Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Nuclear stabilization of beta-catenin and its interaction with TCF/LEF factors are key events in transduction of the Wnt/beta-catenin signal pathway. Our previous study indicated that nuclear beta-catenin accumulation provides an initial signal for trans-differentiation toward the squamoid phenotype of endometrial carcinoma (Em Ca) cells in a TCF4-dependent manner, which makes this a possible factor for a positive prognosis. However, little is known about regulation of TCF4 expression in Em Cas. We show here that beta-catenin can directly induce transcription from the TCF4 promoter, the effect being enhanced by the p300 coactivator. In clinical cases, nuclear beta-catenin accumulation was found to frequently overlap with TCF4 immunoreactivity in morules and surrounding glandular carcinoma lesions, showing a significant positive correlation (r = 0.82, P < 0.0001), in contrast to areas of squamous metaplasia (SqM) within Em Cas. In cases with coexistence of two squamoid features in trans-differentiated areas, loss of nuclear beta-catenin and TCF4 immunoreactivity was closely related to change in the morphology from the morular to the SqM phenotype. The TCF4 promoter contains a single consensus TCF-binding site that is critical for activation by beta-catenin. The p300 coactivator, in particular N-terminal residues 1 to 670, appears sufficient to enhance beta-catenin-dependent transcription, again with TCF4-dependence. These findings indicate that a positive feedback loop of TCF4 expression mediated by beta-catenin/p300 may be important for initial steps during trans-differentiation of Em Ca cells. In addition, its downregulation is associated with induction of a more-differentiated squamoid phenotype.
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PMID:Upregulation of TCF4 expression as a transcriptional target of beta-catenin/p300 complexes during trans-differentiation of endometrial carcinoma cells. 1580 38

p63 and cytokeratin (CK) 5/6 are markers of basal and squamous differentiation in several normal epithelia and human tumors and are also suggested to be markers of progenitor or stem cells in certain stratified epithelia. In endometrial carcinoma, there is very limited information about the expression pattern of p63 or CK5/6 and no prognostic information. The aim of our study was to examine whether the expression of these markers was associated with a certain tumor phenotype in terms of other biomarkers, clinicopathologic characteristics and patient prognosis. Immunohistochemical expression of p63 and CK5/6 was examined using tissue microarrays (TMAs) in a large population-based series of 276 endometrial carcinomas with long and complete follow-up. Selected cases of normal and hyperplastic endometrium were examined for comparison (n = 15). Absence of p63 expression (70%) was significantly associated with nonendometrioid carcinomas, high histologic grade (FIGO), higher mitotic count and tumor cell proliferation by Ki-67, microsatellite instability (MSI) and loss of hMSH6 expression. A tendency toward reduced patient survival was also seen (p = 0.098). Presence of CK5/6 expression was more frequent in endometrioid tumors with squamous differentiation, while loss of CK5/6 expression (54%) was significantly associated with high FIGO stage, reduced beta-catenin expression, MSI and reduced patient survival (p = 0.0001); the latter was also found within the endometrioid subgroup (p = 0.0004). Multivariate survival analysis revealed that loss of CK5/6 expression had an independent prognostic impact in addition to well-known prognostic variables. Expression of both markers was increased in simple hyperplasia compared with normal endometrium. In complex hyperplasia, p63 expression was also increased, whereas CK5/6 was positive in areas with squamous differentiation only. Thus, loss of p63 or CK5/6 was associated with features of aggressive tumors, and lack of CK5/6 was significantly associated with reduced survival in multivariate analysis.
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PMID:Loss of p63 and cytokeratin 5/6 expression is associated with more aggressive tumors in endometrial carcinoma patients. 1615 5

