Metformin: a Therapeutic Opportunity in Breast Cancer

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2010 Mar 11

PMID 20215559

Citations 86

Authors

Ana M Gonzalez-Angulo

Funda Meric-Bernstam

Affiliations

Soon will be listed here.

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.

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References

Buzzai M, Jones R, Amaravadi R, Lum J, DeBerardinis R, Zhao F . Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 2007; 67(14):6745-52. DOI: 10.1158/0008-5472.CAN-06-4447. View

Manning B, Cantley L . AKT/PKB signaling: navigating downstream. Cell. 2007; 129(7):1261-74. PMC: 2756685. DOI: 10.1016/j.cell.2007.06.009. View

Dowling R, Zakikhani M, Fantus I, Pollak M, Sonenberg N . Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 2007; 67(22):10804-12. DOI: 10.1158/0008-5472.CAN-07-2310. View

Goodwin P . Insulin in the adjuvant breast cancer setting: a novel therapeutic target for lifestyle and pharmacologic interventions?. J Clin Oncol. 2008; 26(6):833-4. DOI: 10.1200/JCO.2007.14.7132. View

Gwinn D, Shackelford D, Egan D, Mihaylova M, Mery A, Vasquez D . AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008; 30(2):214-26. PMC: 2674027. DOI: 10.1016/j.molcel.2008.03.003. View

Lochhead P, Salt I, Walker K, Hardie D, Sutherland C . 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. 2000; 49(6):896-903. DOI: 10.2337/diabetes.49.6.896. View

Neshat M, Mellinghoff I, Tran C, Stiles B, Thomas G, Petersen R . Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A. 2001; 98(18):10314-9. PMC: 56958. DOI: 10.1073/pnas.171076798. View

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J . Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108(8):1167-74. PMC: 209533. DOI: 10.1172/JCI13505. View

Fisher J, Gao J, Han D, Holloszy J, Nolte L . Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin. Am J Physiol Endocrinol Metab. 2001; 282(1):E18-23. DOI: 10.1152/ajpendo.2002.282.1.E18. View

10.

Lopez T, Hanahan D . Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. Cancer Cell. 2002; 1(4):339-53. DOI: 10.1016/s1535-6108(02)00055-7. View

11.

Krause U, Bertrand L, Hue L . 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. 2002; 269(15):3751-9. DOI: 10.1046/j.1432-1033.2002.03074.x. View

12.

Inoki K, Li Y, Zhu T, Wu J, Guan K . TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 2002; 4(9):648-57. DOI: 10.1038/ncb839. View

13.

Firth S, Baxter R . Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev. 2002; 23(6):824-54. DOI: 10.1210/er.2001-0033. View

14.

Johnson G, Lapadat R . Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002; 298(5600):1911-2. DOI: 10.1126/science.1072682. View

15.

Kovacic S, Soltys C, Barr A, Shiojima I, Walsh K, Dyck J . Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. J Biol Chem. 2003; 278(41):39422-7. DOI: 10.1074/jbc.M305371200. View

16.

Baserga R, Peruzzi F, Reiss K . The IGF-1 receptor in cancer biology. Int J Cancer. 2003; 107(6):873-7. DOI: 10.1002/ijc.11487. View

17.

Inoki K, Zhu T, Guan K . TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003; 115(5):577-90. DOI: 10.1016/s0092-8674(03)00929-2. View

18.

OConnor R . Regulation of IGF-I receptor signaling in tumor cells. Horm Metab Res. 2004; 35(11-12):771-7. DOI: 10.1055/s-2004-814166. View

19.

Bjornsti M, Houghton P . The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 2004; 4(5):335-48. DOI: 10.1038/nrc1362. View

20.

Pollak M, Schernhammer E, Hankinson S . Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004; 4(7):505-18. DOI: 10.1038/nrc1387. View