The Effect of Leptin Administration on Mammary Tumor Growth in Diabetic Mice

K. Bitton-Worms; R. Rostoker; S. Braun; Z. Shen-Orr; D. LeRoith

doi:10.1055/s-0033-1345151

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2013; 45(09): 655-659
DOI: 10.1055/s-0033-1345151

Original Basic

The Effect of Leptin Administration on Mammary Tumor Growth in Diabetic Mice

K. Bitton-Worms

¹Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel

,

R. Rostoker

¹Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel

,

S. Braun

¹Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel

,

Z. Shen-Orr

¹Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel

,

D. LeRoith

¹Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR) and the Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel

› Author Affiliations

Abstract

Obesity is associated with hyperleptinemia and this has led to the suggestion that leptin maybe a factor in cancer progression. To study the effect of leptin on cancer progression we used a mouse model of diabetes that was shown to enhance tumor progression and thereby determine if leptin affects cancer progression despite improvements in metabolic status. Mammary tumors were allowed to develop in male and female mice following orthotopic injection of cells expressing oncogenes. After 2 weeks leptin was administered to the mice using Alzet pumps. In these mice leptin failed to stimulate tumor progression; indeed, in those studies where glucose tolerance improved tumor growth was actually inhibited. Thus, the possibility exists that the effect of leptin on tumor progression maybe opposed by improvements in metabolism.

