Early diagnosis of endometrial cancer (EC) is uncertain and women undergo preventive hysterectomy in cases where a non-invasive treatment can be used instead. To contribute to solving this challenge we investigated if early changes in the nuclear 3D telomere architecture during carcinoma development can be detected prior to the first morphological evidence of precancerous lesions. We utilized Pten heterozygous mice that develop progressive carcinoma in the endometrial tissue similar to EC development in women. We used telomere fluorescence in situ hybridization (FISH), 3D molecular imaging and analysis techniques on interphase nuclei of endometrial glandular epithelial cells to identify alterations in the 3D-telomere profile. We found that telomere dysfunction in Pten heterozygous mice is present already in endometrial simple hyperplasia lesions prior to detectable loss of PTEN protein expression and that the 3D telomere architecture has a specific signature that indicates early telomere dysfunction predictive for endometrial malignant transformation.

Le développement de nouvelles options thérapeutiques est à l’origine d’un changement de paradigme dans le processus de décision médicale. L'émergence de la médecine individualisée et la complexité croissante des données médicales ont conduit à l'avènement des modèles de prédiction. Pour le cancer de l'endomètre, ces modèles (algorithmes, scores et nomogrammes) ont été développés pour stratifier, estimer et prédire le risque de métastase ganglionnaire et de récidive. Le principal enjeu clinique est d’intégrer ces outils en vu d’optimiser les stratégies de prévention, de diagnostic et de traitement. Nous nous sommes intéressés au risque de récidive et d’envahissement ganglionnaire sur la base d’une analyse en population, puis individuelle. À l’échelle de la population, nous avons proposé : i) un travail de comparaison des principales classifications internationales, ii) une nouvelle classification clinicopathologique reposant sur l’incorporation d’un prédicteur histologique, iii) le développement de scores de stratification du risque. À l’échelle individuelle, nous avons développé : i) une méthodologie de validation externe des modèles prédictifs, point de départ indispensable à leur utilisation en pratique, ii) un nomogramme clinicopathologique spécifique d’envahissement ganglionnaire et son seuil de décision clinique. La modélisation mathématique en cancérologie est susceptible de transformer notre façon d’appréhender les stratégies préventives et curatives dans le cancer de l’endomètre. Les pistes d’optimisation sont multiples et laissent entrevoir la possibilité, dans un avenir proche, d’une application clinique à ces outils. / With the abundance of new options in diagnostic and treatment modalities, a shift in the medical decision process for endometrial cancer has been observed. The emergence of individualized medicine and the increasing complexity of available medical data have lead to the development of prediction models. In endometrial cancer, those clinical models (algorithms, nomograms, and risk scoring systems) have been reported, for stratifying and subgrouping patients, with various unanswered questions regarding such things as the optimal surgical staging for lymph node metastasis as well as the assessment of recurrence and survival outcomes. Through this manuscript we developed the question of the risk stratification for recurrence at the population level and the probability of lymph node involvement estimation at an individual level in early stage endometrial cancer. This double approach was adopted with the aim to illustrate the interest of these tools in clinical practice. At the population level, we proposed: i) a comparison of the main international clinicopathological classifications ii) a new clinicopathological classification based on a pathological predictor iii) two risk stratification systems for recurrence and lymph node metastasis. At the individual level we developed: i) a reproducible methodology for external validation of predictive models, ii) a specific clinic pathological nomogram for lymph node metastasis. In the future, the emerging field of molecular or biochemical markers research may substantially improve the predictive approach for preventive and curative strategies in endometrial cancer.

Endometrial cancer is the fourth most common cancer in women and the most common gynecological malignancy. While patient outcome has improved for the majority of cancers, the outlook for endometrial cancer has steadily decreased. In order to address this problem, we must better understand the different mechanisms involved in endometrial cancer development and progression. To this end, we quantified expression of 667 miRNAs in four endometrioid adenocarcinoma and four serous adenocarcinoma using Taqman Low Density Arrays (TLDAs). miR-888 was one of the most highly overexpressed miRNAs in both endometrial cancer subtypes. Analysis of miR-888 expression across multiple cancer types using the The Cancer Genome Atlas database revealed that miR-888 was selectively expressed in endometrial cancer, with a significant association to invasive and high grade tumors. In addition, miR-888 was most predominantly expressed in endometrial carcinosarcoma, a rare but deadly form of endometrial cancer. Therefore, we conclude that miR-888 expression marks an aggressive endometrial tumor phenotype. One of the top predicted targets of miR-888 by TargetScan is the progesterone receptor (PR). PR is a potent tumor suppressor of the endometrium whose expression is often lost in advanced endometrial cancers. We quantified PR mRNA expression in a panel of endometrial tumors and found a statistically significant, negative correlation between miR-888 and PR mRNA expression. Furthermore, overexpression of miR-888 in endometrial cancer cell lines was capable of decreasing PR at the protein level. To determine if miR-888 directly targets PR, we cloned each of the four miR-888 binding sites downstream of Renilla luciferase into the psiCHECK2 reporter vector. miR-888 overexpression was capable of decreasing luciferase activity for all four binding sites, with the second and third binding sites producing the most prominent results. Here we describe a novel mechanism by which miR-888 inhibits PR mRNA translation to negatively regulate PR expression in endometrial tumors. To determine the endogenous function of miR-888 in human cells, we quantified miR-888 in a panel of 21 normal human tissues. Interestingly, miR-888 was highly expressed in testes, with minimal or absence of expression in all other tissues investigated. The restricted expression pattern of miR-888 in testes and cancer suggested that miR-888 may qualify as a novel cancer-testis (CT) antigen. CT-antigens are a large class of genes that demonstrate selective expression normally in testes germ cells and abnormally in various types of cancer. Furthermore, CT-antigen genes are predominantly located on the X chromosome and are part of evolutionarily novel multicopy gene families. Indeed, miR-888 is part of a multicopy, primate-specific miRNA gene family located on the X-chromosome. Furthermore, miRNA in situ hybridization localized miR-888 expression to the early stages of spermatogenesis, as is often observed for CT antigens. Together, these data identify miR-888 as the first miRNA CT antigen and expand the CT antigen field to noncoding RNAs.

