Association of Serum Adiponectin and Leptin Levels with Breast Cancer in Iraqi Women

Dhuha F. Taaban^1, , Eman S. Saleh¹, Zainab M. Hashim¹ and Zuhair B. Kamal²

¹Department of Clinical laboratory sciences, College of Pharmacy, University of Baghdad, Baghdad, Iraq

²Department of Surgery, Alkindy College of Medicine, University of Baghdad, Baghdad, Iraq

Cite this paper:
Dhuha F. Taaban, Eman S. Saleh, Zainab M. Hashim and Zuhair B. Kamal. Association of Serum Adiponectin and Leptin Levels with Breast Cancer in Iraqi Women. American Journal of Pharmacological Sciences. 2014; 2(6):103-109. doi: 10.12691/ajps-2-6-2

Abstract

Obesity has been associated with an increased risk of cancer especially postmenopausal breast cancer. Adipokines have been hypothesized to underlie this association. Adiponectin and leptin are adipocyte-secreted hormones that opposite each other not only in their biological activities but also in their effects on breast neoplastic cells. in addition, Leptin receptor, found in both membrane-bound isoforms and a soluble form (sOB-R), sOB-R bind to leptin in circulation and correlate with its activity. The aim of this study was to investigate the relationship between serum levels of adiponectin, leptin and sOB-R with breast cancer. Methods: In a case-control study Serum adiponectin, leptin and sOB-R levels were measured by enzyme-linked Immunosorbent assay in 48 women with histologically confirmed breast cancer and compared with 41 age and BMI matched women without breast cancer as control groups. Control groups were divided into; Control group 1 (C1) contains 26 healthy women and control group 2(C2) contains 15 women with breast benign diseases. Results: The mean serum levels of adiponectin in both controls (C1 and C2) were significantly higher than that in breast cancer cases (25.08±5.59and 22.49±3.49) versus (15.84±6.21) respectively. Conversely, the mean serum levels of leptin in both controls (C1 and C2) were significantly lower than that in breast cancer cases (27.98±6.85 and 34.50±10.59) versus (48.97±24.56) respectively. Higher circulating levels of sOB-R (140.21±74.20) were significantly associated with an increased risk of breast cancer as compared to controls (47.13±38.30 and 27.68±23.58) for C1 and C2 respectively. In addition, the association of BMI with breast cancer was non-significant. Conclusion: These data suggest that dysregulation in hormones (adipokines) secreted by adipose tissue may be associated with breast cancer independently of BMI. Further prospective studies examining the role of adipokines in the etiology of breast cancer are warranted.

Keywords:
breast cancer obesity adiponectin leptin soluble leptin receptor

This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

References:

[1]	Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11. Lyon, France: International Agency for Research on Cancer; 2013.
[2]	Iraqi Cancer Board. Results of the Iraqi Cancer Registry 2010. Baghdad, Iraqi Cancer Registry Center, Ministry of Health.
[3]	Cheraghi Z, Poorolajal J, Hashem T, Esmailnasab N, Doosti Irani A.: Effect of Body Mass Index on Breast Cancer during Premenopausal and Postmenopausal Periods: A Meta-Analysis. PLoS ONE 2012; 7 (12): 51446.
[4]	Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D. Cancer incidence and mortality in relation to body mass index in the Million Women Study: Cohort study. BMJ 2007; 335: 1134.
[5]	Cleveland RJ, Eng SM, Abrahamson PE, Britton JA, Teitelbaum SL, Neugut AI, et al. Weight gain prior to diagnosis and survival from breast cancer. Cancer Epidemiol Biomarkers Prev 2007; 16:1803-11.
[6]	Cleary MP, Grossmann ME, Obesity and Breast Cancer: The Estrogen Connection. Endocrinology. 2009; 150: 2537-42.
[7]	Iraq Family Health Survey Study Group. Iraq Family Health Survey (IFHS) 2006/7. World Health Organization; 2008.
[8]	Mansour AA, Al-Maliky AA, Salih M: Population Overweight and Obesity Trends of Eight Years in Basrah, Iraq. Epidemiol 2012; 2: 110.
[9]	Dalamaga M. Obesity, insulin resistance, adipocytokines and breast cancer: New biomarkers and attractive therapeutic targets. World J Exp Med. 2013 20; 3: 34-42.
[10]	Vona-Davis L, Rose D P. Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Society for Endocrinology. Endocrine-Related Cancer 2007; 14: 189-206.
[11]	Lorincz AM, Sukumar S, Molecular links between obesity and breast cancer. Endocr Relat Cancer 2006; 13 (2): 279-92.
[12]	Macciò A, Madeddu C, Obesity, Inflammation, and Postmenopausal Breast Cancer: Therapeutic Implications. Scientific World JOURNAL 2011; 11: 2020-36.
[13]	Manabe Y, Toda S, Miyazaki K, Sugihara H. Mature adipocytes, but not preadipocytes, promote the growth of breast carcinoma cells in collagen gel matrix culture through cancer-stromal cell interactions. J Pathol. 2003; 201 (2): 221-8.
[14]	Iyengar P, Combs TP, Shah SJ, Gouon-Evans V, Pollard JW, Albanese C. et al. Adipocyte-secreted factors synergistically promote mammary tumorigenesis through induction of anti-apoptotic transcriptional programs and proto-oncogene stabilization. Oncogene. 2003; 22 (41): 6408-23.
[15]	Ray A, Cleary M P. Leptin as a potential therapeutic target for breast cancer prevention and treatment. Expert Opinion Therapy Targets 2010; 14 (4): 443-51.
[16]	Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: A review of current evidence. Endocr Rev 2012; 33:547-94.
[17]	Ziemke F, Mantzoros CS. Adiponectin in insulin resistance: Lessons from translational research. Am J Clin Nutr. 2010; 91 (1): 258-61.
[18]	Van Kruijsdijk R C M, Van der Wall E, Visseren F L J. Obesity and cancer; The role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev. 2009; 18 (10): 1-10.
[19]	Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395: 763-70.
[20]	Hu X, Juneja SC, Maihle NJ, Cleary MP. Leptin—a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst 2002; 94: 1704-11
[21]	Dieudonne MN, Machinal-Quelin F, Serazin-Leroy V, Leneveu MC, Pecquery R, Giudicelli Y. Leptin mediates a proliferative response in human MCF7 breast cancer cells. Biochemical & Biophysical Research Communications 2002; 293: 622-8.
[22]	Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996; 334: 292-5.
[23]	Mahabir S, Baer D, Johnson LL, Roth M, Campbell W, Clevidence B, et al. Body Mass Index, percent body fat and regional body fat distribution in relation to leptin concentrations in healthy, non-smoking postmenopausal women in a feeding study. Nutr J. 2007; 6: 3.
[24]	Bornstein SR, Abu-Asab M, Glasow A, Päth G, Hauner H, Tsokos M, et al: Immunohistochemical and ultrastructural localization of leptin and leptin receptor in human white adipose tissue and differentiating human adipose cells in primary culture. Diabetes. 2000; 49: 532-8.
