Effect of leptin receptor Q223R polymorphism on breast cancer risk

Document Type : Original Article

Authors

1 Hyperlipidemia Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Cellular and Molecular Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

3 Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

4 Department of Radiation and Oncology of Golestan University Hospital, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

Abstract

Objective(s):Leptin receptor (LEPR) is a member of the class I cytokine receptor super-family that is known implicated in the initiation and progression of breast cancer. We have investigated the effect of Q223R polymorphism on the breast cancer susceptibly in a sample of Iranian subjects.
Materials and Methods:We utilized a polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) method to investigate the association ofLEPRQ223R polymorphism with breast cancer risk in a case control study consisting of 100 breast cancer cases and 100 controls without breast cancer. Serum levels of leptin and soluble leptin receptor (sOB-R) were measured by ELISA method.
Results:The genotype (QQ, QR, and RR) distributions were 25, 56, and 19 % in breast cancer cases and 54, 40, and 6% in controls, respectively. The frequency of 223 RR genotype was significantly elevated in breast cancer cases as compared to controls (χ2= 20.072, P<0.001). Similar significance differences were also found in allele frequencies for Q and R between two groups (χ2= 19.027, P< 0.001). Additionally, there weresignificant association between Q223R genotypes and breast cancer risk; homozygotes for RR genotype (OR= 6.840; 95% confidence interval [CI] = 2.434-19.218), heterozygotes for QR (OR=3.024; 95% CI = 1.620-5.644, P = 0.001), and QR+RR genotype (OR= 3.522; 95% CI = 1.934-6.414, P < 0.001), respectively.
Conclusion:Our results showed thattheLEPRQ223R polymorphism is associated with increased breast cancer risk as well as tumor grade in a sample of Iranian subjects.