Several molecular alterations, most commonly PTEN mutations but also K-ras mutations, microsatellite instability, and beta-catenin mutations have been detected in endometrioid endometrial carcinoma (EEC). Specifically, mutations in the beta-catenin gene are seen in 15% to 20% of EECs, whereas immunohistochemical expression of beta-catenin ranges from 13% to 44%, nuclear staining being concentrated in areas of immature squamous metaplasia (squamous morules). Complex endometrial hyperplasia with atypia (CEH-A) is a well-known precursor of EEC, which can also show immature squamous metaplasia. In this study, we compared the immunohistochemical and molecular profiles of 13 CEH-A with and 11 CEH-A without squamous morules (SM) for mutations of beta-catenin, PTEN, K-ras, and microsatellite instability (MSI). In all cases of CEH-A with SM, beta-catenin immunostaining showed strong and diffuse nuclear expression in areas of SM and weak to moderate nuclear expression in the glandular component. Six different beta-catenin mutations were found in 7 of 13 cases (54%) (G34E, G34V, S33C, D32Y, S33F, D32A); however, no mutations of the PTEN or K-ras genes were identified. beta-Catenin immunostaining showed focal nuclear staining in only 2 cases of CEH-A without SM. Only 1 case had a beta-catenin mutation (S45A), which was associated with a K-ras mutation (G12D). Another 3 cases had both PTEN and K-ras mutations (C296Stop Ex 8 and G12V, 244del C Ex 7 and G12D, 251ins TGAT Ex 7 and G13D), and one had a PTEN mutation (G230E Ex 7) only. Of all 24 cases, only 1 case of CEH-A without SM showed MSI. In conclusion, marked differences in the molecular profiles regarding beta-catenin, PTEN, and K-ras mutations were observed between CEH-A with and without SM. beta-catenin mutations might represent a signaling pathway leading to a distinctive morphology in hyperplastic/neoplastic endometrium with SM. Other molecular events such as K-ras or PTEN mutations are likely to occur in CEH-A independently from beta-catenin. Furthermore, morphologic differences between CEH-A with SM and CEH-A without SM seem to correlate, at least to some extent, with the clinical course of the disease. In our series, cases of CEH-A with SM and beta-catenin alterations appeared to have a less aggressive behavior when compared with CEH-A without SM and with K-ras and PTEN mutations.
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PMID:Distinct molecular alterations in complex endometrial hyperplasia (CEH) with and without immature squamous metaplasia (squamous morules). 1616 Apr 75

PTEN is involved in the regulation of normal cellular functions in addition to its well-known role as a tumor suppressor. In the present study, we have shown that stable transfection of the PTEN gene into PTEN-mutated endometrial carcinoma cells leads to contact inhibition accompanied by a decreased level of phosphorylated-Akt (p-Akt) expression, an increase in p27(Kip1), and a decrease in beta-catenin. PTEN-induced cells with contact inhibition exhibit G0-G1 cell-cycle arrest, and the Ki-67 labeling index is reduced. These changes are canceled by transfection of a double-stranded short-interfering RNA against the PTEN gene. Normal endometrial stromal cells increase their PTEN expression when reaching confluence; this is followed by changes in the expression of Akt-related proteins in the same way as in tumor cells. These results indicate that PTEN, p-Akt, p27, and beta-catenin are involved in the signal transduction of contact inhibition and suggest that PTEN may, in part, control the proliferation of endometrial carcinoma cells through the induction of contact inhibition.
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PMID:PTEN is involved in the signal transduction pathway of contact inhibition in endometrial cells. 1628 92

Tamoxifen treatment for breast cancer increases proliferation of the endometrium, resulting in an enhanced prevalence of endometrial pathologies, including endometrial cancer. An exploratory study was performed to begin to understand the molecular mechanism of tamoxifen action in the endometrium. Gene-expression profiles were generated of endometrial samples of tamoxifen users and compared with matched controls. The pathological classification of samples from both groups included atrophic/inactive endometrium and endometrial polyps. Unsupervised clustering revealed that samples of tamoxifen users were, irrespective of pathological classification, fairly similar and consequently form a subgroup distinct from the matched controls. Using SAM analysis (a statistical method to select genes differentially expressed between groups), 256 differentially expressed genes were selected between the tamoxifen and control groups. Upon comparing these genes with oestrogen-regulated genes, identified under similar circumstances, 95% of the differentially expressed genes turned out to be tamoxifen-specific. Finally, construction of a gene-expression network of the differentially expressed genes revealed that 69 genes centred around five well-known genes: TP53, RELA, MYC, epidermal growth factor receptor and beta-catenin. This could indicate that these well-known genes, and the pathways in which they function, are important for tamoxifen-controlled proliferation of the endometrium.
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PMID:Tamoxifen treatment for breast cancer enforces a distinct gene-expression profile on the human endometrium: an exploratory study. 1632 41

