Metformin: A Therapeutic Opportunity in Breast Cancer

Clinical Cancer Research - Tập 16 Số 6 - Trang 1695-1700 - 2010
Ana María González-Angulo1, Funda Meric‐Bernstam1
1Authors' Affiliations: Departments of 1Breast Medical Oncology, 2Systems Biology, and 3Surgical Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas

Tóm tắt

Abstract Two important, related pathways are involved in cancer growth: the insulin/insulin-like growth factor-1 (IGF1) signaling pathway, which is activated when nutrients are available, and the adenosine mono-phosphate-activated protein kinase (AMPK) pathway, activated when cells are starved for carbohydrates. Metformin inhibits transcription of key gluconeogenesis genes in the liver, increases glucose uptake in skeletal muscle, and decreases circulating insulin levels. Metformin reduces levels of circulating glucose, increases insulin sensitivity, and reduces insulin resistance-associated hyperinsulinemia. At the level of cell signaling, metformin activates AMPK. There are extensive preclinical data showing the anticancer effects of metformin in all breast cancer subtypes as well as in cytotoxic therapy-resistant models. These data, and the epidemiological and retrospective data supporting the antineoplastic effects of metformin, provide the rationale to study the role of metformin for breast cancer therapy in a variety of clinical settings. Clin Cancer Res; 16(6); 1695–700

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Tài liệu tham khảo

Towler, 2007, AMP-activated protein kinase in metabolic control and insulin signaling, Circ Res, 100, 328, 10.1161/01.RES.0000256090.42690.05

Inoki, 2003, TSC2 mediates cellular energy response to control cell growth and survival, Cell, 115, 577, 10.1016/S0092-8674(03)00929-2

Inoki, 2002, TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling, Nat Cell Biol, 4, 648, 10.1038/ncb839

Kovacic, 2003, Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart, J Biol Chem, 278, 39422, 10.1074/jbc.M305371200

Horman, 2006, Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase alpha-subunits in heart via hierarchical phosphorylation of Ser485/491, J Biol Chem, 281, 5335, 10.1074/jbc.M506850200

Kramer, 2006, Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle, Diabetes, 55, 2067, 10.2337/db06-0150

Fisher, 2002, Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin, Am J Physiol Endocrinol Metab, 282, E18, 10.1152/ajpendo.2002.282.1.E18

Um, 2004, Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity, Nature, 431, 200, 10.1038/nature02866

Harrington, 2004, The TSC1–2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins, J Cell Biol, 166, 213, 10.1083/jcb.200403069

Shah, 2004, Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies, Curr Biol, 14, 1650, 10.1016/j.cub.2004.08.026

Lochhead, 2000, 5-Aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase, Diabetes, 49, 896, 10.2337/diabetes.49.6.896

Wijkander, 1998, Insulin-induced phosphorylation and activation of phosphodiesterase 3B in rat adipocytes: possible role for protein kinase B but not mitogen-activated protein kinase or p70 S6 kinase, Endocrinology, 139, 219, 10.1210/endo.139.1.5693

Garton, 1989, Phosphorylation of bovine hormone-sensitive lipase by the AMP-activated protein kinase. A possible antilipolytic mechanism, Eur J Biochem, 179, 249, 10.1111/j.1432-1033.1989.tb14548.x

Baserga, 2003, The IGF-1 receptor in cancer biology, Int J Cancer, 107, 873, 10.1002/ijc.11487

Manning, 2007, AKT/PKB signaling: navigating downstream, Cell, 129, 1261, 10.1016/j.cell.2007.06.009

Johnson, 2002, Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases, Science, 298, 1911, 10.1126/science.1072682

Firth, 2002, Cellular actions of the insulin-like growth factor binding proteins, Endocr Rev, 23, 824, 10.1210/er.2001-0033

O'Connor, 2003, Regulation of IGF-I receptor signaling in tumor cells, Horm Metab Res, 35, 771, 10.1055/s-2004-814166

Wan, 2007, Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism, Oncogene, 26, 1932, 10.1038/sj.onc.1209990

Sell, 1994, Effect of a null mutation of the insulin like factor I receptor gene on growth and transformation of mouse embryo fibroblasts, Mol Cancer Biol, 14, 3604

Lopez, 2002, Elevated levels IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis, Cancer Cell, 1, 339, 10.1016/S1535-6108(02)00055-7

Jones, 2007, Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation, Oncogene, 26, 1636, 10.1038/sj.onc.1209955

Hay, 2004, Upstream and downstream of mTOR, Genes Dev, 18, 1926, 10.1101/gad.1212704

