Abstract
We evaluated the relationship among the leptin receptor (LEPR) gene Gln223Arg polymorphism, body mass index (BMI), waist and hip circumference ratio (WHR), dietary structure, lifestyle, and other biomarkers with breast cancer and determined whether they could be effective for the prevention and treatment of breast cancer. The Gln223Arg polymorphisms in the LEPR gene were investigated in blood deoxyribonucleic acid (DNA) available for 240 breast cancer cases and 500 controls. Genotyping was performed by polymerase chain reaction–restriction fragment length polymorphism. Leptin, insulin were determined by enzyme-linked immunosorbent assays. We found that the serum levels of leptin, insulin, triglyceride (TG), free cholesterol (FCH), apolipoprotain (APO) A1, and BMI were significantly higher in breast cancer cases than the controls, while physical activity was clearly less in breast cancer cases (P < 0.02 ~ P < 0.001, respectively). Moreover, there were significant association between the Gln223Arg genotype and breast cancer risk; homozygotes for AA and heterozygotes for AG,AG + GG genotypes had been proved to increase the risk of breast cancer, and their corresponding odds ratio were 7.14 (95% confidence interval [CI] = 1.92–25.64), 1.33(95% CI = 1.03–2.70), and 2.04 (95% CI = 1.09–3.82). Interestingly, logistic regression analysis showed that LEPR gene Gln223Arg polymorphism and elevated leptin, insulin, TG, FCH, APOA1, WHR, and reduced APOB increased the risk of developing breast cancer, respectively. And, it also suggested that LEPR gene Gln223Arg polymorphisms, elevated leptin, insulin, TG, FCH, APOA1, WHR, and reduced APOB should play a major role in the development of breast cancer.
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Xu GW (2005) Chinese breast cancer deaths jump 40% since one child abortion policy. Life Site News, October 13 (Beijing)
Shu X, Jin F, Dai Q, Rong J, Shi JR, Potter JD, Brinton LA, Hebert JR, Ruan ZX, Gao YT, Zheng W (2001) Association of body size and fat distribution with risk breast cancer among Chinese women. Int J Cancer 94:499–454
Lorincz AM, Sukumar S (2006) Molecular links between obesity and breast cancer. Endocr Relat Cancer 13:279–292
Berclaz G, Li S, Price KN et al (2004) Body mass index as a prognostic feature in operable breast cancer: the International Breast Cancer Study Group experience. Ann Oncol 15:875–884
Asseryanis A, Ruecklinger E, Hellan M, Kubista E, Singer CF (2004) Breast cancer size in postmenopausal women is correlated with body mass index and androgen serum levels. Gynecol Endocrinol 18:29–36
Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625–1638
Hu X, Juneja SC, Maihle NJ, Cleary MP (2002) Leptin—a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst 94:1704–1711
Laud K, Gourdou I, Pessemesse L, Peyrat JP, Djiane J (2002) Identification of leptin receptor in human breast cancer: functional activity in the T47-D breast cancer cell line. Mol Cell Endocrinol 188:219–226
O’Brien SN, Welter BH, Price TM, Clemson U, Glemson SG (1999) Presence of leptin in breast cell lines and breast tumors. Biochem Biophys Res Commun 259:695–698
Han CZ, Zhang XT, Du LL, Lui XY, Jing JX, Zhao XW, Yang X, Tian BG (2005) Serum levels of leptin, insulin, and lipids in relation to breast cancer in China. Endocrine 26:19–24
Tessitore L, Vizio B, Jenkins O, De Stefano I et al (2000) Leptin expression in colorectal and breast cancer patients. Int J Mol Med 5:421–426
Stattin P, Lukanova A, Biessy C, Soderberg S, Palmqvist R, Kaaks R, Olsson T, Jellum E (2004) Obesity and colon cancer: does leptin provide a link? Int J Cancer 109:149–152