Angiopoietin-1 (ANGPT1), Angiopoietin-4 (ANGPT4), VEGF, FGF2, FGF4, HGF, Ephrin, IL8 and CXCL12 (SFD1) are pro-angiogenic factors (angiogenic activators), while Angiopoietin-2 (ANGPT2), Angiostatin, Endostatin, Tumstatin, Canstatin, THBS1, THBS2, TNFSF15 (VEGI) and Vasohibin (VASH1) are anti-angiogenic factors (angiogenic inhibitors). ANGPT1 and ANGPT2 are ligands for TIE family receptor tyrosine kinases, TIE1 and TIE2 (TEK). Angiopoietin family consists of ANGPT1, ANGPT2, ANGPT4, ANGPTL1 (ANGPT3), ANGPTL2, ANGPTL3 (ANGPT5), ANGPTL4, ANGPTL5, ANGPTL6 and ANGPTL7. TCF/LEF binding sites within the promoter region of human Angiopoietin family members were searched for by using bioinformatics and human intelligence (Humint). Because four TCF/LEF-binding sites were identified within the human ANGPTL7 promoter, comparative genomics analyses on ANGPTL7 orthologs were further performed. ANGPTL7 gene at human chromosome 1p36.22 was located within intron 28 of FRAP1 gene encoding mTOR protein. Chimpanzee ANGPTL7 gene, consisting of five exons, was located within NW_101546.1 genome sequence. Chimpanzee ANGPTL7 showed 99.4% and 86.1% total-amino-acid identity with human ANGPTL7 and mouse Angptl7, respectively. Human ANGPTL7 mRNA was expressed in neural tissues, keratoconus cornea, trabecular meshwork, melanotic melanoma and uterus endometrial cancer, while mouse Angptl7 mRNA was expressed in four-cell embryo, synovial fibroblasts, thymus, uterus and testis. Four TCF/LEF-binding sites within human ANGPTL7 promoter were conserved in chimpanzee ANGPTL7 promoter; however, only an unrelated TCF/LEF-binding site occurred in mouse and rat Angptl7 promoters. Human ANGPTL7, characterized as potent target gene of WNT/ beta-catenin signaling pathway, is a pharmacogenomics target in the fields of oncology and regenerative medicine.
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PMID:Comparative integromics on Angiopoietin family members. 1668 28

Cell adhesion molecules, such as epithelial cadherin (E-cadherin), might be involved in the processes of tumor invasion and differentiation. The aim of this study was to investigate the expression of E-cadherin, alpha-catenin, and beta-catenin in endometrial carcinoma and to determine the prognostic value of these factors. We have investigated the expression of E-cadherin, alpha-catenin, and beta-catenin by immunohistochemistry in 225 endometrial carcinomas. The correlation between the E-cadherin and the catenins and their correlation with several histologic and clinical parameters were analyzed. Negative E-cadherin, alpha-catenin, and beta-catenin expression was observed in 44%, 47%, and 33% of endometrial carcinomas, respectively, and was correlated with histologic FIGO grade 3 (P < 0.001). Negative E-cadherin expression was more often observed in nonendometrioid endometrial carcinomas (NEECs) than in endometrioid carcinomas (75% versus 43%; P= 0.04). Combined positive E-cadherin, alpha-catenin, and beta-catenin expression was an independent positive prognostic factor for survival in patients with grade 1-2 carcinomas (P= 0.02). Negative E-cadherin expression was found to be associated with histologic grade 3 and with NEEC. Combined positive E-cadherin, alpha-catenin, and beta-catenin expression was a significant prognostic factor.
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PMID:Combined E-cadherin, alpha-catenin, and beta-catenin expression is a favorable prognostic factor in endometrial carcinoma. 1680 34

