with reduced event-free survival for post-menopausal women in NCIC CTG MA.14 adjuvant breast cancer trial. J. Clin. Oncol.24(Suppl. 18), Abstract 524 (2006).
  Google Scholar
• 9  Goodwin PJ, Ennis M, Bahl M et al.: High insulin levels in newly diagnosed breast cancer patients reflect underlying insulin resistance and are associated with components of the insulin resistance syndrome. Breast Cancer Res. Treat.114(3),517–525 (2009).
  Medline CASGoogle Scholar
• 10  Alberti KG, Eckel RH, Grundy SM 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. Circulation120(16),1640–1645 (2009).
  Medline CASGoogle Scholar
• 11  Healy LA, Ryan AM, Carroll P et al.: Metabolic syndrome, central obesity and insulin resistance are associated with adverse pathological features in postmenopausal breast cancer. Clin. Oncol. (R. Coll. Radiol.)22(4),281–288 (2010).
  Medline CASGoogle Scholar
• 12  Maiti B, Kundranda MN, Spiro TP, Daw HA: The association of metabolic syndrome with triple-negative breast cancer. Breast Cancer Res. Treat.121(2),479–483 (2010).
  Medline CASGoogle Scholar
• 13  Pasanisi P, Berrino F, De Petris M, Venturelli E, Mastroianni A, Panico S: Metabolic syndrome as a prognostic factor for breast cancer recurrences. Int. J. Cancer119(1),236–238 (2006).
  Medline CASGoogle Scholar
• 14  Carboni JM, Lee AV, Hadsell DL et al.: Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor. Cancer Res.65(9),3781–3787 (2005).
  Medline CASGoogle Scholar
• 15  Frasca F, Pandini G, Vigneri R, Goldfine ID: Insulin and hybrid insulin/IGF receptors are major regulators of breast cancer cells. Breast Dis.17,73–89 (2003).
  Medline CASGoogle Scholar
• 16  Zha J, Lackner MR: Targeting the insulin-like growth factor receptor-1R pathway for cancer therapy. Clin. Cancer Res.16(9),2512–2517 (2010).
  Medline CASGoogle Scholar
• 17  Law 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.68(24),10238–10246 (2008).
  Medline CASGoogle Scholar
• 18  Rosenzweig SA, Atreya HS: Defining the pathway to insulin-like growth factor system targeting in cancer. Biochem. Pharmacol.80(8),1115–1124 (2010).
  Medline CASGoogle Scholar
• 19  Ryan PD, Goss PE: The emerging role of the insulin-like growth factor pathway as a therapeutic target in cancer. Oncologist13(1),16–24 (2008).
  Medline CASGoogle Scholar
• 20  Ligibel JA, Campbell N, Partridge A et al.: Impact of a mixed strength and endurance exercise intervention on insulin levels in breast cancer survivors. J. Clin. Oncol.26(6),907–912 (2008).
  Medline CASGoogle Scholar
• 21  Chlebowski RT, Blackburn GL, Thomson CA et al.: Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study. J. Natl Cancer Inst.98(24),1767–1776 (2006).
  MedlineGoogle Scholar
• 22  Goodwin PJ: Metformin lowers fasting insulin levels in hyperinsulinemia early stage breast cancer patients: Results of a Phase II study. Breast Cancer Res. Treat.100,S109(Suppl. 1) Abstract 2085 (2006).
  MedlineGoogle Scholar
• 23  Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD: Metformin and reduced risk of cancer in diabetic patients. BMJ330(7503),1304–1305 (2005).
  MedlineGoogle Scholar
• 24  Bowker SL, Majumdar SR, Veugelers P, Johnson JA: Increased cancer-related mortality for patients with Type 2 diabetes who use sulfonylureas or insulin. Diabetes Care29(2),254–258 (2006).
  MedlineGoogle Scholar
• 25  Landman GW, Kleefstra N, Van Hateren KJ, Groenier KH, Gans RO, Bilo HJ: Metformin associated with lower cancer mortality in Type 2 diabetes: ZODIAC-16. Diabetes Care33(2),322–326 (2010).
  Medline CASGoogle Scholar
• 26  Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM: New users of metformin are at low risk of incident cancer: a cohort study among people with Type 2 diabetes. Diabetes Care32(9),1620–1625 (2009).
  Medline CASGoogle Scholar
• 27  Currie CJ, Poole CD, Gale EA: The influence of glucose-lowering therapies on cancer risk in Type 2 diabetes. Diabetologia52(9),1766–1777 (2009).
