Monika Pawałowska

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

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.

Signalling pathways in endometrial cancer.

Carcinogenesis is a multistage process, during which the activity of signalling pathways responsible for cell cycle regulation and division is disrupted which leads to inhibition of apoptosis and enhanced proliferation. Improper activation of Wnt/β-catenin and PI3K. Akt pathways play essential role in endometrial cancers (EC), mainly type I. Mutations in APC, axin or CTNBB1 may lead to β-catenin overactivation leading to excessive gene expression. PTEN inactivation, mutations in the PIK3CA or Akt result in increased transmission in the PI3K/Akt pathway, apoptosis inhibition, intensive cell division, mTOR excitation. In non-endometrioid cancers, key mutations include suppressor gene TP53 responsible for repairing damaged DNA or apoptosis initiation. Irregularities in gene P16, encoding a protein forming the p16-cyclinD/CDK-pRb have also been described. Understanding the complex relations between specific proteins taking part in signal transduction of the abovementioned pathways is key to research on drugs used in targeted therapy.

The influence of metformin in the etiology of selected cancers

Obesity, hypertension and glucose tolerance disorders have become a growing concern in recent years. It is estimated that over 220 million people suffer from diabetes. It is a condition conducive to cardiovascular diseases, nephropathy, retinopathy and neuropathy but also to the development of many types of cancer. Insulin resistance and hyperinsulinemia lead to increased concentration of insulin-like growth factors, activation of IGF-R receptors, activation of PI3K and Ras-Raf pathways and result in increased cell division. The greatest risk is associated with developing stomach, pancreatic, colorectal, esophageal and lung cancer as well as breast and cervical cancer. Numerous cohort studies have confirmed that diabetic patients treated with metformin show a lower cancer morbidity and mortality rate. The dominant mechanism of action is activation of the AMP-activated protein kinase (AMPK) pathway and inhibition of mTOR protein, the key protein to regulate cell growth, apoptosis, proliferation and protein synthesis. Many clinical trials are currently under way to investigate the effectiveness of metformin in the prevention and treatment of neoplasms.

Infl uence of recreational psychoactive substances on the development of gynecologic cancers

Tea and coffee, beverages most commonly consumed by people, contain flavonoids, which have an antioxidant effect.It has been proven that...