[25]	Ge H, Huang L, Pourbahrami T, Li C :Generation of soluble leptin receptor by ectodomain shedding of membrane-spanning receptors in vitro and in vivo. J Biol Chem 2002; 277: 45898-903.
[26]	Lammert A, Kiess W, Bottner A, Glasow A, Kratzsch J. Soluble leptin receptor represents the main leptin binding activity in human blood. Biochem Biophys Res Commun 2001; 283: 982-8.
[27]	Huang L, Wang Z, Li C. Modulation of circulating leptin levels by its soluble receptor. J Biol Chem 2001; 276: 6343-9.
[28]	Cohen SE, Kokkotou E, Biddinger SB, Kondo T, Gebhardt R, Kratzsch J, Mantzoros CS, Kahn CR. High circulating leptin receptors with normal leptin sensitivity in liver-specific insulin receptor knock-out (LIRKO) mice. J Biol Chem 2007; 282: 23672-8.
[29]	Ashwell M, Chinn S, Stalley S, Garrow JS. Female fat distribution a simple classification based on two circumference measurements. Int J Obes 1982; 6: 143-52.
[30]	Nakano Y1, Tobe T, Choi-Miura NH, Mazda T, Tomita M. Isolation and characterization of GBP28, a noval gelatin-binding protein purified from human plasma. J Biochem. 1996; 120 (4): 803-12.
[31]	Imagawa K, Matsumoto Y, Numata Y, Morita A, Kikuoka S, Tamaki M, et al. Development of a sensitive ELISA for human leptin, using monoclonal antibodies. Clin Chem. 1998; 44: 2165-71.
[32]	Miyoshi Y, Funahashi T, Kihara S, Taguchi T, Tamaki Y, Matsuzawa Y & Noguchi. Association of serum adiponectin levels with breast cancer risk. Clinical Cancer Research 2003; 9: 5699-5704.
[33]	Mantzoros C, Petridou E, Dessypris N, Chavelas C, Dalamaga M, Alexe DM et al. Adiponectin and breast cancer risk. Journal of Clinical Endocrinology and Metabolism 2004; 89: 1102-1107.
[34]	Tworoger SS, Heather Eliassen A, Kelesidis T, Colditz GA, Willett WC, Mantzoros CS & Hankinson. Plasma adiponectin concentrations and risk of incident breast cancer. Journal of Clinical Endocrinology and Metabolism 2007; 92: 1510-1516.
[35]	Kang JH, Yu BY, Youn DS. Relationship of serum adiponectin and resistin levels with breast cancer risk. J Korean Med Sci 2007; 22: 117-121.
[36]	Macis D, Guerrieri-Gonzaga A, Gandini S. Circulating adiponectin and breast cancer risk: a systematic review and meta-analysis. Int J Epidemiol. 2014; 43 (4): 1226-36.
[37]	Ye J1, Jia J, Dong S, Zhang C, Yu S, Li L et al. Circulating adiponectin levels and the risk of breast cancer: a meta-analysis Eur J Cancer Prev. 2014; 23 (3): 158-65.
[38]	Miyatani Y, Yasui T, Uemura H, Yamada M, Matsuzaki T et al. Associations of circulating adiponectin with estradiol and monocyte chemotactic protein-1 in postmenopausal women. Menopause 2008; 15: 536-541.
[39]	Cnop M, Havel PJ, Utzschneider KM, Carr DB, Sinha MK, et al. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia. 2003; 46: 459-469.
[40]	Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004; 4: 505-518.
[41]	Wang Y, Lam JB, Lam KS, et al. Adiponectin modulates the glycogen synthase kinase-3beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice. Cancer Res 2006; 66: 11462-11470.
[42]	Dieudonne MN, Bussiere M, Dos Santos E, et al. Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer cells. Biochem Biophys Res Commun 2006; 345: 271-279.
[43]	Niu J, Jiang L, Guo W, Shao L, Liu Y, Wang L. The association between leptin level and breast cancer: A meta-analysis. PLoS One 2013; 8: e67349.
[44]	Mohammadzadeh G, Ghaffari M, Bafandeh A, Hosseini S. Association of serum soluble leptin receptor and leptin levels with breast cancer. J Res Med Sci 2014; 19: 433-8.
[45]	Rahmati-Yamchi M, Zarghami N, Rahbani M, Montazeri A. Plasma leptin, hTERT gene expression, and anthropometric measures in obese and non-obese women with breast cancer. Breast Cancer (Auckl) 2011; 5: 27-35.
[46]	Alokail MS, Al-Daghri N, Abdulkareem A, Draz HM, Yakout SM, Alnaami AM, Sabico S, Alenad AM, Chrousos GP. Metabolic syndrome biomarkers and early breast cancer in Saudi women: evidence for the presence of a systemic stress response and/or a pre-existing metabolic syndrome-related neoplasia risk? BMC Cancer. 2013 Feb 4; 13: 54.
