311
Views
42
CrossRef citations to date
0
Altmetric
Review

Obesity, hyperinsulinemia and breast cancer: novel targets and a novel role for metformin

&
Pages 509-519 | Published online: 09 Jan 2014

References

  • Pathak DR, Whittemore AS. Combined effects of body size, parity, and menstrual events on breast cancer incidence in seven countries. Am. J. Epidemiol.135(2), 153–168 (1992).
  • Peacock SL, White E, Daling JR, Voigt LF, Malone KE. Relation between obesity and breast cancer in young women. Am. J. Epidemiol.149(4), 339–346 (1999).
  • Weiderpass E, Braaten T, Magnusson C et al. A prospective study of body size in different periods of life and risk of premenopausal breast cancer. Cancer Epidemiol. Biomarkers Prev.13(7), 1121–1127 (2004).
  • Berclaz G, Li S, Price KN et al. Body mass index as a prognostic feature in operable breast cancer: the International Breast Cancer Study Group experience. Ann. Oncol.15(6), 875–884 (2004).
  • Maehle BO, Tretli S, Skjaerven R, Thorsen T. Premorbid body weight and its relations to primary tumour diameter in breast cancer patients; its dependence on estrogen and progesteron receptor status. Breast Cancer Res. Treat.68(2), 159–169 (2001).
  • Feigelson HS, Patel AV, Teras LR, Gansler T, Thun MJ, Calle EE. Adult weight gain and histopathologic characteristics of breast cancer among postmenopausal women. Cancer107(1), 12–21 (2006).
  • Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med.348(17), 1625–1638 (2003).
  • Dal Maso L, Zucchetto A, Talamini R et al. Effect of obesity and other lifestyle factors on mortality in women with breast cancer. Int. J. Cancer123(9), 2188–2194 (2008).
  • Reeves KW, Faulkner K, Modugno F et al. Body mass index and mortality among older breast cancer survivors in the Study of Osteoporotic Fractures. Cancer Epidemiol. Biomarkers Prev.16(7), 1468–1473 (2007).
  • Grodin JM, Siiteri PK, MacDonald PC. Source of estrogen production in postmenopausal women. J. Clin. Endocrinol. Metab.36(2), 207–214 (1973).
  • van Landeghem AA, Poortman J, Nabuurs M, Thijssen JH. Endogenous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue. Cancer Res.45(6), 2900–2906 (1985).
  • Purohit A, Newman SP, Reed MJ. The role of cytokines in regulating estrogen synthesis: implications for the etiology of breast cancer. Breast Cancer Res.4(2), 65–69 (2002).
  • Thomas HV, Reeves GK, Key TJ. Endogenous estrogen and postmenopausal breast cancer: a quantitative review. Cancer Causes Control8(6), 922–928 (1997).
  • Key T, Appleby P, Barnes I, Reeves G. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J. Natl Cancer Inst.94(8), 606–616 (2002).
  • Kaaks R, Rinaldi S, Key TJ et al. Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr. Relat. Cancer12(4), 1071–1082 (2005).
  • Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE. Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J. Natl Cancer Inst.96(24), 1856–1865 (2004).
  • 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).
  • Michels KB, Solomon CG, Hu FB et al. Type 2 diabetes and subsequent incidence of breast cancer in the Nurses’ Health Study. Diabetes Care26(6), 1752–1758 (2003).
  • Maor S, Mayer D, Yarden RI et al. Estrogen receptor regulates insulin-like growth factor-I receptor gene expression in breast tumor cells: involvement of transcription factor Sp1. J. Endocrinol.191(3), 605–612 (2006).
  • Maor S, Papa MZ, Yarden RI et al. Insulin-like growth factor-I controls BRCA1 gene expression through activation of transcription factor Sp1. Horm. Metab. Res.39(3), 179–185 (2007).
  • Maor S, Yosepovich A, Papa MZ et al. Elevated insulin-like growth factor-I receptor (IGF-IR) levels in primary breast tumors associated with BRCA1 mutations. Cancer Lett.257(2), 236–243 (2007).
  • Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr. Rev.30(6), 586–623 (2009).
  • Cox ME, Gleave ME, Zakikhani M et al. Insulin receptor expression by human prostate cancers. Prostate69(1), 33–40 (2009).
  • 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).
  • Osborne CK, Bolan G, Monaco ME, Lippman ME. Hormone responsive human breast cancer in long-term tissue culture: effect of insulin. Proc. Natl Acad. Sci. USA73(12), 4536–4540 (1976).
  • Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat. Rev. Cancer8(12), 915–928 (2008).
  • De Souza AT, Hankins GR, Washington MK, Orton TC, Jirtle RL. M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. Nat. Genet.11(4), 447–449 (1995).
  • Zhu W, Shiojima I, Ito Y et al. IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis. Nature454(7202), 345–349 (2008).
  • Heuson JC, Legros N. Effect of insulin on DNA synthesis and DNA polymerase activity in organ culture of rat mammary carcinoma, and the inflence of insulin pretreatment and of alloxan diabetes. Cancer Res.31(1), 59–65 (1971).
  • Heuson JC, Legros N. Influence of insulin deprivation on growth of the 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats subjected to alloxan diabetes and food restriction. Cancer Res.32(2), 226–232 (1972).
  • Pollak MN, Perdue JF, Margolese RG, Baer K, Richard M. Presence of somatomedin receptors on primary human breast and colon carcinomas. Cancer Lett.38(1–2), 223–230 (1987).
  • Myal Y, Shiu RP, Bhaumick B, Bala M. Receptor binding and growth-promoting activity of insulin-like growth factors in human breast cancer cells (T-47D) in culture. Cancer Res.44(12 Pt 1), 5486–5490 (1984).
  • Sell C, Rubini M, Rubin R, Liu JP, Efstratiadis A, Baserga R. Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor. Proc. Natl Acad. Sci. USA90(23), 11217–11221 (1993).
  • Cohen BD, Baker DA, Soderstrom C et al. Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751,871. Clin. Cancer Res.11(5), 2063–2073 (2005).
  • Goya M, Miyamoto S, Nagai K et al. Growth inhibition of human prostate cancer cells in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice by a ligand-specific antibody to human insulin-like growth factors. Cancer Res.64(17), 6252–6258 (2004).
  • Haluska P, Carboni JM, Loegering DA et al.In vitro and in vivo antitumor effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417. Cancer Res.66(1), 362–371 (2006).
  • Byrne C, Colditz GA, Willett WC, Speizer FE, Pollak M, Hankinson SE. Plasma insulin-like growth factor (IGF) I, IGF-binding protein 3, and mammographic density. Cancer Res.60(14), 3744–3748 (2000).
  • Diorio C, Pollak M, Byrne C et al. Insulin-like growth factor-I, IGF-binding protein-3, and mammographic breast density. Cancer Epidemiol. Biomarkers Prev.14(5), 1065–1073 (2005).
  • Diorio C, Brisson J, Berube S, Pollak M. Genetic polymorphisms involved in insulin-like growth factor (IGF) pathway in relation to mammographic breast density and IGF levels. Cancer Epidemiol. Biomarkers Prev.17(4), 880–888 (2008).
  • Schernhammer ES, Holly JM, Hunter DJ, Pollak MN, Hankinson SE. Insulin-like growth factor-I, its binding proteins (IGFBP-1 and IGFBP-3), and growth hormone and breast cancer risk in The Nurses Health Study II. Endocr. Relat. Cancer13(2), 583–592 (2006).
  • Fagan DH, Yee D. Crosstalk between IGF1R and estrogen receptor signaling in breast cancer. J. Mammary Gland Biol. Neoplasia13(4), 423–429 (2008).
  • Lanzino M, Morelli C, Garofalo C et al. Interaction between estrogen receptor a and insulin/IGF signaling in breast cancer. Curr. Cancer Drug Targets8(7), 597–610 (2008).
