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 p53 gene are associated with a wide variety of human malignancies. Point mutation in one allele and loss of the remaining one generally lead to inactivation of p53 protein. A high frequency of allelic losses corresponding to the 17p13.3 region that contained the p53 gene sequence was also noted in human endometrial carcinoma. Thus, in order to confirm involvement of the p53 gene in endometrial carcinogenesis, we searched for nucleotide sequence change in this gene in 42 endometrial carcinomas that had been subjected to previous LOH analyses. Using the polymerase-chain-reaction-single-strand conformation polymorphism (PCR-SSCP) method, we detected p53 gene mutations in 4 specimens. Two adenocarcinomas with allelic loss on 17p contained a mutant p53 gene in the allele that was retained. One specimen with a p53 gene mutation contained a 17q deletion but was uninformative for LOH on 17p. p53 gene mutation was also noted in the remaining stage-I carcinoma, though the 17p deletion was not detected in the previous LOH examination. However, 5 specimens with the LOH on 17p retained the wild-type p53 gene. In the remaining 33 specimens, both alleles of p53 gene seemed to be normal. The mutations observed in 2 specimens (cases 10 and 24), involving C-to-T and T-to-G substitutions, were located in a highly conserved region. However, the mutations identified in the remaining 2 cases (29 and 35) were at regions positioned outside conserved stretches.
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PMID:Involvement of p53 gene mutations in human endometrial carcinomas. 847 53

The aim of this study was to evaluate the presence and distribution of p53 alterations in pure endometrioid adenocarcinomas (n = 120) of different grades and stages, as opposed to normal endometrium (n = 13) and various risk groups of hyperplasia (n = 39). All samples were initially analysed by immunohistochemistry with the monoclonal antibody Ab-6. Normal endometria were negative. With increasing degrees of malignancy, the number of cases with p53 accumulation rose and ranged from 9% to 18% in hyperplasia, through 25% in low-grade carcinomas (G1), to 69% in high-grade carcinomas (G3). This increase was also seen when comparing tumours by stage. Of carcinomas in stage IA, only 17% showed p53 immunostaining, in contrast with 72% in stage IC. Of this material, 34 carcinomas and 8 hyperplasias were analysed for p53 mutations in exons 5-8 by means of polymerase chain reaction and temperature-gradient gel electrophoresis (TGGE). In none of 5 hyperplasia and 6 of 12 carcinomas showing p53 accumulation by immunohistochemistry, p53 mutations were detected by TGGE. In contrast, 4 of 22 carcinomas harboured mutant p53 but were negative by immunohistochemistry. Immunohistochemical and molecular investigations revealed that p53 alterations are related to the standard prognostic markers of endometrial cancer, i.e. grading and staging. TGGE, an indirect screening procedure for p53 mutations, is used to detect the type of p53 alteration and may provide additional insight into the complex figure of p53 abnormalities in the development and progression of malignant endometrial lesions.
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PMID:Comparison of benign and malignant endometrial lesions for their p53 state, using immunohistochemistry and temperature-gradient gel electrophoresis. 864 68

A number of oncogenes and tumor suppressor genes that may serves as surrogate biomarkers of transformation are altered during the process of endometrial carcinogenesis. Overexpression of HER-2/neu occurs in 10% of endometrial adenocarcinomas and correlates with intraperitoneal spread of disease and poor survival. The c-myc oncogene is amplified in 10% of cases. Point mutations in codon 12 of the K-ras oncogene have been reported to occur in 10-20% of endometrial cancers. K-ras mutations also have been noted in some endometrial hyperplasias, which may represent an early event in the development of some endometrial cancers. Mutation of the p53 tumor suppressor gene, with resultant overexpression of mutant p53 protein, occurs in 20% of endometrial adenocarcinomas. Overexpression of p53 is associated with advanced stage and poor survival. Because p53 mutations have not been observed in endometrial hyperplasias, this is thought to be a relatively late event in endometrial carcinogenesis. Microsatellite instability has also been noted in approximately 15% of sporadic endometrial cancers, but mutations in DNA repair genes have not yet been reported. Chemoprevention trials in endometrial cancer may be feasible due to the existence of a premalignant lesion and surrogate biomarkers.
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PMID:Biomarkers in the endometrium. 874 93

Overexpression of p53 protein has been reported to correlate with a poor prognosis in endometrial cancer. Most endometrial adenocarcinomas are clinical stage I at the time of diagnosis and the majority of women to die of this neoplasm had stage I disease at initial presentation. The aim of our study was to evaluate the prognostic significance of p53 overexpression in early stage endometrial carcinoma. Ninety-two patients with surgically treated endometrial adenocarcinoma FIGO stage I were examined for overexpression of immunohistochemically detected mutant p53 protein. Follow-up time ranged from 0.4 to 137.8 months (mean, 34.8). Thirteen women died of their tumor. A nuclear staining reaction for p53 was observed in eight cases. Women with p53 protein overexpression showed a significant poorer overall survival in univariate analysis (relative risk, 4.78; 95% confidence interval, 1.56-14.61; P = 0.006, Wald test) and also in multiple analysis adjusted for grading (relative risk, 4.39; 95% confidence interval, 1.39-13.90; P = 0.01, Wald test). Histological grading and histologic stage did not correlate with p53 protein overexpression (P = 0.26, P = 1.0, respectively, exact chi 2 test). Immunohistochemically detected p53 protein overexpression in early stage endometrial adenocarcinoma could aid in predicting prognosis and subsequently have some impact on adjuvant therapy.
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PMID:p53 protein overexpression in early stage endometrial cancer. 875 52