Ribeiro R, Lopes C, Medeiros R (2006) The link between obesity and prostate cancer: the leptin pathway and therapeutic perspectives. Prostate Cancer Prostatic Dis 9:19–24
Malik KF, Young WS 3rd (1996) Localization of binding sites in the central nervous system for leptin (OB protein) in normal, obese (ob/ob), and diabetic (db/db) C57BL/6J mice. Endocrinology 137:1497–500
Tsuchiya T, Shimizu H, Hori T, Mori M (1999) Expression of leptin receptor in lung: leptin as a growth factor. Eur J Pharmacol 365:273–279
Mix H, Widjaja A, Jandl O, Cornberg M, Kaul A, Goke M, Beil W, Kuske M, Brabant G, Manns MP, Wagner S (2000) Expression of leptin receptor isoforms in the human stomach. Gut 47:481–486
Hino M, Nakano T, Yamane T, Ohta K, Takubo T, Tatsumi N (2000) Leptin receptor and leukemia. Leuk Lymphoma 36:457–461
Hardwick JC, Van Den Brink GR, Offerhaus GJ, Van Deventer SJ, Peppelenbosch MP (2001) Leptin is a growth factor for colonic epithelial cells. Gastroenterology 121:79–90
Attoub S, Noe V, Pirola L, Bruyneel E, Chastre E, Mareel M, Wymann MP, Gespach C (2000) Leptin promotes invasiveness of kidney and colonic epithelial cells via phosphoinositide 3-kinase-, rho-and rac-dependent signaling pathways. FASEB J 14:2329–2338
Isono M, Inoue R, Kamida T, Kobayashi H, Matsuyama J (2003) Significance of leptin expression in invasive potential of pituitary adenomas. Clin Neurol Neurosurg 105:111–116
Zheng YM, Xiang KS, Zhang R, Jia WP, Lu JS, Tong JL (1999) Association of Gln223Arg variant in leptin receptor gene with metabolic abnormalities and hypertension in type 2 diabetes in Shanghai “Han” population. Chinese Journal of Endocrinology and metabolism 38:174–178
Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625–1638
Bianchini F, Kaaks R, Vainio H (2002) Overweight, obesity, and cancer risk. Lancet Oncol 3:565–574
Tessitore L, Visio B, Pesola D, Cecchini F, Mussa A, Argiles JM, Benedetto C (2004) Adipocytes expression and circulating levels of leptin increase in both gynaecological and breast cancer patients. Int J Cancer 24:1529–1535
Ozet A, Arpaci F, Yilmaz llker M, Ayta H, Ozturk B, Komurcu S, Yavuz AA, Tezcan Y, Acikel C (2001) Effect of tamoxifen on the serum leptin level in patients with breast cancer. Jpn J Clin Oncol 31:424–427
Christo S, Bolhke K, Moschos S, Cramer W (1999) Leptin in relation to carcinoma in situ of the breast: a study of pre-menopausal cases and controls. Int J Cancer 80:523–526
Makoto I, Joji K, Hirokazu N (2004) Enhanced expression of leptin and leptin receptor (LEPR) in human breast cancer. Clin Cancer Res 10:4325–4331
Smith-Kirwin SM, O’Connor DM, Johnston J, de Lancy E, Hassink SG, Funanage VL (1998) Leptin expression in human mammary epithelial cells and breast milk. J Clin Endocrinol Metab 83:1810–1813
Waxler SH, Taber P, Melcher LP (1953) Obesity and the time of appearance of spontaneous mammary carcinoma in C3H mice. Cancer Res 13:276–278
Heston WE, Vlahakis G (1962) Genetic obesity and neoplasia. J Natl Cancer Inst (Bethesda) 29:197–209
Cleary MP, Phillip FC, Getzin SC, Jacobson TL, Jacobson MK, Christensen TA, Juneja SC, Grande JP, Maihle NJ (2003) Genetically obese MMTV-TGF-alph/Lep(ob) Lep(ob) female mice do not develop mammary tumors. Breast Cancer Res Treat 77:205–215
Mantzoros CS, Bolhke K, Moschos S, Cramer CS (1999) Leptin in relation to carcinoma in situ of the breast: a study of pre-menopausal cases and controls. Int J Cancer 80:523–526
Petridou E, Papadiamantis Y, Markopoulos C, Spanos E, Dessypris N, Trichopoulos D (2000) Leptin and insulin growth factor I in relation to breast cancer. Cancer Causes Control 11:383–388
Friedman JM, Leibel RL, Siegel DS, Walsh J, Bahary N (1991) Molecular mapping of the mouse ob mutation. Genomics 11:1054–1062