  • Jackson JG, Zhang X, Yoneda T, Yee D. Regulation of breast cancer cell motility by insulin receptor substrate-2 (IRS-2) in metastatic variants of human breast cancer cell lines. Oncogene20(50), 7318–7325 (2001).
  • Molloy CA, May FE, Westley BR. Insulin receptor substrate-1 expression is regulated by estrogen in the MCF-7 human breast cancer cell line. J. Biol. Chem.275(17), 12565–12571 (2000).
  • Mawson A, Lai A, Carroll JS, Sergio CM, Mitchell CJ, Sarcevic B. Estrogen and insulin/IGF-1 cooperatively stimulate cell cycle progression in MCF-7 breast cancer cells through differential regulation of c-Myc and cyclin D1. Mol. Cell Endocrinol.229(1>–2), 161–173 (2005).
  • Ingle JN, Suman VJ, Kardinal CG et al. A randomized trial of tamoxifen alone or combined with octreotide in the treatment of women with metastatic breast carcinoma. Cancer85(6), 1284–1292 (1999).
  • Bruchim I, Attias Z, Werner H. Targeting the IGF1 axis in cancer proliferation. Expert Opin. Ther. Targets13(10), 1179–1192 (2009).
  • Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat. Rev. Cancer2(7), 489–501 (2002).
  • White MF. The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol. Cell. Biochem.182(1–2), 3–11 (1998).
  • Pandolfi PP. Breast cancer – loss of PTEN predicts resistance to treatment. N. Engl. J. Med.351(22), 2337–2338 (2004).
  • Scheid MP, Woodgett JR. PKB/AKT: functional insights from genetic models. Nat. Rev. Mol. Cell Biol.2(10), 760–768 (2001).
  • Gonzalez E, McGraw TE. The Akt kinases: isoform specificity in metabolism and cancer. Cell Cycle8(16), 2502–2508 (2009).
  • Bellacosa A, Chan TO, Ahmed NN et al. Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene17(3), 313–325 (1998).
  • Alessi DR, James SR, Downes CP et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Ba. Curr. Biol.7(4), 261–269 (1997).
  • Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature411(6835), 355–365 (2001).
  • Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell103(2), 253–262 (2000).
  • Thomas G, Hall MN. TOR signalling and control of cell growth. Curr. Opin. Cell. Biol.9(6), 782–787 (1997).
  • Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat. Rev. Drug Discov.5(8), 671–688 (2006).
  • Kim DH, Sarbassov DD, Ali SM et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell11(4), 895–904 (2003).
  • Kim DH, Sarbassov DD, Ali SM et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell110(2), 163–175 (2002).
  • Sarbassov DD, Ali SM, Kim DH et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol.14(14), 1296–1302 (2004).
  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science3075712), 1098–1101 (2005).
  • Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol. Med.11(8), 353–361 (2005).
  • Martin DE, Hall MN. The expanding TOR signaling network. Curr. Opin. Cell. Biol.17(2), 158–166 (2005).
  • Garcia JA, Danielpour D. Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies. Mol. Cancer Ther.7(6), 1347–1354 (2008).
  • Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSC–mTOR pathway in human disease. Nat. Genet.37(1), 19–24 (2005).
  • Manning BD, Cantley LC. United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. Biochem. Soc. Trans.31(Pt 3), 573–578 (2003).
  • Sancak Y, Thoreen CC, Peterson TR et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell.25(6), 903–915 (2007).
  • Rosenwald IB, Kaspar R, Rousseau D et al. Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels. J. Biol. Chem.270(36), 21176–21180 (1995).
  • Rousseau D, Kaspar R, Rosenwald I, Gehrke L, Sonenberg N. Translation initiation of ornithine decarboxylase and nucleocytoplasmic transport of cyclin D1 mRNA are increased in cells overexpressing eukaryotic initiation factor 4E. Proc. Natl Acad. Sci. USA93(3), 1065–1070 (1996).