The p21 protein inhibits cyclin-dependent kinases and mediates cell-cycle arrest and cell differentiation. It is induced by wild-type p53, but not by mutant p53. This study of 75 patients with endometrial carcinoma investigates the relationship between p21 expression and the functional status of p53, and the usefulness of p21 as a prognostic marker. Correlations were determined between p21 immunoreactivity, p53 overexpression as examined by immunohistochemistry, p53 DNA mutations as examined by polymerase chain reaction-single-stranded conformation polymorphism (PCR-SSCP) analysis, and clinicopathological features, including the clinical outcome. Immunoreactivity for p21 and p53 mutations were detected in 47 (62.7 per cent), 37 (49 per cent), and 23 (31 per cent) patients, respectively. There were no significant correlations between the presence or absence of p21 immunoreactivity and p53 overexpression and DNA mutations. Survival curves revealed that patients with p53 overexpression tended to have a poorer prognosis than those without p53 overexpression (P = 0.104), that patients with p53 mutations had a significantly worse prognosis than those without mutations (P = 0.035), and that patients with p21 expression tended to have a better prognosis than those without p21 expression (P = 0.074). Immunohistochemical analysis of p21 was not useful for evaluating the functional status of p53 in patients with endometrial carcinoma. Both p21 expression and p53 abnormalities were considered as prognostic indicators in patients with endometrioid endometrial carcinoma.
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PMID:Correlations between p21 expression and clinicopathological findings, p53 gene and protein alterations, and survival in patients with endometrial carcinoma. 942 88

Clinicopathological, immunohistochemical and molecular genetic analyses of endometrial carcinoma suggest different pathogenetic pathways for endometrioid and serous carcinoma. Most endometrioid carcinomas are associated with endometrial hyperplasia, are ER/PR positive, p53 negative and express low Ki-67. In contrast, almost all serous carcinomas develop from endometrial intraepithelial carcinoma (EIC) in a background of atrophy. These tumors are ER/PR negative, strongly express p53 and show high Ki-67 labeling. On the molecular genetic level, 25-30% of endometrioid carcinomas show microsatellite instability (MI), 25-30% harbor mutant K-ras and less than 10% have mutant p53. In contrast, more than 90% of serous carcinomas have p53 mutations, 2% K-ras mutations and none MI. Among endometrioid carcinomas, K-ras mutations occur most frequently in FIGO grade 2 and 3 tumors and p53 mutations in FIGO grade 3 tumors. In contrast, MI is equally distributed among all FIGO grades. These findings support the view that endometrioid carcinoma develops slowly in a progressive fashion from endometrial hyperplasia. Mutation of p53 occurs late in tumor progression. Thus, endometrioid carcinogenesis resembles the proposed model for colorectal carcinogenesis. In contrast, serous carcinoma develops rapidly from EIC in a background of atrophy. Mutation of p53 occurs early in serous carcinogenesis and this may account for the highly aggressive behavior of this tumor.
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PMID:A dualistic model for endometrial carcinogenesis based on immunohistochemical and molecular genetic analyses. 947 74

Vascular endothelial growth factor (VEGF) that activates endothelial cell growth induces angiogenesis, which is indispensable to tumor igenesis and tumor progression. On the other hand, tumor suppressor gene p53 has been considered to regulate VEGF expression, but the detailed relationship between them remains unclear. In this study, we aimed to study VEGF expression in endometrial carcinoma cells and the effect of p53 gene transfection on VEGF expression using p53-mutated endometrial carcinoma cell line, HEC-50B. Immunoblotting for detecting VEGF protein, p53 protein and beta-actin was performed using 11 endometrial carcinoma cell lines. Levels of VEGF in the cultured media were measured by Enzyme immunoassay(EIA). Transfection of wild p53 gene was carried out by SuperFect method in HEC-50B cells, which had mutant p53 gene and did not express p53 protein. The results of immunoblotting were analyzed by NIH image and expressed as values. The results of EIA were expressed as the relative value. The VEGF value was 0.8 +/- 0.3 (n = 6) in p53-wild group, whereas in p53-mutant group it was 1.6 +/- 0.8 (n = 5). VEGF expression was correlated significantly with p53 status (P < 0.05). VEGF levels in p53 gene-transfected cells and the conditioned medium were decreased in 48 hours after p53 gene transfection. VEGF expression was down-regulated by p53 in endometrial carcinoma cells.
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PMID:VEGF expression and its reguration by p53 gene transfection in endometrial carcinoma cells. 1297 25

