Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the beta-catenin gene (CTNNB 1) with abnormal nuclear accumulation of beta-catenin have recently been identified in endometrial carcinoma (EC). Their relationship with microsatellite instability (MI) is unclear. It has been suggested that matrix metalloproteinase-7 (MMP-7) and cyclin D1 (cD) genes are targets for beta-catenin activation. DNA from 73 patients with EC was obtained from tumor and normal tissue (59 endometrioid and 14 nonendometrioid). CTNNB 1 mutations in exon 3 were assessed by single-strand conformation polymorphism and DNA sequencing. The results were correlated with immunostaining for beta-catenin, MMP-7, and cD. Three (CA)n repeats and mononucleotide tracts BAT 25 and BAT 26 had been previously used for MI analysis. CTNNB1 mutations were identified in 15 ECs (20.5%), all of them endometrioid carcinomas (15 of 59; 25.4%). They occurred in 6 of 19 MI-positive ECs (31.5%) and in 9 of 54 MI-negative ECs (16.6%). Eleven of the 15 CTNNB 1-mutated ECs showed beta-catenin nuclear immunostaining (P <.05). MMP-7 expression (>50% cells) was observed in 23 ECs, with 7 of these showing CTNNB 1 mutations. Significant expression of cD (>50% cells) was detected in 8 ECs, with 5 of these exhibiting CTNNB 1 mutations (P <.05). The results confirm that beta-catenin plays a role in endometrial carcinogenesis, particularly in endometrioid carcinomas. The results also suggest that MMP-7 and particularly cD may be targets of beta-catenin activation in ECs.
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PMID:CTNNB1 mutations and beta-catenin expression in endometrial carcinomas. 1195 46

Endometrial hyperplasia is a recognized effect of excessive or unopposed estrogen stimulation and is considered to be a precancerous condition of endometrial adenocarcinoma. We have previously shown that the subcellular localization of beta-catenin in the human endometrium is changed according to cell proliferation, suggesting a role of intercellular transduction in cell-growth control in human endometrium, not only in the physiological condition but also in the carcinogenic endometrium. In the present study, to clarify at which stage of endometrial carcinogenesis molecular alteration of the beta-catenin gene occurs, we analyzed the subcellular localization of beta-catenin by immunohistochemistry, and we analyzed exon 3 of the beta-catenin gene, in 25 patients - with endometrial hyperplasia and 20 patients with endometrial cancers associated with endometrial hyperplasia, digesting DNA from the cancer and hyperplasia parts, separately. Fourteen of the 25 (56.0%) endometrial hyperplasia samples, 12 (60.0%) endometrial cancers, and 11 (55.0%) associated hyperplasias of the 20 endometrial cancers associated with hyperplasia showed nuclear localization of beta-catenin. Mutation in exon 3 of the beta-catenin gene was found in 2 of the 20 endometrial cancer samples; however, it was not found in the 25 endometrial hyperplasias or the 20 associated hyperplasias. The results suggest that molecular alteration of the beta-catenin gene occurs in atypical hyperplasia or cancer, rather than in simple or complex hyperplasia without atypia, during endometrial carcinogenesis.
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PMID:Mutation of beta-catenin gene in endometrial cancer but not in associated hyperplasia. 1211 2

