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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

To elucidate potential mechanisms involved in the increased incidence of endometrial carcinomas in tamoxifen-treated patients, we examined the in-vitro effects of tamoxifen on endometrial cancer cells. The effects of tamoxifen, alone and in combination with oestradiol, on cell proliferation, plasminogen activator (PA) activity, glycogen synthase and phosphorylase activities, p53 protein concentration, and collagenase expression were assessed in two human adenocarcinoma cell lines. These lines were the oestrogen receptor-positive (Ishikawa) cells, representing a well-differentiated endometrial adenocarcinoma, and oestrogen receptor-negative (HEC-1A) cells, derived from a poorly differentiated endometrial adenocarcinoma. Tamoxifen or oestradiol alone and their combination significantly enhanced cellular proliferation of Ishikawa but not of HEC-1A cells. Both lines produced appreciable PA activity, most of which was of the urokinase type. Tamoxifen and oestradiol stimulated this activity in Ishikawa cells but not in HEC-1A cells. The effect of oestradiol was dose-dependent in a linear fashion, while tamoxifen produced a stimulation peaking at 10(-8) M and declining at higher concentrations. Tamoxifen in combination with oestradiol exhibited a synergistic effect on proliferation and on PA activity. The response of PA extended beyond the increase in proliferation, leading to higher specific activity of PA in the tamoxifen-treated cultures. In Ishikawa cells, oestradiol also increased glycogen synthase and glycogen phosphorylase activities, while tamoxifen markedly suppressed these enzymes. Oestradiol, tamoxifen, and their combination had no apparent effect on the expression of protein p53 in Ishikawa cells, or on gelatinase activity in either Ishikawa or HEC-1A cells. The present findings imply that tamoxifen produces oestrogen-agonistic effects on cell proliferation and PA activity, and oestrogen antagonistic effects on glycogen synthase and glycogen phosphorylase activities, but fails to regulate p53 and gelatinase expression. The tamoxifen-responsive systems were only observed in oestrogen-responsive adenocarcinoma cells. Thus, only certain potential oncogenic effects of tamoxifen can be simulated in vitro, and when present, these effects are enhanced in the presence of oestradiol.
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PMID:Tamoxifen exerts oestrogen-agonistic effects on proliferation and plasminogen activation, but not on gelatinase activity, glycogen metabolism and p53 protein expression, in cultures of oestrogen-responsive human endometrial adenocarcinoma cells. 946 46

The molecular events that occur during the development of endometrial carcinoma are largely uncharacterized. Carcinomas of the endometrium are associated as extracolonic malignant tumors in patients with hereditary nonpolyposis colorectal cancer syndrome. Endometrium and ovary may develop histologically homologue cancers especially endometrioid and papillary serous carcinomas. Colon and ovarian carcinoma might serve as model systems for the molecular analysis in endometrial carcinoma. We sought to analyze in endometrial carcinoma frequent molecular mechanisms of colon and ovarian carcinoma, including Ki-ras codon 12 mutations, microsatellite instability, p53 and c-erb B-2 immunohistochemical expression and allelic loss on chromosome 17q. Our results indicate that molecular mechanisms in endometrial carcinoma are different than those responsible for colorectal carcinomas and that uterine papillary serous carcinomas shares with its ovarian counterpart several molecular alterations in contrast to the histologically homologue uterine and ovarian endometrioid carcinoma. Furthermore there is a molecular basis to distinguish uterine endometrioid and papillary serous carcinoma.
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PMID:Molecular analysis in endometrial cancer. 947 73

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

The two types of endometrial carcinomas are preceded by precancerous lesions. Type I endometrial carcinomas are most commonly encountered in perimenopausal women with the classical risk factors associated with estrogen exposure: obesity, multiparity, diabetes, estrogen treatment, ... Hyperplasia (simple, followed by complex forms without cellular atypias and subsequently by complex hyperplasias with cellular transformation) precede such cancers. Estrogens exert a promoting effect on these lesions but do not initiate them. Progesterone and progestins exert a preventive and protective effect. However, the progressive loss of steroidal receptors is correlated to the progression of tissular anomalies and to the onset of cytogenetic anomalies and to mutations of p53 anti-oncogene. The preventive role of progestin is well established, but their curative beneficial effect on atypical precursors forms of endometrial cancers and on endometrial carcinomas remains controversial. The second type of endometrial cancer appears during the postmenopause and is characterized by an increased invasiveness and a poor prognosis, devoid of identifiable risks factors, these aggressive cancers are not preceded by hormone-sensitive precancerous lesions, but by an intra-epithelial endometrial carcinoma. This lesion appears most often in an atrophic endometrium. Finally, the two types of precancerous states are characterized by distinct gene anomalies suggesting two different pathogenic mechanisms of cancerisation.
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PMID:[Precancerous states of the endometrium: hormonal aspects]. 952 83

Angiogenesis is thought to be an important factor for tumour growth and metastatic spread, and microvessel counts may provide useful prognostic information for several tumour types. To investigate the prognostic impact of angiogenesis in endometrial carcinoma patients, the intratumour microvessel density, which was determined immunohistochemically, has been related to survival. Sixty patients with endometrial carcinoma with long (median 19 years) and complete follow-up have been studied. Patients with increased mean microvessel density (MVDmean > 68 mm2) had a significantly shorter 5-year survival compared with the rest (57% vs 90%, P = 0.004). In multivariate survival analyses, MVDmean had an independent prognostic impact (P = 0.03) when FIGO stage, histological type, histological grade as well as nuclear p53 protein expression was adjusted for. These findings indicate that intratumour microvessel density may contribute additional prognostic information to that obtained from the known risk factors and may be helpful in identifying endometrial carcinoma patients at high risk for disease progression.
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PMID:Independent prognostic importance of microvessel density in endometrial carcinoma. 956 52