Excessive beta-catenin is considered to contribute to tumor progression by inducing transcription of cell cycle-related genes such as cyclin D1 and c-myc. In contrast, our recent studies demonstrated that beta-catenin could inhibit cell proliferation through activation of p14(ARF)/p53/p21(WAF1) pathway during trans-differentiation toward morular phenotype of endometrial carcinoma (Em Ca) cells. Here, we focused on associations with alterations in p16(INK4A) and pRb expression during this process. In clinical cases, p16(INK4A) immunoreactivity was found to frequently overlap with nuclear beta-catenin accumulation in small-sized morules and surrounding glandular carcinomas (Sur-Ca), demonstrating a significant positive correlation (r = 0.447, p < 0.0001) overall, while the immunoreactions showed stepwise decrease in enlarged morules, despite persistent accumulation of beta-catenin and p21(WAF1) in nuclei. Immunoreactivity for both total pRb and its phosphorylated form was apparently decreased in all morules as compared to Sur-Ca lesions, with a significantly positive correlation. In cell lines, transcriptional activation of p16(INK) (4A) promoter by active form beta-catenin, as well as p21(WAF1), occurred through the region from -385 to -280 bp relative to the translation start site, in a TCF4-independent manner. Moreover, cell proliferation was accompanied with phosphorylation of pRb and increased p16(INK4A) expression, while its inhibition by serum starvation caused decreased expression of total pRb but not p16(INK4A), resulting in high relative amounts of the latter. These findings indicate that induction of p16(INK4A) mediated by nuclear beta-catenin and p21(WAF1), along with loss of pRb expression, may be important for initial steps during trans-differentiation of Em Ca cells. In addition, its down-regulation is associated with progression of lesions.
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PMID:Induction of p16INK4A mediated by beta-catenin in a TCF4-independent manner: implications for alterations in p16INK4A and pRb expression during trans-differentiation of endometrial carcinoma cells. 1685 82

Endometrial cancer is the most common gynecological malignancy, with 41,000 new cases projected in the United States for 2006. Two different clinicopathologic subtypes are recognized: the estrogen-related (type I, endometrioid) and the non-estrogen-related types (type II, nonendometrioid such as papillary serous and clear cell). The morphologic differences in these cancers are mirrored in their molecular genetic profile with type I showing defects in DNA-mismatch repair and mutations in PTEN, K-ras, and beta-catenin, and type II showing aneuploidy and p53 mutations. This article reviews the genetic aspects of endometrial carcinogenesis and progression. We will define the precursor lesion of type I endometrioid cancer and the role of genetics and estrogen in its progression.
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PMID:Molecular and pathologic aspects of endometrial carcinogenesis. 1702 94

Recently, it has been shown that mice deficient in the proapoptotic protein prostate apoptosis response 4 (Par-4) are specifically prone to develop endometrial carcinomas. Based on this, we have examined here the possible role of Par-4 as a tumor suppressor gene in human endometrial cancer. Using cDNA arrays, quantitative reverse transcription-PCR, and immunohistochemistry, we detected Par-4 down-regulation in approximately 40% of endometrial carcinomas. This alteration was not associated with phosphatase and tensin homologue (PTEN), K-RAS, or beta-catenin mutations, but was more frequent among tumors showing microsatellite instability (MSI) or among tumors that were estrogen receptor positive. Mutational analysis of the complete coding sequence of Par-4 in endometrial cancer cell lines (n = 6) and carcinomas (n = 69) detected a mutation in a single carcinoma, which was localized in exon 3 [Arg (CGA) 189 (TGA) Stop]. Interestingly, Par-4 promoter hypermethylation was detected in 32% of the tumors in association with low levels of Par-4 protein and was more common in MSI-positive carcinomas. Par-4 promoter hypermethylation and silencing was also detected in endometrial cancer cell lines SKUT1B and AN3CA, and reexpression was achieved by treatment with the demethylating agent 5'-aza-2'-deoxycytidine. Together, these data show that Par-4 is a relevant tumor suppressor gene in human endometrial carcinogenesis.
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PMID:Inactivation of the candidate tumor suppressor par-4 in endometrial cancer. 1733 19


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