Does Metformin affect ER, PR, IGF-1R, β-catenin and PAX-2 expression in women with diabetes mellitus and endometrial cancer?

Diabetology & Metabolic Syndrome

Janina Markowska⁴  Jolanta Lubin⁴  Beata Śpiewankiewicz²  Wiesława Bednarek⁶  Anita Olejek³  Stefan Sajdak⁸  Marian Gryboś¹  Konstanty Korski⁷  Violetta Filas⁷  Monika Pawałowska⁴  Anna Markowska⁵ 

[1] Wrocław University of Medical Sciences, Wrocław, Poland;Department of Gynecology Oncology, Memorial Cancer Centre and Institute of Oncology, Warszawa, Poland;Department of Gynecology, Obstetrics and Gynecological Oncology, Silesian Medical University, Bytom, Poland;Gynecological Oncology Department, Poznań University of Medical Sciences, Szamarzewskiego 82/84, 60-569 Poznań, Poland;Perinatology and Gynecology Department, Poznań University of Medical Sciences, Poznań, Poland;I Chair and Department of Oncological Gynecology and Gynecology, Lublin University of Medical Sciences, Lublin, Poland;Department of Pathology, Poznań University of Medical Sciences, Poznań, Poland;Clinic of Gynecological Surgery, Poznań University of Medical Sciences, Poznań, Poland

关键词: PAX-2;    Beta catenin;    IGF-1R;    IGF-1;    ER;    PR;    Diabetes;    Metformin;    Endometrial cancer;   

Others  :  812394
DOI  :  10.1186/1758-5996-5-76

 received in 2013-08-23, accepted in 2013-11-27,  发布年份 2013

【 摘 要 】

Objective

Diabetes mellitus, as a risk factor for endometrial cancer (EC), causes an increase in insulin and IGF-1 concentrations in the blood serum. The increase in insulin and IGF-1 are considered mitogenic factors contributory to cancer development. Studies suggest that metformin has preventive activity, decreasing mortality and the risk of neoplasms. Since estrogen (ER), progesterone (PR) and IGF-1 (IGF-1R) receptor expression and β-catenin and PAX-2 mutations are significant in the development of endometrial cancer, it was decided to study these factors in patients with endometrial cancer and type 2 diabetes mellitus (DM2), and to establish the effects of metformin on their expression.

Methods

The expression of ER, PR, IGF-1R, β-catenin and PAX-2 have been immunohistochemically investigated in 86 type I endometrial cancer specimens. Patients were grouped according to the presence of DM2 and the type of hypoglycemic treatment administered.

Results

Comparing EC patients with DM2 and normal glycemic status, we found increased IGF-1R expression in women with DM2. A decrease in ER expression was noted in women with EC and DM2 receiving metformin as compared to women treated with insulin (p = 0.004). There was no statistically significant difference in PR, IGF-1R, β-catenin and PAX-2 expression among women receiving metformin and other hypoglycemic treatment.

Conclusion

Although epidemiological studies suggest the beneficial role of metformin in many human cancers, there are still few studies confirming its favorable effect on endometrial cancer. Decreased ER expression in patients receiving metformin needs further research to allow evaluation of its clinical significance.