In contrast to endometrioid carcinoma, uterine papillary serous carcinoma (UPSC) is an aggressive type of endometrial cancer. Loss of p53 function is critical for the molecular pathogenesis of UPSC. Both UPSC and its putative precursor, endometrial intraepithelial carcinoma (EIC), show abnormal p53 overexpression in most tumors. To further assess the nature of p53 alterations in UPSC, we systematically reevaluated a subset of our previous cohort of UPSC patients. In the current study, we correlate mutations of the p53 gene as detected by direct sequencing of exons 5 through 8 with p53 accumulation and expression of Waf-1 in 32 UPSC tumors. Waf-1 is a downstream effector of p53-mediated G1 arrest after DNA damage and, thus, an indicator of p53 functionality. Although 78% of tumors exhibited strong nuclear p53 immunoreactivity in 100% of tumor cells, we were able to detect p53 mutations in 53%. As expected, all p53 mutant tumors (17 cases) exhibited p53 overexpression. Seventy percent of those (12 tumors) showed concomitant lack of Waf-1 expression consistent with transcriptionally inactive p53, whereas the other five tumors showed Waf-1 staining in only a minor fraction of tumor cells consistent with p53-independent Waf-1 expression. In contrast, 47% (15 cases) of tumors failed to exhibit p53 mutations; interestingly, more than half of those (eight cases) showed strong nuclear p53 accumulation in all tumor cells but lacked concomitant Waf-1 expression. These findings are consistent with a mutation-dependent and -independent type of p53 inactivation in UPSC that are both associated with nuclear overexpression. Our findings suggest that the combined immunocytochemical analysis of p53 and Waf-1 is a valuable means of assessing the functional status of p53. In summary, p53 alterations are common in UPSC and probably responsible for its aggressive biological behavior.
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PMID:Loss of p53 function in uterine papillary serous carcinoma. 963 83

Instability at microsatellite repeat sequences (MI) has been observed in endometrial carcinomas (EC) arising sporadically or in association with the hereditary colon cancer syndrome. However, the clinical and pathological features of the EC with MI have not been characterized. DNA of 42 patients with EC was extracted from blood and from fresh-frozen and paraffin-embedded tumor tissue. Microsatellite loci on chromosomes 4, 5, 10, 12, 17, and 18 were amplified by polymerase chain reaction. MI was defined by a mobility shift in the tumor DNA as compared with normal DNA. Results were correlated with the clinical and pathological features of the tumors. MI at three or more loci was detected in 12 of 42 cases (28%). There were no significant differences between EC with and without MI with regard to age of presentation, stage, evidence of estrogenic stimulation, mucinous differentiation, estrogen receptor, c-erbB2, or p53 immunostaining. However, MI was more frequent in endometrioid (11/33, 33.3%) than in nonendometrioid (1/9, 11%) carcinomas. Only one papillary serous carcinomas showed MI. MI was found in one of two cases of endometrial hyperplasia adjacent to EC. It was concluded that MI is a common genetic abnormality of endometrial carcinoma and appears to be more frequent in endometrioid than in nonendometrioid tumors.
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PMID:Microsatellite instability in endometrial carcinomas: clinicopathologic correlations in a series of 42 cases. 978 37

Recently, microsatellite instability (MI) has been demonstrated in some types of human cancers. In this study, we attempted to determine the frequency of MI in endometrial cancers and evaluate whether replication error (RER)-positive phenotype is correlated with known genetic mutations or the aberrations of other pathways in endometrial cancers. Seventy-two primary endometrial cancers were examined for microsatellite instability. Eleven tumors (15%) had RERs at two or more microsatellite loci, suggesting that generalized MI may be a molecular manifestation of endometrial cancers. We next examined whether the MI was associated with changes in the K-ras protooncogene, p53 tumor suppressor gene, and 18q LOH, which were frequently detected in endometrial cancers. The MI did not confer the potential to produce point mutations in the K-ras gene or 18q LOH, whereas the data were insufficient to identify the correlation between MI and p53 mutations in the cancers. These results suggest the presence of multiple mutation subsets that act in a complementary fashion in endometrial cancer development.
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PMID:Microsatellite instability and somatic mutations in endometrial carcinomas. 978 19

Uterine papillary serous carcinoma (UPSC) is an uncommon but aggressive type of endometrial cancer associated with rapid progression of disease and poor prognosis. We investigated 23 cases of UPSC. p53 expression was studied in archival paraffin-embedded tissue by immunohistochemistry. Eleven tumors (47.8%) showed p53 overexpression whereas 12 tumors (52.2%) were p53 negative. One of 8 stage I/II (12.5%) and 10/15 stage III/IV (66.6%) tumors revealed p53 staining (P = 0.027). The median overall survival was 43.3 months. Patients with advanced-stage (III, IV) disease had a 5-year overall survival probability (5-year OS%) of 24% compared to 100% in those in stages I and II (log-rank, P = 0.018). Myometrial invasion, lymphatic space invasion, or lymph node involvement did not correlate with the 5-year OS of these patients. Patients whose tumors overexpressed p53 had a significantly shorter survival than those whose tumors did not (P = 0.033). This study confirms the influence of p53 overexpression on survival in UPSC patients.
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PMID:p53 protein overexpression: a strong prognostic factor in uterine papillary serous carcinoma. 978 20


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