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/ß-catenin and PI3K. Akt pathways play essential role in endometrial cancers (EC), mainly type I. Mutations in APC, axin or CTNBB1 may lead to ß-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.

[Influence of oncological treatment on fertility of women and pregnancy outcome]. / Wplyw leczenia onkologicznego na plodnosc kobiet i posiadanie potomstwa.

Advances in cancer treatment of young patients have resulted in markedly improved survival rates and quality of life. However infertility remains to be one of adverse effects of anticancer therapy. Female patients who receive high-dose abdominal and/or pelvic irradiation or chemotherapy based on alkylating agents are at highest risk of developing ovarian failure. Among women whose fertility was not impaired during oncologic treatment, there is a significantly increased number of premature labors. High-dose irradiation also predisposes to low-birthweight infants. Neither chemotherapy nor radiotherapy increase a risk of congenital malformations.

Replication study for the association of seven genome- GWAS-identified Loci with susceptibility to ovarian cancer in the Polish population.

We investigated the previously-demonstrated association of seven genome-wide association studies (GWAS) single nucleotide polymorphisms (SNPs), including rs2072590 (HOXD-AS1), rs2665390 (TIPARP), rs10088218 and rs10098821 (8q24), rs3814113 (9p22), rs9303542 (SKAP1) and rs2363956 (ANKLE1), as risk factors of epithelial ovarian tumors (EOTs). These SNPs were genotyped in two hundred seventy three patients with EOTs and four hundred sixty four unrelated healthy females from the Polish population. We observed the lowest p values of the trend test for the 9p22 rs3814113 and 8q24 rs10098821 SNPs in patients with all subtypes of ovarian cancer (p(trend) = 0.010 and p(trend) = 0.014, respectively). There were also significant p values for the trend of the 9p22 rs3814113 and the 8q24 rs10098821 SNPs for serous histological subtypes of ovarian cancer (p(trend) = 0.006, p(trend) = 0.033, respectively). Moreover, stratification of the patients based on their histological type of cancer demonstrated, in the dominant hereditary model, a significant association of the 9p22 rs3814113 SNP with serous ovarian carcinoma OR = 0.532 (95% CI = 0.342 - 0.827, p = 0.005, p(corr) = 0.035). Despite the relatively small sample size of cases and controls, our studies confirmed some of the previously-demonstrated GWAS SNPs as genetic risk factors for EOTs.

An analysis of polymorphisms within the Wnt signaling pathway in relation to ovarian cancer risk in a Polish population.

BACKGROUND AND OBJECTIVE: The Wnt/ß-catenin signaling pathway has been considered to be a factor in the development and progression of ovarian cancer. METHODS: All patients with ovarian cancer and controls were tested for BRCA1 mutations (5382incC, C61G, 4153delA) with HybProbe assays and for BRCA2 mutation (5946delT) using high-resolution melting curve analysis (HRM). Mutation carriers were excluded from the association analysis. We studied nine single nucleotide polymorphisms (SNPs) located in CTNNB1 (ß-catenin) [rs4533622, rs2953], APC (rs11954856, rs351771, rs459552), and AXIN2 (rs4074947, rs7224837, rs3923087, rs2240308) in women with ovarian cancer without BRCA1/BRCA2 mutations (n = 228) and controls (n = 282). Genotyping of CTNNB1 rs4533622, rs2953, APC rs351771, AXIN2 rs4074947, rs3923087, and rs2240308 was performed by HRM, while that of APC rs11954856, rs459552 and AXIN2 rs7224837 was conducted by PCR followed by the appropriate restriction enzyme digestion [PCR­restriction fragment length polymorphism (PCR-RFLP)]. RESULTS: The most common BRCA1/BRCA2 mutations were identified in 30 patients with ovarian cancer. These mutations were not found in controls. The lowest p values of the trend test (p trend) were observed for the APC rs351771 and rs11954856 SNPs in patients with ovarian cancer (p trend = 0.006 and p trend = 0.007, respectively). Using a dominant inheritance model, we found that the APC rs11954856 SNP is associated with an increased risk of ovarian cancer development [odds ratio = 2.034 (95 % CI 1.302­3.178); p = 0.002]. We also observed significant allelic differences for the APC rs351771 SNP between patients and controls (p = 0.006). CONCLUSION: Our study demonstrated significantly increased APC rs11954856 and rs351771 SNP frequencies in Polish women with ovarian cancer.

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

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 ß-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, ß-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, ß-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.