Key words

cancer - leptin - metabolism

Full Text

References

References
1 Loi S, Milne RL, Friedlander ML, McCredie MRE, Giles GG, Hopper JL, Phillips KA. Obesity and outcomes in premenopausal and postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev 2005; 14: 1686-1691
2 Porter GA, Inglis KM, Wood LA, Veugelers PJ. Effect of obesity on presentation of breast cancer. Ann Surg Oncol 2006; 13: 327-332
3 Harvie M, Hooper L, Howell A. Central obesity and breast cancer risk: a systematic review. Obesity Rev 2003; 4: 157-173
4 Dawood S, Broglio K, Gonzalez-Angulo AM, Kau SW, Islam R, Hortobagyi GN, Cristofanilli M. Prognostic value of body mass index in locally advanced breast cancer. Clin Cancer Res 2008; 14: 1718-1725
5 Daling JR, Malone KE, Doody DR, Johnson LG, Gralow JR, Porter PL. Relation of body mass index to tumor markers and survival among young women with invasive ductal breast carcinoma. Cancer 2001; 92: 720-729
6 Agnoli C, Berrino F, Abagnato CA, Muti P, Panico S, Crosignani P, Krogh V. Metabolic syndrome and postmenopausal breast cancer in the ORDET cohort: A nested case-control study. Nutr Metab Cardiovasc Dis 2010; 20: 41-48
7 Pasanisi P, Berrino F, De Petris M, Venturelli E, Mastroianni A, Panico S. Metabolic syndrome as a prognostic factor for breast cancer recurrences. Inter J Cancer 2006; 119: 236-238
8 Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Taylor SK, Hood N. Insulin-and obesity-related variables in early-stage breast cancer: correlations and time course of prognostic associations. J Clin Oncol 2012; 30: 164-171
9 De Stefani E, Mendilaharsu M, Deneo-Pellegrini H, Ronco A. Influence of dietary levels of fat, cholesterol, and calcium on colorectal cancer. Nutr Cancer 1997; 29: 83-89
10 Platz EA, Clinton SK, Giovannucci E. Association between plasma cholesterol and prostate cancer in the PSA era. Inter J Cancer 2008; 123: 1693-1698
11 Zielinski C, Stuller I, Rausch P, Müller C. Increased serum concentrations of cholesterol and triglycerides in the progression of breast cancer. J Cancer Res Clin Oncol 1988; 114: 514-518
12 Calle EE, Thun MJ. Obesity and cancer. Oncogene 2004; 23: 6365-6378
13 Yin N, Wang D, Zhang H, Yi X, Sun X, Shi B, Wu H, Wu G, Wang X, Shang Y. Molecular mechanisms involved in the growth stimulation of breast cancer cells by leptin. Cancer Res 2004; 64: 5870-5875
14 Okumura M, Yamamoto M, Sakuma H, Kojima T, Maruyama T, Jamali M, Cooper DR, Yasuda K. Leptin and high glucose stimulate cell proliferation in MCF-7 human breast cancer cells: reciprocal involvement of PKC-α and PPAR expression. Biochim Biophys Acta (BBA) Molecul Cell Res 2002; 1592: 107-116
15 Mitrunen K, Hirvonen A. Molecular epidemiology of sporadic breast cancer. The role of polymorphic genes involved in oestrogen biosynthesis and metabolism. Mutat Res 2003; 544: 9-41
16 Hausman G, Richardson R. Adipose tissue angiogenesis. J Anim Sci 2004; 82: 925-934
17 Folkman J. Angiogenesis and apoptosis. In: Seminars Cancer Biol. 2003. Elsevier; 159-167
18 Liang Y, Brekken RA, Hyder SM. Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones. Endocr Rel Cancer 2006; 13: 905-919
19 Sharma D, Wang J, Fu PP, Sharma S, Nagalingam A, Mells J, Handy J, Page AJ, Cohen C, Anania FA. Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis. Hepatology 2010; 52: 1713-1722
20 Toyoshima Y, Gavrilova O, Yakar S, Jou W, Pack S, Asghar Z, Wheeler MB, LeRoith D. Leptin improves insulin resistance and hyperglycemia in a mouse model of type 2 diabetes. Endocrinology 2005; 146: 4024-4035
21 Ferguson RD, Novosyadlyy R, Fierz Y, Alikhani N, Sun H, Yakar S, LeRoith D. Hyperinsulinemia enhances c-Myc-mediated mammary tumor development and advances metastatic progression to the lung in a mouse model of type 2 diabetes. Breast Cancer Res 2012; 14: R8
22 Fernández AM, Kim JK, Yakar S, Dupont J, Hernandez-Sanchez C, Castle AL, Filmore J, Shulman GI, Le Roith D. Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes. Genes Develop 2001; 15: 1926-1934
23 Carroll PA, Healy L, Lysaght J, Boyle T, Reynolds JV, Kennedy MJ, Pidgeon G, Connolly EM. Influence of the metabolic syndrome on leptin and leptin receptor in breast cancer. Mol Carcinogen 2011; 50: 643-651
24 Vona-Davis L, Rose DP. Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Rel Cancer 2007; 14: 189-206
25 Somasundar P, Yu AK, Vona-Davis L, McFadden DW. Differential effects of leptin on cancer in vitro. J Surg Res 2003; 113: 50-55
26 Frankenberry KA, Skinner H, Somasundar P, McFadden DW, Vona-Davis LC. Leptin receptor expression and cell signaling in breast cancer. Inter J Oncol 2006; 28: 985-993
27 Hsieh FC, Cheng G, Lin J. Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophys Res Commun 2005; 335: 292-299
28 Patel AC, Nunez NP, Perkins SN, Barrett JC, Hursting SD. Effects of energy balance on cancer in genetically altered mice. J Nutr 2004; 134: 3394S-3398S
29 Li X, Wu X, Camacho R, Schwartz GJ, LeRoith D. Intracerebroventricular leptin infusion improves glucose homeostasis in lean type 2 diabetic MKR mice via hepatic vagal and non-vagal mechanisms. PLoS One 2011; 6: e17058
30 Martignoni ME, Kunze P, Friess H. Cancer cachexia. Mol Cancer 2003; 2: 36
31 Kotler DP. Cachexia. Ann Inter Med 2000; 133: 622-634
32 Bayliss TJ, Smith JT, Schuster M, Dragnev KH, Rigas JR. A humanized anti-IL-6 antibody (ALD518) in non-small cell lung cancer. Exp Opin Biol Ther 2011; 11: 1663-1668
33 Han L, Ma Q, Li J, Liu H, Li W, Ma G, Xu Q, Zhou S, Wu E. High glucose promotes pancreatic cancer cell proliferation via the induction of EGF expression and transactivation of EGFR. PLoS One 2011; 6: e27074
34 Liu H, Ma Q, Li J. High glucose promotes cell proliferation and enhances GDNF and RET expression in pancreatic cancer cells. Mol Cell Biochem 2011; 347: 95-101
35 Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, Christofk HR, Wagner G, Rabinowitz JD, Asara JM. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Sci Signal 2010; 329: 1492-1499