Coleman DL (1978) Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14:141–148
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432
Mammes O, Betoulle D, Aubert R, Herbeth B, Siest G, Fumeron F (2000) Association of the G-2548A polymorphism in the 5′ region of the LEP gene with overweight. Ann Hum Genet 64:391–394
Mattevi VS, Zembrzuski VM, Hutz MH (2002) Association analysis of genes involved in the leptin-signaling pathway with obesity in Brazil. Int J Obes Relat Metab Disord 26:1179–1185
Hager J, Clement K, Francke S, Raison J, Lahlou N, Rich N, Pelloux V, Basdevant A, GuyGrand B, North M, Froguel P (1998) A polymorphism in the 5′ untranslated region of the human ob gene is associated with low leptin levels. Int J Obes Relat Metab Disord 22:200–205
Lamas O, Marti A, Martinez JA (2002) Obesity and immunocompetence. Eur J Clin Nutr 56(3):S42–S45
Gotoda T, Manning BS, Goldstone AP, Imrie H, Evans AL, Strosberg AD, McKeigue PM, Scott J, Aitman TJ (1997) Leptin receptor gene variation and obesity: lack of association in a white British male population. Hum Mol Genet 6:869–876
Yiannakouris N, Yannakoulia M, Melistas L, Chan JL, Klimis-Zacas D, Mantzoros CS (2001) 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 86:4434–4439
Hoffstedt J, Eriksson P, Mottagui-Tabar S, Arner P (2002) A polymorphism in the leptin promoter region (−2548 G/A) influences gene expression and adipose tissue secretion of leptin. Horm Metab Res 34:355–359
Snoussi K, Strosberg AD, Bouaouina N, Ahmed SB, Helal AN, Chouchane L (2006) Leptin and leptin receptor polymorphisms are associated with increased risk and poor prognosis of breast carcinoma. BMC Cancer 6:38–51
Woo HY, Park H, Ki CS, Park YL, Bae WG (2005) Relationships among serum leptin, leptin receptor gene polymorphisms, and breast cancer in Korea. Cancer Lett 9:1–6
Jerome L, Shiry L, Leyland JB (2004) Anti-insulin-like growth factor strategies in breast cancer. Semin Oncol 31:54–63
Allen NE, Appleby PN, Kaaks R, Rinaldi S, Davey GK, Key TJ (2003) Lifestyle determinants of serum insulin-like growth-factor-I (IGF-I), C-peptide and hormone binding protein levels in British women. Cancer Causes Control 14:65–74
Zefang R, Qiuyin C, Xiao-Ou S, Hui C, Chun LI, Herbert YU, Yu-Tang G, Wei Z (2004) Genetic polymorphisms in the IGFBP3 gene: association with breast cancer risk and blood IGFBP3 protein levels among Chinese women. Cancer Epidemiol Biomark Prev 13:1290–1295
Takahashi Yasuno A, Masuzaki H, Miyawaki T, Ogawa Y, Matsuaka N, Hosoda K, Inoue G, Yoshimasa Y, Nakao K (2003) Leptin receptor polymorphism is association with serum lipids levels and impairment of cholesterol lowering effect in Japanese men. Diabetes Res Clin Pract 62:169–175
Coskun U, Gunel N, Torunner FB et al (2003) Serum leptin, prolactin and vascular endothelial growth factor (VEGF) levels in patients with breast cancer. Neoplasma 50:41–46
Du L-L, Han C-Z, Liu X-Y et al (2006) Relationship between serum leptin level BMI and breast cancer incidence. Cancer Res Clin 18:307–310
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This study was supported by grants from Board of Health of Shanxi Province (200413) and Science and Technology Committee of Shanxi Province (2006011129).
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Han, CZ., Du, LL., Jing, JX. et al. Associations among Lipids, Leptin, and Leptin Receptor Gene Gin223Arg Polymorphisms and Breast Cancer in China. Biol Trace Elem Res 126, 38–48 (2008). https://doi.org/10.1007/s12011-008-8182-z
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DOI: https://doi.org/10.1007/s12011-008-8182-z