Mutant p53 protein is not degradated but accumulates in the nuclei. However, the relation between p53 gene mutation and quantity of p53 protein has not been clarified yet in endometrial carcinoma. We investigated the correlation between p53 gene mutation and its protein expression quantitatively using 11 cell lines of endometrial adenocarcinoma, endometrioid type and two serous-type cell lines. To examine p53 mutation, PCR-SSCP analysis in exon 5 to 8 and direct sequence were carried out. p53 expression was determined by immunocytochemistry and immunoblotting. The percentage of positive staining in the nuclei by immunocytochemistry was calculated as a labeling index (LI). The amount of p53 detected by immunoblotting was expressed as a comparative value of Ishikawa cells. Point mutation of p53 gene was detected in four of 11 (36.4%) cell lines of endometrioid adenocarcinoma, and all two of serous adenocarcinoma. There was a significant positive correlation between p53 LI and p53 values. The LI and the values of p53 were significantly higher in the mutant group than the wild one, thus showing a quantitative correlation between p53 protein expression and p53 gene mutation in endometrial carcinoma cell lines. It is plausible that immunohistochemical analysis of p53 could be qualified to be a convenient indicator of p53 gene mutation on clinical materials, if p53 LI is more than 40 (M-SD in mutant p53).
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PMID:Quantitative study on the correlation between p53 gene mutation and its expression in endometrial carcinoma cell lines. 1505 63

In addition to the loss of function, mutant p53 can possess a dominant-negative effect on wild-type p53 and may also exert gain-of-function activity. It is not clear whether the functional status of p53 mutation contributes to differences in outcome in endometrial cancer. We collected a total of 92 RNA samples of high quality from endometrial cancer tissues, and the samples were subjected to yeast functional assay and sequencing for p53 mutations. The detected mutant p53 genes were further investigated for their dominant-negative activity using a yeast-based transdominance assay. p53 mutation was found in 24 out of 92 (26.1%) tumors, of which 10 exhibited no dominant-negative activity (recessive mutation) and 14 showed dominant-negative activity. Dominant-negative p53 mutation was related to advanced stages (p = 0.01), nonendometrioid type tumors (p = 0.01) and grade 3 tumors (p = 0.04). The patients with dominant-negative mutation had significantly shorter survival than patients with no mutation (p < 0.0001) and those with a recessive mutation (p = 0.01) in the p53 gene. No difference in survival was found between the patients with tumors harboring a recessive p53 mutation and those with tumors harboring a wild-type p53. Multivariate analysis revealed that dominant-negative p53 mutation (p = 0.019), FIGO stage (p = 0.0037) and histologic subtype (p = 0.014) were independently related to patient survival. Dominant-negative p53 mutation was the most important prognostic factor for stage III/IV endometrial cancer (p = 0.0023). In conclusion, dominant-negative p53 mutation is often found in advanced stages and aggressive histologic subtypes of endometrial cancer and it is a strong predictor of survival of patients with advanced endometrial cancer. To elucidate further the role of p53 mutation in endometrial cancer, it is necessary to investigate gain-of-function activity involving dominant-negative p53 mutant proteins.
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PMID:Functional analysis of p53 gene and the prognostic impact of dominant-negative p53 mutation in endometrial cancer. 1582 82

This study is the first to investigate the antiproliferative effect of eupatilin in human endometrial cancer cells. Eupatilin, a naturally occurring flavonoid isolated from Artemisia princeps, has anti-inflammatory, anti-oxidative, and anti-tumor activities. In the present study, we investigated the potential effect of eupatilin on cell growth and its molecular mechanism of action in human endometrial cancer cells. Eupatilin was more potent than cisplatin in inhibiting cell viability in the human endometrial cancer cell lines Hec1A and KLE. Eupatilin showed relatively low cytotoxicity in normal human endometrial cells HES and HESC cells when compared to cisplatin. Eupatilin induced G2/M phase cell cycle arrest in a time- and dose-dependent manner, as indicated by flow cytometry analysis. In addition, treatment of Hec1A cells with eupatilin resulted in a significant increase in the expression of p21(WAF1/CIP1) and in the phosphorylation of Cdc25C and Cdc2. Knockdown of p21 using specific siRNAs significantly compromised eupatilin-induced cell growth inhibition. Interestingly, levels of mutant p53 in Hec1A cells decreased markedly upon treatment with eupatilin, and p53 siRNA significantly increased p21 expression. Moreover, eupatilin modulated the phosphorylation of protein kinases ERK1/2, Akt, ATM, and Chk2. These results suggest that eupatilin inhibits the growth of human endometrial cancer cells via G2/M phase cell cycle arrest through the up-regulation of p21 by the inhibition of mutant p53 and the activation of the ATM/Chk2/Cdc25C/Cdc2 checkpoint pathway.
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PMID:Eupatilin, a dietary flavonoid, induces G2/M cell cycle arrest in human endometrial cancer cells. 2155 18


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