Loss of the cell adhesion molecule E-cadherin is suggested to promote tumor invasion and distant metastasis in tumor development. Recently, it has been proposed that E-cadherin function requires its linkage to the cytoskeleton through catenins. We evaluated the expression of E-cadherin and alpha-, beta-, gamma-catenins in tissues of human endometrial carcinoma, analyzed the patterns of cell adhesion molecules' expression in endometrial carcinoma and investigated the relationship between the statuses of cell adhesion molecules and various clinicopathological factors. This study investigated the immunohistochemical expression of E-cadherin and alpha-, beta-, gamma-catenins in 33 paraffin embedded formalin fixed tissues of endometrial carcinomas. Aberrant E-cadherin, and alpha-, beta-, gamma-catenin expression was observed in 33.3 (11 of 33), 27.3 (9 of 33), 18.2 (6 of 33), and 51.5 (17 of 33) % of the specimens, respectively. Statistically significant correlation was found between aberrant expression of E-cadherin and lymph node metastasis and cell types other than endometrioid adenocarcinoma. Aberrant pattern of gamma-catenin expression was also correlated with deep myometrial invasion. However, alpha-, and beta-catenin expression was not correlated with any clinicopathological parameters. Using the Kaplan-Meier method and log-rank comparison test, abnormal expression of E-cadherin was correlated closely with poor survival (p < 0.05), but cases with loss of both E-cadherin and catenin expression predicted even poorer survival than cases with only one or no aberrant expression in E-cadherin and catenins. We revealed aberrant expression of these cell adhesion molecules among patients with endometrial carcinoma. Aberrant expression of E-cadherin was correlated with lymph node metastasis and cell types other than endometrioid adenocarcinoma, while aberrant expression of gamma-catenin was related with deep myometrial invasion. The expression of E-cadherin might be a possible prognostic factor for endometrial cancer while the expression of catenins may help predict patient's survival.
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PMID:Expression of E-cadherin and alpha-, beta-, gamma-catenin proteins in endometrial carcinoma. 1249 52

Ovarian hormones are considered to be capable of regulating expression of beta-catenins. A possible role of beta-catenin in alteration of cell morphology has been proposed, but little is known about beta-catenin expression during changes in the tumor morphology of endometrial carcinomas induced by progesterone therapy. To clarify changes in expression of beta-catenin and their relation to morphological alteration, expression of hormone receptors and several cell kinetic markers, sequential biopsy and hysterectomy specimens of 23 endometrial carcinoma and 6 complex hyperplasia with atypia (atypical hyperplasia) cases receiving progesterone therapy were investigated. In vitro assay was also conducted using two endometrial carcinoma cell lines (HEC265 and Ishikawa) expressing progesterone receptors (PRs). An increase of nuclear beta-catenin accumulation was evident during progesterone therapy in endometrial carcinomas and atypical hyperplasias. The nuclear labeling indices were significantly associated with gene mutations and alteration in morphological features in response to progesterone, independently of the status of Ki-67, p21WAF1 and p27Kip1, and hormone receptors. In HEC265 having a beta-catenin gene mutation (A32V), cytoplasmic beta-catenin levels were elevated by progesterone treatment, linked to down-regulation of PR expression, but such changes were relatively minor in Ishikawa without the gene alterations. These findings demonstrate a possible role of progesterone in regulation of beta-catenin expression in endometrial tumors. Moreover, nuclear beta-catenin accumulation, like gene abnormalities, is associated with the alteration of tumor morphology due to progesterone, indicating that beta-catenin may be a clinically useful marker of hormone therapeutic effects.
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PMID:Up-regulation and nuclear localization of beta-catenin in endometrial carcinoma in response to progesterone therapy. 1270 83

Endometrial cancer is a common gynaecological malignancy in the industrialised world. Unopposed stimulation of the endometrium by oestrogens is the classic aetiological factor associated with the development of this malignancy. However, not all are associated with oestrogen exposure and two different clinicopathological types can be distinguished: the oestrogen-related of endometrioid type (type I) and the non-oestrogen-related of non-endometrioid type (mainly papillary serous or clear cell carcinomas) (type II). Recent advances in the knowledge on the molecular genetics of endometrial cancer have shown that the molecular changes involved in its the development differ in oestrogen-dependent type I and non-oestrogen-dependent type II. Type I carcinomas frequently show mutations of DNA-mismatch repair genes (MLH1, MSH2, MSH6), PTEN, k-ras and beta-catenin genes whereas type II malignancies are characterised by aneuploidy, p53 mutations and her2/neu amplification. This article reviews the latest findings concerning common gene mutations involved in the development and progression of endometrial cancer.
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PMID:Molecular genetics and endometrial cancer. 1280 10