  • Hudson CC, Liu M, Chiang GG et al. Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol. Cell. Biol.22(20), 7004–7014 (2002).
  • Toschi A, Lee E, Gadir N, Ohh M, Foster DA. Differential dependence of hypoxia-inducible factors 1{α} and 2{α} on mTORC1 and mTORC2. J. Biol. Chem.283(50), 34495–34499 (2008).
  • Adjei AA, Hidalgo M. Intracellular signal transduction pathway proteins as targets for cancer therapy. J. Clin. Oncol.23(23), 5386–5403 (2005).
  • Jacinto E, Facchinetti V, Liu D et al. SIN1/MIP1 maintains rictor–mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell127(1), 125–137 (2006).
  • Clark AS, West K, Streicher S, Dennis PA. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol. Cancer Ther.1(9), 707–717 (2002).
  • Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res.62(12), 3387–3394 (2002).
  • Bos R, van Diest PJ, de Jong JS, van der Groep P, van der Valk P, van der Wall E. Hypoxia-inducible factor-1α is associated with angiogenesis, and expression of bFGF, PDGF-BB, and EGFR in invasive breast cancer. Histopathology46(1), 31–36 (2005).
  • Sullivan R, Graham CH. Hypoxia prevents etoposide-induced DNA damage in cancer cells through a mechanism involving hypoxia-inducible factor 1. Mol. Cancer Ther.8(6), 1702–1713 (2009).
  • Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature407(6803), 538–541 (2000).
  • deGraffenried LA, Friedrichs WE, Russell DH et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin. Cancer Res.10(23), 8059–8067 (2004).
  • Cui X, Zhang P, Deng W et al. Insulin-like growth factor-I inhibits progesterone receptor expression in breast cancer cells via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway: progesterone receptor as a potential indicator of growth factor activity in breast cancer. Mol. Endocrinol.17(4), 575–588 (2003).
  • Yatscoff RW, LeGatt DF, Kneteman NM. Therapeutic monitoring of rapamycin: a new immunosuppressive drug. Ther. Drug Monit.15(6), 478–482 (1993).
  • Neshat MS, Mellinghoff IK, Tran C et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl Acad. Sci. USA98(18), 10314–10319 (2001).
  • Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J. Natl Cancer Inst.92(18), 1472–1489 (2000).
  • Fung AS, Wu L, Tannock IF. Concurrent and sequential administration of chemotherapy and the Mammalian target of rapamycin inhibitor temsirolimus in human cancer cells and xenografts. Clin. Cancer Res.15(17), 5389–5395 (2009).
  • Chan S, Scheulen ME, Johnston S et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J. Clin. Oncol.23(23), 5314–5322 (2005).
  • Baselga J, Semiglazov V, van Dam P et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J. Clin. Oncol.27(16), 2630–2637 (2009).
  • Barb D, Pazaitou-Panayiotou K, Mantzoros CS. Adiponectin: a link between obesity and cancer. Expert Opin. Investig. Drugs15(8), 917–931 (2006).
  • Tsuchida A, Yamauchi T, Ito Y et al. Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity. J. Biol. Chem.279(29), 30817–30822 (2004).
  • Mantzoros C, Petridou E, Dessypris N et al. Adiponectin and breast cancer risk. J. Clin. Endocrinol. Metab.89(3), 1102–1107 (2004).
  • Miyoshi Y, Funahashi T, Kihara S et al. Association of serum adiponectin levels with breast cancer risk. Clin. Cancer Res.9(15), 5699–5704 (2003).
  • Denzel MS, Hebbard LW, Shostak G, Shapiro L, Cardiff RD, Ranscht B. Adiponectin deficiency limits tumor vascularization in the MMTV-PyV-mT mouse model of mammary cancer. Clin. Cancer Res.15(10), 3256–3264 (2009).
  • Landskroner-Eiger S, Qian B, Muise ES et al. Proangiogenic contribution of adiponectin toward mammary tumor growth in vivo. Clin. Cancer Res.15(10), 3265–3276 (2009).
