Effect of long-term metformin treatment in endometrial cancer development and progression

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Endometrial cancer (EC) is one of the most common gynecological malignancies worldwide, and is classified into an estrogen-dependent type I, and an estrogen-independent type II cancer. Type I accounts for 75-85% of all cases. Estrogen stimulates endometrial cell proliferation and inhibits apoptosis supporting EC development. Insulin resistance (IR; hyperinsulinemia & normoglycemia), in combination with obesity, diabetes mellitus type II (DM II) and Polycystic Ovary Syndrome (PCOS) are also considered significant risk factors for the development and progression of type I EC. In PCOS patients with isolated IR, the hyperinsulinemia appears to be the sole promoting factor for EC initiation and progression. However, hyperglycemia is also considered an independent risk factor and is a critical link for cancer development observed in patients with DM II. Therefore insulin-sensitizing agents that reduce insulin and glucose levels are thought to prevent and treat cancer. In order to better understand additional local metformin effects within endometrial tissue, we elucidate the molecular changes during endometrial cancer development and progression under long-term metformin therapy in a hyperinsulinemic environment exposed to high glucose (reflecting diabetes) and normal glucose (reflecting IR) under estrogen exposure. By using a screening array of known genes relevant in cancer development and progression, we plan to define target genes of EC development under hyperinsulinemia in the different glucose environments that may be affected by metformin. After this we will confirm the suggested underling mechanisms of the metformin therapy by gene and protein expression change analysis under the different culture conditions. To understand further the molecular changes in EC development and progression under hyperglycemia and hyperinsulinemia we will knockdown these preselected target genes using siRNA to inhibit their gene function, followed by the analysis of the endometrial cell proliferation, migration/invasion and gene-/protein expression changes under the various conditions. This will help us gain novel mechanistic insights in the long-term physiological metformin treatment antitumor effects in endometrial cancer development and metastasis. Last, but not least, using the knockout tool CRISPR/cas9 we will evaluate if the endometrial cancer cell behavior is reestablished by the environment (insulin / high glucose effects), even when the potential drivers of the malignant state are knocked out. The long-term goal of this research is not only to further establish metformin in the prevention and/or treatment of endometrial carcinoma in patients at risk but also to elucidate unknown mechanisms how endometrial cells become malignant and aggressive in the conditions of hyperinsulimenia and hyperglycemia, therefore identifying possible new molecular therapeutic targets.