Two types of endometrial carcinoma can be distinguished: type I tumours, which are oestrogen-related and are typically low-grade endometrioid carcinomas; and type II tumours, which are unrelated to oestrogen stimulation and are often non-endometrioid carcinomas. The molecular abnormalities involved in carcinogenesis appear to be different for these tumour types. The aim of this study was to test the hypothesis that an abnormality in the Wnt/beta-catenin signalling pathway is a molecular feature of type I endometrial carcinoma. This study investigated nuclear beta-catenin by immunohistochemistry in 233 endometrial carcinomas and analysed its correlation with several immunohistochemical, histological, and clinical parameters, such as proliferation rate (Ki-67), expression of oestrogen and progesterone receptors, and survival. Nuclear beta-catenin expression was observed in 39 cases (16%). All tumours expressing nuclear beta-catenin were endometrioid adenocarcinomas, were significantly better differentiated, and were more often hormone receptor-positive than tumours without nuclear beta-catenin. No correlation with proliferation rate was found. It was found that several features of type I endometrial carcinoma occur significantly more often in tumours expressing nuclear beta-catenin, suggesting that an abnormality in the Wnt/beta-catenin signalling pathway, resulting in nuclear beta-catenin immunopositivity, is a molecular feature of a subset of type I endometrial carcinomas.
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PMID:Nuclear beta-catenin is a molecular feature of type I endometrial carcinoma. 1509 79

Two types of endometrial carcinoma are distinguished with respect to biology and clinical course. Type-I carcinoma is related to hyperestrogenism by association with endometrial hyperplasia, frequent expression of estrogen and progesterone receptors and younger age, whereas type-II carcinoma is unrelated to estrogen, associated with atrophic endometrium, frequent lack of estrogen and progesterone receptors and older age. Histologically, endometrioid and mucinous carcinomas are considered type I, serous and clear cell carcinomas type II. Molecular data from multiple studies support the hypothesis of different genetic pathways in the development of endometrioid and serous carcinoma. The most frequent genetic alteration in endometrioid carcinoma is PTEN inactivation by mutation, followed by microsatellite instability (MIN) and mutations of K-ras and beta-catenin. PTEN and K-ras mutations and MIN are considered early events, occurring in a subset of atypical endometrial hyperplasia, whereas p53 mutation is considered a late event, during progression of about 10-20% of endometrioid carcinomas. In serous carcinoma, p53 mutation is the most frequent genetic alteration, followed by inactivation of p16 and e-cadherin and amplification of her2/neu. p53 mutation occurs in endometrial intraepithelial carcinoma, the putative precursor of serous carcinoma. Considering these genetic pathways, the current histological classification of endometrial carcinoma is molecular based.
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PMID:Molecular genetic pathways in various types of endometrial carcinoma: from a phenotypical to a molecular-based classification. 1474 44

The functional consequences of up-regulation of beta-catenin as a transcription factor are complex in different tumors. To clarify roles during squamous differentiation (SqD) of endometrial carcinoma (Em Ca) cells, we investigated expression of beta-catenin, as well as cyclin D1, p53, p21WAF1, and PML (promyelocytic leukemia) in 80 cases of Em Ca with SqD areas, in comparison with cell proliferation determined with reference to Ki-67 antigen positivity. The impact of beta-catenin-T-cell factor (TCF)-mediated transcription was also examined using Em Ca cells. In clinical cases, nuclear beta-catenin accumulation was more frequent in SqD areas, being positively linked with expression of cyclin D1, p53, and p21WAF1, and inversely with Ki-67 and PML immunoreactivity. Significant correlations of nuclear beta-catenin, cyclin D1, p53, and p21WAF1 were noted between SqD and the surrounding carcinoma lesions. The Ishikawa cell line, with stable or tetracycline-regulated expression of mutant beta-catenin, showed an increase in expression levels of cyclin D1, p14ARF, p53, and p21WAF1 but not PML, and activation of beta-catenin-TCF4-mediated transcription determined with TOP/FOP constructs. The cell morphology was senescence-like rather than squamoid in appearance. Moreover, overexpressed beta-catenin could activate transcription from p14ARF and cyclin D1 promoters, in a TCF4-dependent manner. These findings indicate that in Em Cas, nuclear beta-catenin can simultaneously induce activation of the p53-p21WAF1 pathway and overexpression of cyclin D1, leading to suppression of cell proliferation or induction of cell senescence. However, overexpression of beta-catenin alone is not sufficient for development of a squamoid phenotype in Em Ca cells, suggesting that nuclear accumulation is an initial signal for trans-differentiation.
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PMID:Beta-catenin simultaneously induces activation of the p53-p21WAF1 pathway and overexpression of cyclin D1 during squamous differentiation of endometrial carcinoma cells. 1511 20

