UMLS:C0476089 - FACTA Search

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

The aim of this study was to identify amplified oncogenes in endometrial cancer using array-based comparative genomic hybridization (array CGH). Despite its prevalence, the molecular mechanisms of endometrial carcinogenesis are still poorly understood. The selected array CGH allows the simultaneous examination of 58 oncogenes commonly amplified in human cancers and is capable of achieving increased mapping resolution compared with conventional CGH. A subset of 8 specimens from a bank of 60 malignant and normal specimens was selected for array analysis to identify potential genes of interest. TaqMan polymerase chain reaction was carried out on the 60 specimens to examine if aberrations at the genomic level correlated with gene expression and to compare expression in normal and malignant samples. Oncogenes amplified in the endometrial cancers included AR, PIK3CA, MET, HRAS, NRAS, D17S1670, FGFR1, CTSB, RPS6KB1, LAMC2, MYC, PDGFRA, FGF4/FGF3, PAKI, and FGR. Three genes were examined at the messenger RNA level. AR and PIK3CA were higher in normal specimens, and MET was higher in malignant samples, suggesting a role for MET in endometrial cancer. Newer arrays examining more genes and larger sample numbers are necessary to elucidate the carcinogenic pathway in endometrial cancer.
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PMID:Genome-wide analysis of deoxyribonucleic acid in endometrial cancer using comparative genomic hybridization microarrays. 1668 70

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

The EPH/EFN family of receptor tyrosine kinases regulates cell adhesion and migration and has an important role in controlling cell positioning in the normal intestinal epithelium. Inactivation of EPHB2 has recently been shown to accelerate tumorigenesis in the colon and rectum, and we have previously demonstrated frequent frameshift mutations (41%) in an A9 coding microsatellite repeat in exon 17 of EPHB2 in colorectal tumors with microsatellite instability (MSI). In this study, we extended these analyses to extracolonic MSI cancers, and found frameshift EPHB2 mutations in 39% (25/64) of gastric tumors and 14% (8/56) of endometrial tumors. Regression analysis of these EPHB2 mutation data on the basis of our previously proposed statistical model identified EPHB2 as a selective target of frameshift mutations in MSI gastric cancers but not in MSI endometrial carcinomas. These results suggest a functional role for EPHB2 in gastric tumor progression, and emphasize the differences between the tumorigenic processes in MSI gastrointestinal and endometrial cancer.
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PMID:High EPHB2 mutation rate in gastric but not endometrial tumors with microsatellite instability. 1681 8

This years ASCO-meeting reinforced the trend of the recent years to get off from empirical treatment concepts to tailored and individualized diagnostics and therapy. However, the basis for an individual therapy is a specific molecular diagnostic which can be reflected in the analysis of hormonal receptor, HER-1, HER-2 and topoisomerase IIalpha in breast cancer. All these markers are not only able to prognosticate the course of disease but they also can predict the success of specific treatment approaches. Trastuzumab is standard therapy in HER-2 positive breast cancer both in the adjuvant and palliative setting. But new therapeutic agents, as e. g. lapatinib, are promising in the treatment of HER-2 positive breast cancer even if trastuzumab is failing. Otherwise it might possibly be an alternative option but adequate clinical results have to be awaited. The targeted inactivation of EGFR-related signal transduction pathways by e. g. gefitinib did not show a substantial improvement neither as a single agent nor in combination with endocrine treatment. However, the appropriate subgroup which might benefit from this therapy has to be defined even if molecular data suggest that patients with ER positive and PR negative breast cancer might be such a group. The increasing knowledge in terms of the biology of bone metastasis led to the development of new treatment options as e. g. denosumab, a humanized monoclonal antibody for RANK ligand. Two adjuvant cytotoxic treatment trials revealed that taxanes improve the prognosis of node positive breast cancer and should be administered sequentially. The advantage of switching to an aromatase inhibitor after two to three years of tamoxifen in endocrine treatment of postmenopausal patients is proved by two clinical trials (IES, ARNO) which could demonstrate a survival benefit. In conclusion it seems to be evident that new targeted therapy options are effective and will set new standards for the treatment of breast cancer patients in the near future. The presentation for the ovarian cancer focused on the addition of a third cytotoxic agent to carboplatin and paclitaxel as the standard therapy for the primary treatment of ovarian cancer. New data of Bevacizumab in the treatment of primary and recurrent ovarian cancer were presented. However, this is not yet a standard treatment for all patients and needs further investigations within large, multicentre, randomised trials. The lymphonodectomy as part of the primary therapy of the endometrial cancer seems to be a benefit at least in patients with advanced disease or high risk stage I tumours. The adjuvant therapy of uterine sarcomas is still not yet very well investigated and clear. A trial which recruited 12 years demonstrated a benefit in overall survival which has to be interpreted with caution. In this year again there have been registered an increasing number of interesting contributions from Germany, which also received international attention.
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PMID:[Molecular diagnostic and targeted therapy--"Barking dogs are going to bite": presentations from the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta 2006]. 1700 57