Neshat, 2001, Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR, Proc Natl Acad Sci U S A, 98, 10314, 10.1073/pnas.171076798

Bjornsti, 2004, The TOR pathway: a target for cancer therapy, Nat Rev Cancer, 4, 335, 10.1038/nrc1362

Petroulakis, 2006, mTOR signaling: implications for cancer and anticancer therapy, Br J Cancer, 94, 195, 10.1038/sj.bjc.6602902

Meric-Bernstam, 2009, Targeting the mTOR signaling network for cancer therapy, J Clin Oncol, 27, 2278, 10.1200/JCO.2008.20.0766

Evans, 2005, Metformin and reduced risk of cancer in diabetic patients, BMJ, 330, 1304, 10.1136/bmj.38415.708634.F7

Bowker, 2006, Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin, Diabetes Care, 29, 254, 10.2337/diacare.29.02.06.dc05-1558

Goodwin, 2008, Insulin in the adjuvant breast cancer setting: a novel therapeutic target for lifestyle and pharmacologic interventions?, J Clin Oncol, 26, 833, 10.1200/JCO.2007.14.7132

Wolf, 2005, Diabetes mellitus and breast cancer, Lancet Oncol, 6, 103, 10.1016/S1470-2045(05)01736-5

Calle, 2004, Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms, Nat Rev Cancer, 4, 579, 10.1038/nrc1408

Renehan, 2006, Obesity and cancer risk: the role of the insulin-IGF axis, Trends Endocrinol Metab, 17, 328, 10.1016/j.tem.2006.08.006

Pollak, 2004, Insulin-like growth factors and neoplasia, Nat Rev Cancer, 4, 505, 10.1038/nrc1387

Yee, 2006, Targeting insulin-like growth factor pathways, Br J Cancer, 94, 465, 10.1038/sj.bjc.6602963

Alimova, 2009, Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro, Cell Cycle, 8, 910, 10.4161/cc.8.6.7933

Zakikhani, 2006, Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells, Cancer Res, 66, 10269, 10.1158/0008-5472.CAN-06-1500

Dowling, 2007, Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells, Cancer Res, 67, 10804, 10.1158/0008-5472.CAN-07-2310

Ben Sahra, 2008, The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level, Oncogene, 27, 3576, 10.1038/sj.onc.1211024

Buzzai, 2007, Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth, Cancer Res, 67, 6745, 10.1158/0008-5472.CAN-06-4447

Jiralerspong, 2009, Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer, J Clin Oncol, 27, 3297, 10.1200/JCO.2009.19.6410

Cusi, 1998, Metformin: A review of its metabolic effects, Diabetes Res, 6, 89

Zhou, 2001, Role of AMP-activated protein kinase in mechanism of metformin action, J Clin Invest, 108, 1167, 10.1172/JCI13505

Alessi, 2006, Lkb1-dependent signaling pathways, Annu Rev Biochem, 75, 137, 10.1146/annurev.biochem.75.103004.142702

Hardie, 2007, AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy, Nat Rev Mol Cell Biol, 8, 774, 10.1038/nrm2249

Krause, 2002, Control of p70 ribosomal protein S6 kinase and acetyl-CoA carboxylase by AMP-activated protein kinase and protein phosphatases in isolated hepatocytes, Eur J Biochem, 269, 3751, 10.1046/j.1432-1033.2002.03074.x

Gwinn, 2008, AMPK phosphorylation of raptor mediates a metabolic checkpoint, Mol Cell, 30, 214, 10.1016/j.molcel.2008.03.003

Hardie, 2008, AMPK and Raptor: Matching Cell Growth with Energy Supply, Mol Cell, 30, 263, 10.1016/j.molcel.2008.04.012

Phoenix, 2009, Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERa negative MDA-MB-435 breast cancer model, Breast Cancer Res Treat, 113, 101, 10.1007/s10549-008-9916-5

Liu, 2009, Metformin induces unique biological and molecular responses in triple negative breast cancer cells, Cell Cycle, 8, 2031, 10.4161/cc.8.13.8814

Hirsch, 2009, Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission, Cancer Res, 69, 7507, 10.1158/0008-5472.CAN-09-2994

Martin-Castillo, 2009, 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, 187, 10.1093/annonc/mdp494

Cazzaniga, 2009, Is it time to test metformin in breast cancer clinical trials?, Cancer Epidemiol Biomarkers Prev, 18, 701, 10.1158/1055-9965.EPI-08-0871

Bailey, 1996, Metformin, N Engl J Med, 334, 574, 10.1056/NEJM199602293340906

Ehrmann, 1997, Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome, J Clin Endocrinol Metab, 82, 524