【 授权许可】

   
2013 Markowska et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. http://globocan.iarc.fr webcite
• [2]Maki RG: Small is beautiful: Insulin-like growth factors and their role in growth, development and cancer. J Clin Oncol 2010, 28(33):4985-4995.
• [3]Zhang G, Li X, Zhang L, Zhao L, Jiang J, Wang J, Wei L: The expression and role of hybrid insulin/insulin-like growth factor receptor type 1 in endometrial carcinoma cells. Cancer Genet Cytogenet 2010, 200(2):140-148.
• [4]McCampbell A, Broaddus R, Loose D, Davies PJ: Overexpression of the Insulin-Like Growth Factor I Receptor and Activation of the Akt Pathway in Hyperplastic Endometrium. Clin Cancer Res 2006, 12:6373-6378.
• [5]Evans J, Donnelly L, Emslie-Smith AM, Alessi DR, Morris AD: Metformin and reduced risk of cancer in diabetic patients. BMJ 2005, 330:1304-1305.
• [6]Bowker S, Majumdar S, Veugelers P, Johnson JA: Increased Cancer-Related Mortality for Patients With Type 2 Diabetes Who Use Sulfonylureas or Insulin. Diabetes Care 2006, 29:254-258.
• [7]Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, Gandini S: Metformin and cancer risk in diabetic patients. A systemic review and meta-analysis. Cancer Prev Res 2010, 3:1451-1461.
• [8]Bosco JL, Antonsen S, Sorensen HT, Pedersen L, Lash TL: Metformin and incident breast cancer among diabetic women: A population-based control–case study in Denmark. Cancer Epidemiol Biomarkers Prev 2011, 20:101-111.
• [9]Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA, Bae-Jump VL: Metformin is a potent inhibitor of endometrial cancer cell proliferation – implications for a novel treatment strategy. Gynecol Oncol 2010, 116(1):92-98.
• [10]Steinberg GR, Kemp B: AMPK in health and disease. Physiol Rev 2009, 89:1025-1078.
• [11]Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M: Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 2006, 66:10269-10273.
• [12]Chin YR, Tokr A: Function of Akt/PKB signaling to cell molility, invasion and tumor stroma cancer. Cell Signal 2009, 21:470-476.
• [13]Ouban A, Muraca P, Yeatman T, Coppola D: Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas. Hum Pathol 2003, 34:803-808.
• [14]Boone DN, Lee AV: Targeting the insulin-like growth factor receptor: developing biomarkers from gene expression profiling. Crit Rev Oncol 2012, 17(2):161-173.
• [15]Moreno-Bueno G, Hardisson D, Sarrio D, Sánchez C, Cassia R, Prat J, Herman JG, Esteller M, Matías-Guiu X, Palacios J: Abnormalities of E and P-cadherin and catenin (beta-, gamma-catenin, and p120ctn) expression in endometrial cancer and endometrial atypical hyperplasia. J Pathol 2003, 199:471-478.
• [16]Fujimoto J, Ichigo S, Hirose R, Sakaguchi H, Tamaya T: Suppression of E-cadherin and alpha- and beta-catenin mRNA expression in the metastatic lesions of gynecological cancers. Eur J Gynaecol Oncol 1997, 18:484-487.
• [17]Li CG, Eccles MR: PAX genes in cancer; friends or foes? Front Genet 2012, 3(6):1-7.
• [18]Lang D, Powell SK, Plummer RS, Young KP, Ruggeri BA: PAX genes: roles in development, pathophysiology and cancer. Biochem Pharmacol 2007, 73(1):1-14.
• [19]Rabban JT, McAlhany S, Lerwill MF, Grenert JP, Zaloudek CJ: PAX2 distinguishes benign mesonephric and mullerian glandular lesions of the cervix from endocervical adenocarcinoma, including minimal deviation adenocarcinoma. Am J Surg Pathol 2010, 34(2):137-146.
• [20]Monte NM, Webster KA, Neuberg D, Dressler GR, Mutter GL: Joint loss of PAX2 and PTEN expression in endometrial precancers and cancer. Cancer Res 2010, 70(15):6225-6232.
• [21]Ritz-Laser B, Estreicher A, Gauthier B, Philippe J: The paired homeodomain transcription factor PAX2 is expressed in the endocrine pancreas and transactivates the glucagon gene promoter. J Biol Chem 2000, 275(42):32708-32715.
• [22]Harvey JM, Clark GM, Osborne CK, Allred DC: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999, 17(5):1474-1481.
• [23]Friberg E, Orsini N, Mantzoros CS, Wolk A: Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia 2007, 50:1365-1374.
• [24]Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Manson JE, Li J, Harris TG, Rohan TE, Xue X, Ho GY, Einstein MH, Kaplan RC, Burk RD, Wylie-Rosett J, Pollak MN, Anderson G, Howard BV, Strickler HD: A Prospective Evaluation of Insulin and Insulin-like Growth Factor-I as Risk Factors for Endometrial Cancer. Cancer Epidemiol Biomarkers Prev 2008, 17(4):921-929.
• [25]Cust AE, Allen NE, Rinaldi S, et al.: Serum levels of C-peptide, IGFBP-1 and IGFBP-2 and endometrial cancer risk; results from the European prospective investigation into cancer and nutrition. Int J Cancer 2007, 120:2656-2664.
• [26]Halperin R, Zehavi S, Habler L, Hadas E, Bukovsky I, Schneider D: Comparative immunohistochemical study of endometrioid and serous papillary carcinoma of endometrium. Eur J Gynaecol Oncol 2001, 22(2):122-126.