Family history of endometrial cancer increases the risk of developing the disease, but it is still largely unknown which germ-line genetic factors are involved in the aetiology of endometrial cancer. In a Swedish population-based case-control study including 705 cases and 1565 controls, we examined common variation in the ATM, CHEK2 and ERBB2 genes in relation to endometrial cancer risk overall, restricted to tumours of certain characteristics or stratified by various endometrial cancer risk factors. We genotyped a large number of single-nucleotide polymorphisms (SNPs) in the genes and selected seven haplotype-tagging SNPs (tagSNPs) in ATM, six tagSNPs in CHEK2 and seven tagSNPs in ERBB2 that could predict common variants and haplotypes (frequency > or =0.03) in each gene with R(2) > or = 0.8. We included the tagSNPs or their haplotypes as explanatory variables in unconditional logistic regression models adjusted for age. Our results indicated an increased risk of developing endometroid endometrial cancer for homozygous carriers of the rare allele (AA) of a tagSNP (rs4987886) in CHEK2 (P = 0.005) when contrasted with GG carriers. We also found a decreased endometrial cancer risk among non-smoking carriers of a haplotype in ATM (P = 0.0007) and among carriers of a haplotype in CHEK2, who had experienced menopause below 49 years of age (P = 0.0009) compared with non-carriers of these haplotypes. We found no effect of genetic variation in ERBB2 on endometrial cancer risk. In conclusion, it is possible that common variants in the ATM and CHEK2 genes, in interaction with oestrogen-related exposures, are involved in endometrial cancer aetiology.
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PMID:Effect of ATM, CHEK2 and ERBB2 TAGSNPs and haplotypes on endometrial cancer risk. 1716 60

Endometrial carcinoma is the most common gynecological malignancy in the United States. Although most women present with early disease confined to the uterus, the majority of persistent or recurrent tumors are refractory to current chemotherapies. We have identified a total of 11 different FGFR2 mutations in 3/10 (30%) of endometrial cell lines and 19/187 (10%) of primary uterine tumors. Mutations were seen primarily in tumors of the endometrioid histologic subtype (18/115 cases investigated, 16%). The majority of the somatic mutations identified were identical to germline activating mutations in FGFR2 and FGFR3 that cause Apert Syndrome, Beare-Stevenson Syndrome, hypochondroplasia, achondroplasia and SADDAN syndrome. The two most common somatic mutations identified were S252W (in eight tumors) and N550K (in five samples). Four novel mutations were identified, three of which are also likely to result in receptor gain-of-function. Extensive functional analyses have already been performed on many of these mutations, demonstrating they result in receptor activation through a variety of mechanisms. The discovery of activating FGFR2 mutations in endometrial carcinoma raises the possibility of employing anti-FGFR molecularly targeted therapies in patients with advanced or recurrent endometrial carcinoma.
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PMID:Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. 1752 45

The development of kinase inhibitors is revolutionizing cancer treatment. Assessing the oncogenic potential of individual kinase activities and ensuring that a drug of interest acts by direct inhibition of its putative target kinase are clear priorities. We developed a genetic strategy to selectively inactivate the catalytic activity of kinases. This approach generates isogenic cells in which a given kinase gene is expressed but is devoid of enzymatic activity. As a model to test this approach, we chose the MET receptor, which is involved in multiple cancers and is the focus of several therapeutic efforts. The exon encoding the ATP-binding site of MET was deleted from the genome of colorectal, bladder, and endometrial cancer cells. The derivative isogenic cells expressed a kinase-inactive Met (MET-KD) and were completely unresponsive to its ligand hepatocyte growth factor (HGF), indicating the exclusivity of this ligand-receptor axis. The in vivo tumorigenic potential of MET-KD cells was reduced but could be partially restored by HGF, suggesting that concomitant targeting of the receptor and its ligand should be therapeutically exploited. A reportedly selective Met-kinase inhibitor (SU-11274) markedly affected the growth of MET-KD cancer cells, indicating this compound exerts its effects not only through the intended target. The genetic strategy presented here is not limited to kinase genes but could be broadly applicable to any drug/protein combination in which the target enzymatic domain is known.
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PMID:Genetic targeting of the kinase activity of the Met receptor in cancer cells. 1759 99