Keywords

References

1. Smigal C, Jemal A, Ward E, Cokkinides V, Smith R, Howe HL, et al. Trends in breast cancer by race and ethnicity: update 2006. Cancer J Clin 2006; 56:168–183.
2. Berclaz G, Li S, Price KN, Coates AS, Castiglione-Gertsch M, Rudenstam CM, et al. Body mass index as a prognostic feature in operable breast cancer: the international breast cancer study group experience. Ann Oncol 2004; 15:875–884.
3. Asseryanis E, Ruecklinger E, Hellan M, Kubista E, Singer CF. Breast cancer size in postmenopausal women is correlated with body mass index and androgen serum levels. Gynecol Endocrinol 2004; 18:29–36.
4. Lorincz AM, Sukumar S. Molecular links between obesity and breast cancer. Endocr Relat Cancer 2006; 13:279–292.
5. Cao H, Yang ZH, Jiang JQ. Expression and clinical significance of activating transcription factor 3 in human breast cancer. Iran J Basic Med Sci 2013; 16:1151-1154.
6. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372:425-432.
7. Halaas JL Gajiwala, KS, , Maffei M, Chohen S, Chait BT, Rabinowitz D, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269:543-546.
8. Tartaglia LA. The leptin receptor. J Biol Chem 1997; 272:6093-6096.
9. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM. Abnormal splicing of the leptin receptor in diabetic mice. Nature1996; 379:632-635.
10. Zabeau L, Lavens D, Peelman F, Eyckerman S, Vandekerckhove J, Tavernier J. The ins and outs of leptin receptor activation. FEBS Lett 2003; 546:45-50.
11. Chung WK, Power-Kehoe L, Chua M, Chu F, Aronne L, Huma Z, et al. Exonic and intronic sequence variation in the human leptin receptor gene (LEPR). Diabetes 1997; 46:1509–1511.
12. Gotoda T, Manning BS, Goldstone AP, Imrie H, Evans AL, Strosberg AD, et al. Leptin receptor gene variation and obesity: lack of association in a white british male population. Hum Mol Genet 1997; 6:869-876.
13. Quinton ND, Lee AJ, Ross RJ, Eastell R, Blakemore Al. A single nucleotide polymorphism (SNP) in the leptin receptor is associated with BMI, fat mass and leptin levels in postmenopausal Caucasian woman. Hum Genet 2001; 108:233-236.
14. Yiannakouris N, Yannakoulia M, Melistas L, Chan JL, Klimis- Zacas D, Mantzoros CS. The Q223R polymorphism of the leptin receptor gene is significantly associated with obesity and predicts a small percentage of body weight and body composition variability. J Clin Endocrinol Metab 2001; 86:4434–4439.
15. Snoussi K, Strosberg AD, Bouaounia N, Ben Ahmed S, Helal AN, Chouchane L. Leptin and leptin receptor polymorphisms are associated with increased risk and poor prognosis of breast carcinoma. BMC Cancer 2006; 6:38.
16. Catalano S, Mauro L, Marsico S, Giordano C, Rizza P, Rago V, et al. Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor alpha in MCF-7 cells. J Boil Chem2004; 279:19908-19915.
17. 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; 12:1447–1453.
18. 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.
19. O'brien SN, Welter BH, Price TM. Presence of leptin in breast cell lines and breast tumors. Biochem Biophys Res Commun 1999; 259:695–698.
20. He BS, Pan YQ, Zhang Y, Xu YQ, Wang SK. Effect of LEPR Gln223Arg polymorphism on breast cancer risk in different ethnic populations: a meta-analysis. Mol Biol Rep 2012; 39:3117-3122.
21. Cleveland RJ, Gammon MD, Long CM, Gaudet MM, Eng SM, Teitelbaum SL, et al. Common genetic variations in the LEP and LEPR genes, obesity and breast cancer incidence and survival. Breast Cancer Res Treat 2010; 120:745–752.
22. Han CZ, Du LL, Jing JX,  Zhao XW, Tian FG, Shi J, et al. Associations among lipids, leptin, and leptin receptor gene Gin223Arg polymorphisms and breast cancer in China. Biol Trace Elem Res 2008; 126:38–48.
23. Harris HR, Tworoger SS, Hankinson SE, Rosner BA, Michels KB. Plasma leptin levels and risk of breast cancer in premenopausal women. Cancer Prev Res 2011; 4:1449-1456.
24. Teras LR, Goodman M, Patel AV, Bouzyk M, Tang W, et al. No association between polymorphisms in LEP, LEPR, ADIPOQ, ADIPOR1, or ADIPOR2 and postmenopausal breast cancer risk. Cancer Epidemiol Biomarkers Prev 2009; 18:2553-2557.
25. Woo HY, Parka H, Ki CS, Park YL, Bae WG. Relationships among serum leptin, leptin receptor gene polymorphisms, and breast cancer in Korea. Cancer Lett 2006; 237:137–142.
26. Harrichi I, Karbakhsh M, Kashefi A, Momtahen AJ. Breast cancer in Iran: results of a multi-center study. Asian Pac J Cancer Prev 2004; 5:24-27.
27. Paracchini V, Pedotti P, Taioli E. Genetics of leptin and obesity: a HuGE review. Am J Epidemiol 2005; 162:101-114.
28. Thorisson GA, Smith AV, Krishnan L, Stein LD. The International HapMap Project Web site. Genome Res 2005; 15:1592–1593.
29. Le Stunff C, Le Bihan C, Schrk NJ, Bougneres P. A common promoter variant of the leptin gene Is associated with changes in the relationship between serum leptin and fat mass in obese girls. Diabetes 2000; 49:2196-2200.
30. Hoffstedt J, Eriksson P, Mottagui-Tabar S, Arner P. A polymorphism in the leptin promoter region                   (-2548 G/A) influences gene expression and adipose tissue secretion of leptin. Horm Metab Res 2002; 34:355-359.
31. Mantzoros CS, Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno TA, Kim SY, et al. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab 2011; 301:E567-E584.
32. Sierra-Honigmann MR, Nath AK, Murakami C, Garcia-Cardena G, Papapetropoulos A, Sessa WC, et al. Biological action of leptin as an angiogenic factor. Science 1998; 281:1683-1686.
33. Ribatti D, Nico B, Belloni AS, Vacca A, Roncali L, Nussdorfer GG. Angiogenic activity of leptin in the chick embryo chorioallantoic membrane is in part mediated by endogenous fibroblast growth factor-2. Int J Mol Med 2001; 8:265-268.
34.  Park KS, Shin HD, Park BL, Cheong HS, Cho YM, Lee HK, et al. Polymorphisms in the leptin receptor (LEPR)-putative association with obesity and T2DM. J Hum Genet 2009; 51:85-91.
35. Zhang YY, Gottardo L, Mlynarski W, Frazier W, Nolan D, Duffy J, et al.  Genetic variability at the leptin receptor (LEPR) locus is a determinant of plasma fibrinogen and C-reactive protein levels. Atherosclerosis 2007; 191:121-127.
36. Chagnon YC, Chung WK, Perusse L, Chagnon M, Leibel RL, Bouchard C. Linkages and associations between the leptin receptor (LEPR) gene and human body composition in the Quebec Family Study. Int J Obes Relat Metab Disord 1999; 23:278-286.
37. Chagnon YC, Wilmore JH, Borecki IB, Gagnon J, Perusse L, Chagnon M, et al. Associations between the leptin receptor gene and adiposity in middle-aged Caucasian males from the HERITAGE family study. J Clin Endocrinol Metab 2000; 85:29-34.
38. Petridou E, Papadiamantis Y, Markopoulos C, Spanos E, Dessypris N, Trichopoulos D. Leptin and insulin growth factor I in relation to breast cancer (Greece). Cancer Causes Control 2000; 11:383-388.
39. Mantzoros CS, Bolhke K, Moschos S, Cramer DW. Leptin in relation to carcinoma in situ of the breast: a study of pre-menopausal cases and controls. Int J Cancer 1999; 80:523-526.
Iranian Journal of Basic Medical Sciences
Volume 17, Issue 8 - Serial Number 8
August 2014
Pages 588-594

Files

Share

How to cite

Statistics