[47]	Llanos AA, Dumitrescu RG, Marian C, Makambi KH, Spear SL, Kallakury BV, et al. Adipokines in plasma and breast tissues: Associations with breast cancer risk factors. Cancer Epidemiol Biomarkers Prev 2012; 21: 1745-55.
[48]	Macciò A, Madeddu C, Gramignano G, Mulas C, Floris C, Massa D, et al. Correlation of body mass index and leptin with tumor size and stage of disease in hormone-dependent postmenopausal breast cancer: Preliminary results and therapeutic implications. J Mol Med (Berl) 2010; 88: 677-86.
[49]	Ray A, Nkhata KJ, Grande JP, Cleary MP. Diet-induced obesity and mammary tumor development in relation to estrogen receptor status. Cancer Le 2007; 253: 291-300.
[50]	McMurtry V, Simeone AM, Nieves-Alicea R, Tari AM. Leptin utilizes Jun N-terminal kinases to stimulate the invasion of MCF-7 breast cancer cells. Clin Exp Metastasis 2009; 26:197-204.
[51]	Rene Gonzalez R, Wa ers A, Xu Y, Singh UP, Mann DR, Rueda BR, et al. Leptin-signaling inhibition results in effi cient anti-tumor activity in estrogen receptor positive or negative breast cancer. Breast Cancer Res 2009; 11:R36.
[52]	Ishikawa M, Kitayama J, Nagawa H. Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res 2004; 10: 4325-4331.
[53]	Garofalo C, Sisci D, Surmacz E. Leptin interferes with the effects of the antiestrogen ICI 182,780 in MCF-7 breast cancer cells. Clin Cancer Res 2004; 10: 6466-6475.
[54]	Cleary MP, Juneja SC, Phillips FC, et al. Leptin receptor-deficient MMTV-204;TGF-alpha/Lepr(db)Lepr(db) female mice do not develop oncogene-induced mammary tumors. Exp Biol Med (Maywood) 2004; 229: 182-193.
[55]	Otvos L Jr, Kovalszky I, Riolfi M, Ferla R, Olah J, et al. Efficacy of a leptin receptor antagonist peptide in a mouse model of triple-negative breast cancer. Eur J Cancer 2011; 47: 1578-1584.
[56]	Jarde T, Caldefie-Chezet F, Damez M, et al. Leptin and leptin receptor involvement in cancer development: a study on human primary breast carcinoma. Oncol Rep 2008; 19 (4): 905-11.
[57]	Fusco R, Galgani M, Procaccini C, et al. Cellular and molecular crosstalk between leptin receptor and estrogen receptor-{alpha} in breast cancer: molecular basis for a novel therapeutic setting. Endocr Relat Cancer 2010; 17 (2): 373-82.
[58]	Catalano S, Marsico S, Giordano C, et al. Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line. J Biol Chem 2003; 278 (31): 28668-76.
[59]	Chen C, Chang YC, Liu CL, Chang KJ, Guo IC. Leptin-induced growth of human ZR-75-1 breast cancer cells is associated with up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21WAF1/CIP1. Breast Cancer Res Treat 2006; 98 (2): 121-32.
[60]	Jarde T, Caldefie-Chezet F, Goncalves-Mendes N, et al. Involvement of adiponectin and leptin in breast cancer: clinical and in vitro studies. Endocr Relat Cancer 2009; 16 (4): 1197-210.
[61]	Somasundar P, Yu AK, Vona-Davis L, McFadden DW. Differential effects of leptin on cancer in vitro. J Surg Res 2003; 113 (1): 50-5.
[62]	Laud K, Gourdou I, Pessemesse L, Peyrat JP, Djiane J. Identification of leptin receptors in human breast cancer: functional activity in the T47-D breast cancer cell line. Mol Cell Endocrinol 2002; 188 (1-2): 219-26.
[63]	Okumura M, Yamamoto M, Sakuma H, Kojima T, Maruyama T, Jamali M, et al. Leptin and high glucose stimulate cell proliferation in MCF-7 human breast cancer cells: Reciprocal involvement of PKC-alpha and PPAR expression. Biochim Biophys Acta 2002; 1592: 107-16.
[64]	Yuan HJ, Sun KW, Yu K. Leptin promotes the proliferation and migration of human breast cancer through the extracellular-signal regulated kinase pathway. Mol Med Rep 2014; 9: 350-4.
[65]	Garofalo C, Koda M, Cascio S, Sulkowska M, Kanczuga-Koda L, Golaszewska J, et al. Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: Possible role of obesity-related stimuli. Clin Cancer Res 2006; 12:1447-53.
[66]	Magni P, Liuzzi A, Ruscica M, Dozio E, Ferrario S, Bussi I, et al. Free and bound plasma leptin in normal weight and obese men and women: Relationship with body composition, resting energy expenditure, insulin-sensitivity, lipid profi le and macronutrient preference. Clin Endocrinol (Oxf) 2005; 62: 189-96.