Background: Resveratrol is emerging as a novel anticancer agent. However, the mechanism(s) by which resveratrol exerts its effects on endometrial cancer (EC) are unknown. We previously reported that β-arrestin 2 plays a critical role in cell apoptosis. The role of β-arrestin 2 in resveratrol modulation of endometrial cancer cell apoptosis remains to be established. Scope of Review: EC cells HEC1B and Ishikawa were transfected with either β-arrestin 2 RNA interfering (RNAi) plasmid or β-arrestin 2 full-length plasmid and control vector. The cells were then exposed to differing concentrations of resveratrol. Apoptotic cells were detected by TUNEL assay. Expression of total and phosphorylated Akt (p-Akt), total and phosphorylated glycogen synthase kinase 3 beta (p-GSK3β), and caspase-3 were determined by Western blot analysis. Our data demonstrate that inhibition of β-arrestin 2 increases the number of apoptotic cells and caspase-3 activation. Additionally β-arrestin 2 exerted an additive effect on resveratrol-reduced levels of p-Akt and p-GSK3β. Overexpression of β-arrestin 2 decreased the percentage of apoptosis and caspase-3 activation and attenuated resveratrol-reduced levels of p-Akt and p-GSK3β. Taken together, our studies demonstrate for the first time that β-arrestin 2 mediated signaling plays a critical role in resveratrol-induced apoptosis in EC cells. Major Conclusions: Resveratrol primes EC cells to undergo apoptosis by modulating β-arrestin 2 mediated Akt/GSK3β signaling pathways. General significance: These inspiring findings would provide a new molecular basis for further understanding of cell apoptotic mechanisms mediated by β-arrestin 2 and may provide insights into a potential clinical relevance in EC.

Approximately 40,000 women in the U.S. are diagnosed with endometrial cancer annually. Biological data suggest coffee or tea consumption may lower endometrial cancer risk through estrogenic and insulin-mediated pathways. Epidemiologic data are inconsistent, with two of three prospective cohort studies showing an inverse association with coffee consumption and two prospective cohort studies finding no association with tea consumption. We used publicly available data from the Women's Health Initiative Observational Study to evaluate the association between coffee, tea and endometrial cancer risk. We identified 48,912 eligible post-menopausal women with a mean follow-up time of 7.5 years. During this period there were 452 incident endometrial cancer cases. We used Cox-proportional hazard models to evaluate the effects of coffee and tea consumption on endometrial cancer risk, while adjusting for potential confounders including age, body mass index and hormone therapy use. Overall, we did not find an association between coffee consumption and endometrial cancer risk. Compared to women who did not drink coffee on a daily basis (none or < 1 cup/day), the multivariable adjusted hazard ratios for women who drank 2-3 cups/day was 0.95 [95% confidence interval (CI) 0.74,1.22] for total coffee, 0.91 (95% CI 0.68,1.23) for regular coffee, and 0.94 (0.62,1.42) for decaf coffee. Compared to obese women who did not drink coffee on a daily basis (none or < 1 cup/day), the multivariable adjusted hazard ratios (HR) for obese women who drank ≥ 2cups/day as reported at baseline were: 0.79 (95% CI 0.53,1.17] for total coffee, 0.62 (95% CI 0.39,1.00) for regular coffee, and 0.78 (95% CI 0.40,1.50) for decaf coffee. Furthermore, obese women who consistently reported drinking ≥2 cups of regular coffee/day had an even further reduced risk [HR 0.40 (95% CI 0.18,0.91)]. In comparison to women who did not drink tea on a daily basis, obese women who drank 1 cup and ≥ 2cups of tea/day had multivariable adjusted hazard ratios of 0.45 (95% CI 0.22,0.92) and 0.99 (95% CI 0.60,1.62), respectively. The results from our study suggest that regular coffee consumption may be protective against endometrial cancer among obese postmenopausal women, with inconclusive results for tea. Our study adds to the biological understanding and to the small body of prevalent epidemiologic literature on coffee consumption and endometrial cancer risk.

