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

Anna Markowska,Wiesława Bednarek,Janina Markowska,Stefan Sajdak,Jolanta Lubin,Beata Śpiewankiewicz,Marian Gryboś,Monika Pawałowska,Konstanty Korski,Anita Olejek,Violetta Filas

doi:10.1186/1758-5996-5-76

Abstract

ObjectiveDiabetes 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.MethodsThe 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.ResultsComparing 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.ConclusionAlthough 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.

Highlights

Endometrial carcinoma (EC) is the sixth most commonly diagnosed cancer in women [1]
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)

Summary

Introduction

Endometrial carcinoma (EC) is the sixth most commonly diagnosed cancer in women [1]. Among the women diagnosed with endometrial carcinoma, only 20-30% present normal body weight. Population studies show that metformin significantly reduces cancer risk in diabetic patients. A comparison of metformin patients with those taking sulfonylurea derivatives shows a 23% decrease in incidence of malignant neoplasms [5]. In a five-year observation period of 10,309 DM2 patients, a significant reduction in cancer mortality was noted among those on metformin when compared to patients on sulfonylurea derivatives or insulin (3.5% vs 4.9% vs 5.8%) [6], - esophageal, liver, colorectal, pancreatic, breast and lung cancers having the greatest risk reduction [7,8]. Recent studies have showed that metformin can inhibit cell proliferation and induce apoptosis in endometrial cancer cell lines [9]

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