Endometrial cancer is associated with both EGFR and HER2 receptor activation. The EGFR and HER2 genes could be disease susceptibility candidate genes for this cancer. This study was conducted to investigate a possible association between EGFR and HER2 gene polymorphisms and endometrial cancer and the influence of these polymorphisms on the clinical outcome of endometrial cancer patients in a Japanese population. The authors compare the genotype distributions and allele frequencies of the EGFR +2073 A/T and HER2 +655 A/G polymorphisms in 116 endometrial cancer patients and 213 controls using polymerase chain reaction-restriction fragment length polymorphism (RFLP) analysis. RFLP results were confirmed by direct DNA sequencing. Of the 116 patients, 76 (65.5%) could be followed up. Disease-free survival estimates were computed using the Kaplan-Meier method, and differences between survival periods were assessed using the log-rank test. No significant differences were observed in either genotype distributions or allele frequencies in the EGFR +2073 A/T and HER2 +655 A/G polymorphisms between endometrial cancer patients and controls. The stratification by histological types and staging failed to identify significant differences between endometrial cancer patients and controls. No statistical differences were noted between these polymorphisms and disease-free survival (Kaplan-Meier log-rank test P = .55 and .66, for the EGFR +2073 A/T and HER2 +655 A/G, respectively). These results suggest that the EGFR +2073 A/T and HER2 +655 A/G polymorphisms are not associated with endometrial cancer in a Japanese population. These conclusions are based on relatively small numbers and will require verification from additional independent studies.
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PMID:Epidermal growth factor receptor and human epidermal growth factor receptor 2 gene polymorphisms in endometrial cancer in a Japanese population. 1764 7

Cyclooxygenase-2 (COX-2) has been implicated in the promotion of carcinogenesis. Although the role of COX-2 in endometrial cancer remains unclear, recent experiments suggest that COX-2 antagonizes cell apoptosis, increases the invasiveness of malignant cells, and promotes angiogenesis. Hepatocyte growth factor (HGF) is a mesenchymal-derived cytokine and the interaction between HGF and its tyrosine kinase receptor, c-Met proto-oncogene, is associated with tumor progression and metastasis. To investigate the molecular mechanism of HGF-induced anoikis resistance, we analyzed the signal transduction and COX-2 expression in endometrial cancer cells. Here, we show i) the expression of COX-2 protein significantly increased in a dose-dependent manner after HGF stimulation in endometrial cancer cell lines (HEC-IB and RL95-2), reaching 200-270% stimulation at the highest doses of HGF tested (40 ng/ml); ii) flow cytometry and TUNEL analyses revealed that HGF significantly inhibited anoikis of RL95-2 cells; iii) phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), but not mitogen-activated protein kinase/ERK kinase (MEK) inhibitor (PD98059), specifically blocked HGF-mediated anoikis resistance in RL95-2 cells; and iv) COX-2 inhibitor, Meloxicam, abrogated HGF-mediated anoikis resistance. Our data suggest that HGF induces anoikis resistance in endometrial cancer cells possibly through PI3K/Akt pathway-dependent up-regulation of COX-2 expression.
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PMID:Hepatocyte growth factor induces anoikis resistance by up-regulation of cyclooxygenase-2 expression in uterine endometrial cancer cells. 1809 84

Gene alterations and overexpression of various oncogenes and cell-cycle regulators are important in tumor development. In a population based series of 316 endometrial carcinomas with long and complete follow-up we investigated the distribution of HER-2/neu and EGFR expression and copy number alteration in endometrial cancers. HER-2/ neu, EGFR and Ki-67 expression in curettage and hysterectomy specimens were studied immunohistochemically for expression in relation to molecular markers and clinical phenotype. Fresh tumor samples (n=76) were studied by global characterization of genetic alterations by single nucleotide polymorphism (SNP) array for detection of high level amplification for HER-2/neu and EGFR. Pathological expression of HER-2/neu in curettage was detected in 23% which significantly correlated to high FIGO stage, non-endometrioid subtype, high grade and aneuploidy. In hysterectomy specimens, pathological HER-2/neu staining was seen in 13% which correlated significantly with high FIGO stage, non-endometrioid subtype, high proliferation and poor survival (p=0.009). Expression of EGFR was examined with three different antibodies, but none showed significant correlation with molecular markers or clinical phenotype. High level amplification of HER-2/neu or EGFR was seen in only one out of 76 samples, respectively. High proliferation estimated in tumors from hysterectomy specimens showed independent prognostic impact and was superior to estimation in curettage specimens as a prognostic marker. In conclusion, high level amplification of HER-2/neu or EGFR is infrequent in endometrial cancer. Pathological HER-2/neu staining identifies endometrial carcinomas with an aggressive phenotype, high proliferation and patients with poor survival in a population based setting. These results motivate further clinical trials with trastuzumab based on HER-2/neu status in endometrial carcinomas.
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PMID:HER-2/neu expression is associated with high tumor cell proliferation and aggressive phenotype in a population based patient series of endometrial carcinomas. 1820 52

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