  • Stefan N, Vozarova B, Funahashi T et al. Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans. Diabetes51(6), 1884–1888 (2002).
  • Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell103(2), 239–252 (2000).
  • Hirosumi J, Tuncman G, Chang L et al. A central role for JNK in obesity and insulin resistance. Nature420(6913), 333–336 (2002).
  • Frank DA. STAT3 as a central mediator of neoplastic cellular transformation. Cancer Lett.251(2), 199–210 (2007).
  • Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet RJ Jr, Sledge GW Jr. Constitutive activation of NF-kB during progression of breast cancer to hormone-independent growth. Mol. Cell. Biol.17(7), 3629–3639 (1997).
  • Ahmed KM, Dong S, Fan M, Li JJ. Nuclear factor-κB p65 inhibits mitogen-activated protein kinase signaling pathway in radioresistant breast cancer cells. Mol. Cancer Res.4(12), 945–955 (2006).
  • Ouchi N, Kihara S, Arita Y et al. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-κB signaling through a cAMP-dependent pathway. Circulation102(11), 1296–1301 (2000).
  • Gwinn DM, Shackelford DB, Egan DF et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell30(2), 214–226 (2008).
  • Lee JH, Koh H, Kim M et al. Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature447(7147), 1017–1020 (2007).
  • Mirouse V, Swick LL, Kazgan N, St Johnston D, Brenman JE. LKB1 and AMPK maintain epithelial cell polarity under energetic stress. J. Cell Biol.177(3), 387–392 (2007).
  • Sakamoto K, McCarthy A, Smith D et al. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J.24(10), 1810–1820 (2005).
  • 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).
  • 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).
  • 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).
  • 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 (2009).
  • 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).
  • 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).
  • Anisimov VN, Egormin PA, Piskunova TS 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 Cycle9(1), 188–197 (2010).
  • 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).
  • 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).
  • Millikan RC, Newman B, Tse CK et al. Epidemiology of basal-like breast cancer. Breast Cancer Res. Treat.109(1), 123–139 (2008).
  • Yang XR, Sherman ME, Rimm DL et al. Differences in risk factors for breast cancer molecular subtypes in a population-based study. Cancer Epidemiol. Biomarkers Prev.16(3), 439–443 (2007).
  • Menendez JA, Vellon L, Mehmi I et al. Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc. Natl Acad. Sci. USA101(29), 10715–10720 (2004).
  • Pike LJ. Lipid rafts: bringing order to chaos. J. Lipid Res.44(4), 655–667 (2003).
  • Menendez JA, Vellon L, Lupu R. Targeting fatty acid synthase-driven lipid rafts: a novel strategy to overcome trastuzumab resistance in breast cancer cells. Med. Hypotheses64(5), 997–1001 (2005).
  • 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).
  • Ginestier C, Hur MH, Charafe-Jauffret E et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell1(5), 555–567 (2007).
  • 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).
  • Wysocki PJ. mTOR in renal cell cancer: modulator of tumor biology and therapeutic target. Expert Rev. Mol. Diagn.9(3), 231–241 (2009).
  • 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).
  • Ellison G, Klinowska T, Westwood RF, Docter E, French T, Fox JC. Further evidence to support the melanocytic origin of MDA-MB-435. Mol. Pathol.55(5), 294–299 (2002).
  • Willer A. Reduction of the individual cancer risk by physical exercise. Onkologie26(3), 283–289 (2003).
  • Wysocki PJ, Wysocki H. Cardiovascular complications associated with biological therapies for breast cancer. Expert Opin. Biol. Ther.8(10), 1551–1559 (2008).
  • 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).
  • Buzzai M, Jones RG, Amaravadi RK et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res.67(14), 6745–6752 (2007).
  • Memmott RM, Dennis PA. LKB1 and mammalian target of rapamycin as predictive factors for the anticancer efficacy of metformin. J. Clin. Oncol.27(34), e226; author reply e227 (2009).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.