  Medline CASGoogle Scholar
• 28  Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR: Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care33(6),1304–1308 (2010).
  Medline CASGoogle Scholar
• 29  Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M: Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res.66(21),10269–10273 (2006).▪ Preclinical study identifies metformin as an AMPK activator.
  Medline CASGoogle Scholar
• 30  Shaw RJ, Lamia KA, Vasquez D et al.: The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science310(5754),1642–1646 (2005).
  Medline CASGoogle Scholar
• 31  Giardiello FM, Brensinger JD, Tersmette AC et al.: Very high risk of cancer in familial Peutz–Jeghers syndrome. Gastroenterology119(6),1447–1453 (2000).
  Medline CASGoogle Scholar
• 32  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 Cancer8(6),501–505 (2008).
  Medline CASGoogle Scholar
• 33  Rozengurt E, Sinnett-Smith J, Kisfalvi K: Crosstalk between insulin/insulin-like growth factor-1 receptors and G protein-coupled receptor signaling systems: a novel target for the antidiabetic drug metformin in pancreatic cancer. Clin. Cancer Res.16(9),2505–2511 (2010).
  Medline CASGoogle Scholar
• 34  Ning J, Clemmons DR: AMP-activated protein kinase inhibits IGF-I signaling and protein synthesis in vascular smooth muscle cells via stimulation of insulin receptor substrate 1 S794 and tuberous sclerosis 2 S1345 phosphorylation. Mol. Endocrinol.24(6),1218–1229 (2010).
  Medline CASGoogle Scholar
• 35  Zhou G, Myers R, Li Y et al.: Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest.108(8),1167–1174 (2001).
  Medline CASGoogle Scholar
• 36  Hawley SA, Gadalla AE, Olsen GS, Hardie DG: The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes51(8),2420–2425 (2002).
  Medline CASGoogle Scholar
• 37  Cazzaniga M, Bonanni B, Guerrieri-Gonzaga A, Decensi A: Is it time to test metformin in breast cancer clinical trials? Cancer Epidemiol. Biomarkers Prev.18(3),701–705 (2009).
  Medline CASGoogle Scholar
• 38  Bachman KE, Argani P, Samuels Y et al.: The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol. Ther.3(8),772–775 (2004).
  Medline CASGoogle Scholar
• 39  Kondo Y, Kanzawa T, Sawaya R, Kondo S: The role of autophagy in cancer development and response to therapy. Nat. Rev. Cancer5(9),726–734 (2005).
  Medline CASGoogle Scholar
• 40  Wang W, Guan KL: AMP-activated protein kinase and cancer. Acta Physiol. (Oxf.)196(1),55–63 (2009).
  Medline CASGoogle Scholar
• 41  Ben Sahra I, Laurent K, Giuliano S et al.: Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res.70(6),2465–2475 (2010).
  Medline CASGoogle Scholar
• 42  Bailey CJ, Turner RC: Metformin. N. Engl. J. Med.334(9),574–579 (1996).
  Medline CASGoogle Scholar
• 43  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. Oncogene27(25),3576–3586 (2008).
  Medline CASGoogle Scholar
• 44  Alimova IN, Liu B, Fan Z et al.: Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle8(6),909–915 (2009).
  Medline CASGoogle Scholar
• 45  Pollak M: Insulin and insulin-like growth factor signalling in neoplasia. Nat. Rev. Cancer8(12),915–928 (2008).
  Medline CASGoogle Scholar
• 46  Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N: Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res.67(22),10804–10812 (2007).
  Medline CASGoogle Scholar
• 47  Bojkova B, Orendas P, Garajova M et al.: Metformin in chemically-induced mammary carcinogenesis in rats. Neoplasma56(3),269–274 (2009).
  Medline CASGoogle Scholar
• 48  Phoenix KN, 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.113(1),101–111 (2009).
  Medline CASGoogle Scholar
• 49  Liu B, Fan Z, Edgerton SM et al.: Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle8(13),2031–2040 (2009).
  Medline CASGoogle Scholar
• 50  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.69(19),7507–7511 (2009).
  Medline CASGoogle Scholar
• 51  Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA: The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells. Cell Cycle8(1),88–96 (2009).
  Medline CASGoogle Scholar
• 52  Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin-Castillo B, Menendez JA: The antidiabetic drug metformin: a pharmaceutical AMPK activator to overcome breast cancer resistance to HER2 inhibitors while decreasing risk of cardiomyopathy. Ann. Oncol.20(3),592–595 (2009).