Endometrial carcinoma, generally, has a good prognosis. However, in some patients, the tumor appears to behave very aggressively, a course that cannot be explained with histopathological characteristics. More insight into the molecular background can be valuable to clarify these differences in tumor behavior. The three components associated with the Wnt pathway--i.e., adenomatous polyposis coli (APC), beta-catenin, and E-cadherin--were evaluated in a case-control study of 28 patients with stage-I endometrial carcinomas to determine their involvement in the development of recurrent disease. Mutation analysis of the mutation cluster region of the APC gene, determination of gene promoter methylation status of the APC-1A and E-cadherin genes, and immunohistochemical analysis of APC, E-cadherin, and beta-catenin were performed using paraffin-embedded tumor tissue. Twenty-one APC gene mutations were detected in 12 of 28 (43%) patients. Only three mutations would result in a stopcodon in the APC gene. APC gene promoter methylation was assessed in 12 of 28 (43%) patients. APC immunostaining was absent in two of 24 (8.3%) patients. The occurrence of APC mutations, APC gene promoter methylation, and APC immunostaining were not predictive for recurrence. No E-cadherin expression was observed in four of 24 patients (17%). E-cadherin gene promoter methylation could not be detected in any of the patients. The absence of E-cadherin expression was predictive for distant metastases, but not for local recurrence. Nuclear localization of beta-catenin was present in nine of 24 (38%) patients and was not predictive for recurrent disease. Involvement of epigenetic and genetic aberrations in APC and beta-catenin genes seems to be of minor importance for the development of local recurrences and distant metastases. Although the number of patients is limited, E-cadherin expression appears to be predictive for the development of distant metastases in endometrial carcinoma.
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PMID:APC, beta-catenin, and E-cadherin and the development of recurrent endometrial carcinoma. 1536 Dec 8

PTEN: and beta-catenin mutations constitute the predominant genetic alterations in endometrioid carcinomas of the endometrium. PTEN encodes a dual-specificity phosphatase with lipid phosphatase and protein tyrosine phosphatase activities that regulate both apoptosis and interactions with the extracellular matrix. Recent studies have associated PTEN mutations with tumorigenesis of prostate carcinoma via the Wnt signaling pathway, leading to nuclear beta-catenin accumulation. To elucidate the potential interaction of PTEN and beta-catenin in endometrial cancer, we performed mutation analyses of the entire PTEN gene and of exon 3 of the beta-catenin gene that is most frequently targeted by mutations. A total of 82 endometrial carcinomas comprising 62 type I endometrioid carcinomas and 20 type II high-grade carcinomas were investigated. In addition in a subset of 22 carcinomas, the intracellular beta-catenin distribution was analyzed by immunohistochemistry. Overall, 20 (24.4%) of 82 tumors revealed mutations in the PTEN gene, and 16 (19.5%) of 82, in the beta-catenin gene. Six tumors (7.3%) showed mutations in both the PTEN and beta-catenin gene. Mutations were mainly detected in endometrioid carcinomas of the endometrium. As expected, a striking nuclear accumulation of beta-catenin could be shown in tumors with beta-catenin mutations. In the vast majority of tumors with PTEN mutations, a regular staining pattern of the cytoplasmic and membranous compartments was found. We therefore conclude that, in contrast to prostate cancer, mutations in the PTEN gene seem not to affect cellular distribution of the beta-catenin protein in endometrial carcinomas.
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PMID:PTEN mutations do not cause nuclear beta-catenin accumulation in endometrial carcinomas. 1549 94


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