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Endometrial adenocarcinoma (EAC) is the most frequently diagnosed gynecological cancer of the female genital tract in the Western world. Research studies in EC is difficult to conduct on human tumor samples due to the complex nature of tumor arousal and genetic heterogeneousness in the human population. Therefore, inbred animal models can be promising tools to use in EC research due to similar histopathology and pathogenesis as humans. Studies performed on MAP2K1 and CCND1 has shown that their altered expression play a crucial role in carcinogenesis. CCND1 has been demonstrated to have oncogenic properties when overexpressed in human neoplasias. The aim of this study is to investigate gene expression levels of MAP2K1 and CCND1 in BDII rat model of endometrial adenocarcinoma cells. Quantitative real-time PCR was used to analyze expression levels of MAP2K1 and CCND1 genes in BDII/Han rat model of endometrial cancer cells using TaqMan approach. The differences in gene expression levels of MAP2K1 and CCND1 between pathologically EAC malignant and nonmalignant cells showed an upregulation of MAP2K1 and CCND1 in EAC malignant cells. The analyzed data presented observable mean differences between MAP2K1 and CCND1 in several endometrial cell lines that were examined. Although no statistical significance was reached, an alteration in gene expression levels in malignant and nonmalignant endometrial cells could be observed. Furthermore, this present study shows observable upregulation of MAP2K1 and CCND1 in endometrial carcinoma cells vs. nonmalignant endometrium cells and encourages further investigation of the role of CCND1 and MAP2K genes in endometrial carcinogenesis.

No description available.

The evaluation of microsatellite instability in cancer patients might be of clinical importance as a prognostic and predictor factor. The aim of this study − evaluate the frequency and status of microsatellite instability and DNA mismatch repair protein expression in endometrial cancer and to relate the obtained results to clinicopathologic characteristics as well as patient survival. This study enrolled 109 patients.The objectives of the study: to determine the frequency and status of microsatellite instability by using two marker panels (earlier created BAT-25, BAT-26, NR-21, NR-24, MONO-27 and a new BAT-52, BAT-55, BAT-56, BAT-57, BAT-59 panels) recommended by Promega Corporation (USA); to compare the frequency and status of microsatellite instability with tumor clinicopathologic characteristics; to investigate the expression of DNA mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) in tumors with high-frequency microsatellite instability; to evaluate the impact of microsatellite instability on the survival of patients. The results showed that high-frequency microsatellite instability was detected two times more frequently with the new panel of markers in comparison while using earlier created panel. A statistically significant difference regarding tumor grade and myometrial invasion was found between the groups with high-frequency microsatellite instability and stable phenotype. There was no association between the survival of patients and microsatellite instability. / Mikrosatelitų nestabilumo tyrimai svarbūs vėžio ligos prognozei vertinti bei parenkant individualų gydymą. Darbo tikslas − ištirti mikrosatelitų nestabilumo dažnį, pobūdį ir klaidingai suporuotų nukleotidų DNR pažaidų taisymo sistemos baltymų raišką sergant gimdos kūno vėžiu ir gautus rezultatus susieti su pacienčių klinikinėmis-patologinėmis charakteristikomis bei jų išgyvenamumu. Į stebėsenos perspektyvinį tyrimą buvo įtrauktos 109 pacientės. Darbo uždaviniai: nustatyti mikrosatelitų nestabilumo dažnį ir pobūdį tarp sergančiųjų gimdos kūno vėžiu, panaudojus Promega Corporation (JAV) sukurtus du žymenų rinkinius (anksčiau sukurtą BAT-25, BAT-26, NR-21, NR-24, MONO-27 ir naująjį BAT-52, BAT-55, BAT-56, BAT-57, BAT-59); palyginti mikrosatelitų nestabilumo dažnį ir pobūdį su pacienčių klinikinėmis-patologinėmis charakteristikomis; ištirti DNR pažaidų taisymo sistemos baltymų (MLH1, PMS2, MSH2, MSH6) raišką gimdos kūno navikuose, kuriuose nustatytas didelio dažnio mikrosatelitų nestabilumas; įvertinti mikrosatelitų nestabilumo įtaką pacienčių išgyvenamumui. Tyrimų rezultatai parodė, kad mikrosatelitų didelio dažnio nestabilumas dvigubai dažniau nustatytas naudojant naująjį žymenų rinkinį, palyginti su anksčiau sukurtu žymenų rinkiniu. Statistiškai reikšminga sąsaja konstatuota tarp mikrosatelitų didelio dažnio nestabilumo arba jo nebuvimo ir naviko diferenciacijos laipsnio bei invazijos į miometriumą gylio. Sergančiųjų išgyvenamumas nebuvo susijęs su mikrosatelitų nestabilumu. ... [toliau žr. visą tekstą]