• [27]Jongen V, Briet J, De Jong R, Ten Hoor K, Boezen M, van der Zee A, Nijman H, Hollema H: Expression of estrogen receptor-alpha and -beta and progesterone receptor-A and -B in a large cohort of patients with endometrioid endometrial cancer. Gynecol Oncol 2009, 112(3):537-542.
• [28]Zhou J, Dsupin BA, Giudice LC, Bondy CA: Insulin-like growth factor system gene expression in human endometrium during the menstrual cycle. J Clin Endocrinol Metab 1994, 79:1723-1734.
• [29]Cenni B, Picard D: Ligand-independent Activation of Steroid Receptors: New Roles for Old Players. Trends Endocrinol Metab 1999, 10(2):41-46.
• [30]Kleinman D, Karas M, Roberts CT Jr, et al.: Modulation of insulin-like growth factor I (IGF-I) receptors and membrane-associated IGF-binding proteins in endometrial cancer cells by estradiol. Endocrinology 1995, 136(6):2531-2537.
• [31]Attias-Geva Z, Bentov I, Kidron D, Amichay K, Sarfstein R, Fishman A, Bruchim I, Werner H: p53 regulates insulin-like growth factor- I receptor gene expression in uterine serous carcinoma and predicts responsiveness to an insulin-like growth factor-I receptor-directed targeted therapy. Eur J Cancer 2012, 48(10):1570-1580.
• [32]Zhang L, Zhou W, Velculescu VE, et al.: Gene expression profiles in normal and cancer cells. Science 1997, 276:1268-1272.
• [33]Hellawell GO, Turner GD, Davies DR, Poulsom R, Brewster SF, Macaulay VM: Expression of the type 1 insulinlike growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease. Cancer Res 2002, 62:2942-2950.
• [34]Lacey JV Jr, Potischman N, Madigan MP, Berman ML, Mortel R, Twiggs LB, Barrett RJ, Wilbanks GD, Lurain JR, Fillmore CM, Sherman ME, Brinton LA: Insulin-Like Growth Factors, Insulin-Like Growth Factor-Binding Proteins, and Endometrial Cancer in Postmenopausal Women: Results from a U.S. Case–control Study. Cancer Epidemiol Biomarkers Prev 2004, 13(4):607-612.
• [35]Lathi RB, Hess AP, Tulac S, Nayak NR, Conti M, Giudice LC: Dose-dependent insulin regulation of insulin-like growth factor binding protein-1 in human endometrial stromal cells is mediated by distinct signaling pathways. J Clin Endocrinol Metab 2005, 90:1599-1606.
• [36]Creasman WT: Prognostic significance of hormone receptors in endometrial cancer. Cancer 1993, 71:1467-1470.
• [37]Xie Y, Wang Y, Tu L, Hu Q, Ji L, Zhang Y, Liao QP: Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells. J Steroid Biochem Mol Biol 2011, 126:113-120.
• [38]Bernstein LM, Boyarkina MP, Tsyrlina EV, Turkevich EA, Semiglazov VF: More favorable progesterone receptor phenotype of breast cancer in diabetics treated with metformin. Med Oncol 2010, 6:1313-1323.
• [39]Brown K, Hunger N, Docanto M, Simpson ER: Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase. Breast Cancer Res Treat 2010, 123:591-596.
• [40]Pengchong H, Tao H: Expression of IGF-1R, VEGF-C and D2–40 and their correlation with lymph node metastasis in endometrial adenocarcinoma. Eur J Gynaecol Oncol 2011, 32(6):660-664.
• [41]Roy RN, Gerulath AH, Cecutti A, Bhavnani BR: Discordant expression of insulin-like growth factors and their receptor messenger ribonucleic acids in endometrial carcinomas relative to normal endometrium. Mol Cell Endocrinol 1999, 153:19-27.
• [42]Saegusa M, Hashimura M, Yoshida T, Okayasu I: beta- Catenin mutations and aberrant nuclear expression during endometrial tumorigenesis. Br J Cancer 2001, 84(2):209-217.
• [43]Miyakoshi T, Kajiya H, Miyajima K, Takei M, Tobita M, Takekoshi S, Osamura RY: The expression of Wnt4 is regulated by estrogen via an estrogen receptor alpha-dependent pathway in rat pituitary growth hormone-producing cells. Acta Histochem Cytochem 2009, 42:205-213.
• [44]Wagner J, Lehmann L: Estrogens modulate the gene expression of Wnt-7a in cultured endometrial adenocarcinoma cells. Mol Nutr Food Res 2006, 50:368-372.
• [45]Varea O, Arevalo MA, Garrido JJ, Garcia-Segura LM, Wandosell F, Mendez P: Interaction of estrogen receptors with insulin-like growth factor-I and Wnt signaling in the nervous system. Steroids 2010, 75:565-569.
• [46]Moreno-Bueno G, Hardisson D, Sanchez C, Sarrio D, Cassia R, García-Rostán G, Jaime P, Guo M, Herman JG, Matías-Guiu X, Esteller M, Palacios J: Abnormalities of the APC/beta-catenin pathway in endometrial cancer. Oncogene 2002, 21:7981-7990.
• [47]Konopka B, Janiec-Jankowska A, Czapczak D, Paszko Z, Bidziński M, Olszewski W, Goluda C: Molecular genetic defects in endometrial carcinomas: microsatellite instability, PTEN and beta-catenin (CTNNB1) genes mutations. J Cancer Res Clin Oncol 2007, 133:361-371.
• [48]Nout R, Bosse T, Creutzberg C, Jürgenliemk-Schulz IM, Jobsen JJ, Lutgens LC, van der Steen-Banasik EM, Van Eijk R, Ter Haar NT, Smit VT: Improved risk assessment of endometrial cancer by combined analysis of MSI, PI3K–Akt, Wnt/β-catenin and P53 pathway activation. Gynecol Oncol 2012, 126:466-473.
• [49]Allison KH, Upson K, Reed SD, Jordan CD, Newton KM, Doherty J, Swisher EM, Garcia RL: PAX2 loss by immunohistochemistry occurs early and often in endometrial hyperplasia. Int J Gynecol Pathol 2012, 31(2):151-159.