  Medline CASGoogle Scholar
• 53  Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin-Castillo B, Menendez JA: mTOR inhibitors and the anti-diabetic biguanide metformin: new insights into the molecular management of breast cancer resistance to the HER2 tyrosine kinase inhibitor lapatinib (Tykerb). Clin. Transl Oncol.11(7),455–459 (2009).
  Medline CASGoogle Scholar
• 54  Xia W, Bisi J, Strum J et al.: Regulation of survivin by ErbB2 signaling: therapeutic implications for ErbB2-overexpressing breast cancers. Cancer Res.66(3),1640–1647 (2006).
  Medline CASGoogle Scholar
• 55  Zhang L, He H, Balschi JA: Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration. Am. J. Physiol. Heart Circ. Physiol.293(1),H457–H466 (2007).
  Medline CASGoogle Scholar
• 56  Shell SA, Lyass L, Trusk PB, Pry KJ, Wappel RL, Bacus SS: Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells. Cell Cycle7(12),1769–1775 (2008).
  Medline CASGoogle Scholar
• 57  Phoenix KN, Vumbaca F, Fox MM, Evans R, Claffey KP: Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy. Breast Cancer Res. Treat.123(2),333–344 (2010).
  Medline CASGoogle Scholar
• 58  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.27(20),3297–3302 (2009).▪ The first retrospective analysis linking metformin with clinical response in breast cancer patients.
  Medline CASGoogle Scholar
• 59  Martin-Castillo B, Dorca J, Vazquez-Martin A et al.: Incorporating the antidiabetic drug metformin in HER2-positive breast cancer treated with neo-adjuvant chemotherapy and trastuzumab: an ongoing clinical–translational research experience at the Catalan Institute of Oncology. Ann. Oncol.21(1),187–189 (2010).
  Medline CASGoogle Scholar
• 60  Muti P, Berrino F, Krogh V et al.: Metformin, diet and breast cancer: an avenue for chemoprevention. Cell Cycle8(16),2661 (2009).
  Medline CASGoogle Scholar
• 61  Hezel AF, Bardeesy N: LKB1; linking cell structure and tumor suppression. Oncogene27(55),6908–6919 (2008).
  Medline CASGoogle Scholar
• 62  Eechoute K, Sparreboom A, Burger H et al.: Drug transporters and imatinib treatment: implications for clinical practice. Clin. Cancer Res.17(3),406–415 (2010).
  MedlineGoogle Scholar
• 63  Legro RS, Barnhart HX, Schlaff WD et al.: Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. J. Clin. Endocrinol. Metab.93(3),792–800 (2008).
  Medline CASGoogle Scholar
• 64  Glamoclija U, Jevric-Causevic A: Genetic polymorphisms in diabetes: influence on therapy with oral antidiabetics. Acta Pharm.60(4),387–406 (2010).
  Medline CASGoogle Scholar
• 65  Ozulker T, Ozulker F, Mert M, Ozpacaci T: Clearance of the high intestinal (18)F-FDG uptake associated with metformin after stopping the drug. Eur. J. Nucl. Med. Mol. Imaging37(5),1011–1017 (2010).
  MedlineGoogle Scholar
• 101  Cancer Research UK website Detailed information regarding UK cancer survival statistics for individual tumor types http://info.cancerresearchuk.org/cancerstats/mortality/females
  Google Scholar
• 102  ClinicalTrials.gov A searchable database which provides patients, family members and the public with information about current ongoing clinical research studies taking place world-wide http://ClinicalTrials.gov
  Google Scholar
• 103  Metformin Pre-Surgical Pilot Study http://clinicaltrials.gov/ct2/show/NCT00930579?term=breast+cancer+metformin&rank=7
  Google Scholar
• 104  The Use of Metformin in Early Breast Cancer Patients Pre-Surgery http://clinicaltrials.gov/ct2/show?term=breast+cancer+metformin&rank=1
  Google Scholar
• 105  Metformin and Temsirolimus in Treating Patients With Metastatic or Unresectable Solid Tumor or Lymphoma http://clinicaltrials.gov/ct2/show/NCT00659568?term=metformin+and+cancer&rank=6
  Google Scholar
• 106  Metformin Hydrochloride in Treating Women With Stage I or Stage II Breast Cancer That Can Be Removed By Surgery http://clinicaltrials.gov/ct2/show?term=breast+cancer+metformin&rank=4
  Google Scholar