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: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA amplification at 17q is frequently detected in upper gastrointestinal adenocarcinomas (UGC; stomach and esophagus). In this study, we did fluorescence in situ hybridization on a tissue microarray that contained 304 UGCs and 89 normal stomach samples using a approximately 168-kb BAC clone (CTD-2019C10) that maps to 17q12-q21.1. This 168-kb region contains the following genes: PPP1R1B/DARPP-32, STARD3, TCAP, PNMT, PERLD1, ERBB2, C17orf37, and GRB7 as well as the first two exons of ZNFN1A3. DNA amplification (> or =5 signals) was detected in 85 of 282 (30%) of UGCs, and high-level amplification (> or =10 signals) was seen in 28 of 282 (10%) of all tumors. Adenocarcinomas of gastroesophageal junction and lower esophagus had the highest frequency of amplification (45%) compared with stomach tumors (27%; P = 0.04). On the other hand, 38% of tumors with intestinal-type morphology had amplification compared with 26% of diffuse-type tumors (P = 0.02). We further did quantitative real-time reverse transcription-PCR on 74 frozen tissue samples from UGCs for 11 genes located within or adjacent to the boundaries of this approximately 168-kb genomic region. These genes include all 9 genes that are fully or partially located inside the CTD-2019C10 clone as well as 2 additional adjacent genes (NEUROD and TOP2A). Overexpression of PPP1R1B/DARPP-32, TCAP, and TOP2A was seen in approximately half of the tumors, whereas STARD3 and ZNFN1A3 were rarely overexpressed (12%). Interestingly, there was a statistical correlation between expression of all 8 genes that map between PPP1R1B/DARPP-32 and GRB7, whereas expression of NEUROD, ZNFN1A3, and TOP2A that are partially inside or adjacent to the boundaries of the CTD-2019C10 clone did not correlate with the expression of any of these 8 genes. These data show a transcriptionally active oncogenomic region bounded by PPP1R1B/DARPP-32 and GRB7 in UGCs and provide further insight into expression levels of several critical genes.
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PMID:Molecular dissection of 17q12 amplicon in upper gastrointestinal adenocarcinomas. 1684 20

The purpose of this study was to evaluate amplification of topoisomerase IIalpha (TOP2A) and HER2 genes as predictors of response to chemotherapy in advanced breast cancer. Gene copy number of TOP2A and HER2 were analysed with chromogenic in situ hybridization (CISH) on paraffin-embedded tissue sections from the primary tumour of 85 patients treated with anthracycline containing chemotherapy. TOP2A gene amplification was present in 14 (16%) and HER2 gene amplification in 38 (45%) of the primary tumours. Two of the 14 cases with TOP2A amplification were amplified without concurrent HER2 amplification. Neither TOP2A nor HER2 gene amplification were significantly associated with response to chemotherapy (p = 0.35 and p = 0.49, respectively).
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PMID:TOP2A and HER2 gene amplification as predictors of response to anthracycline treatment in breast cancer. 1686 74

The aim of our study was to assess the ERBB2 and TOP2A gene status in breast carcinoma tissue using fluorescence in situ hybridization (FISH) and to compare their amplification with immunohistochemistry assay (IHC) of the ERBB2, resp. topoisomerase IIalpha proteins. TOP2A status is important in tailored treatment as topoisomerase IIalpha is the molecular target for topoisomerase IIalpha inhibitors. This study was conducted to determine whether the methods are equivalent in their assessment of TOP2A status and to correlate the genetic findings with basic tumor and disease characteristics. Locus specific ERBB2, TOP2A genes and chromosome 17 centromeres (CEP17) probes were hybridized to 72 formalin-fixed paraffin-embedded (FFPE) tissue samples from patients with non-metastatic breast carcinoma (M0). The ERBB2, TOP2A and CEP17 signals were counted and gene numbers per nucleus or per CEP17 were calculated, respectively. Sections were also stained with commercial polyclonal antibody (HercepTestTM), anti-topoisomerase IIalpha monoclonal antibody (clone SWT3D1) and scored for the presence of membrane/nuclear staining. ERBB2 amplification was found in 20.3%, ERBB2 and TOP2A co-amplification was detected in 14.5% of cases. Deletion of the ERBB2/TOP2A gene was found in 1.4/2.8% of sections, respectively. Concordance of FISH and IHC techniques in the evaluation of ERBB2 and TOP2A status was found in 88.4% and 66.7%, respectively. The low concordance of FISH versus IHC in the evaluation of TOP2A status was mainly due to the presence of TOP2A amplified tumors in IHC negative or weakly positive specimens. Topoisomerase IIalpha expression was increased in bigger tumors, although direct correlation with tumor grading was not found. ERBB2 amplification was found in more aggressive breast cancers with grades 2 and 3, respectively. Interestingly, chromosome 17 polysomy was more frequently observed among older women (>55 years), suffering usually from less aggressive disease. Our results confirm the high concordance of the ERBB2 and TOP2A gene co-amplification in breast carcinoma. Differences between FISH and IHC in the case of ERBB2 gene status were found only in IHC 2+ sections as reported in the literature. However, our study points to the importance of FISH examination of TOP2A gene status in all tumors with ERBB2 amplification.
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PMID:Analysis of ERBB2 and TOP2A gene status using fluorescence in situ hybridization versus immunohistochemistry in localized breast cancer. 1701 33

The HER-2 (also known as ERBB2/ErbB2/c-erbB2/HER-2/neu) oncogene is the most frequently amplified oncogene in breast cancer and is also amplified in other forms of cancer. Beside its important role in tumor induction, growth and progression, HER-2 is also a target for new therapeutic approaches such as Herceptin (trastuzumab), a recombinant antibody designed to block signaling through the HER-2 receptor. In addition to Herceptin, which is in a wide clinical use for HER-2 amplified breast cancer, a number of various HER-2 directed immunological and genetic strategies, either targeting the HER-2 receptor, its signaling pathways or both HER-2 and epidermal growth factor receptor (EGFR) simultaneously, have demonstrated promising pre-clinical activity in HER-2 amplified carcinomas. Moreover, the HER-2 amplicon is known to contain more than 30 genes with altered copy numbers that could be therapeutic targets for chemotherapy. The topoisomerase IIalpha gene, TOP2A, is located adjacent to the HER-2 oncogene at the chromosome location 17q12-q21 and is either amplified or deleted (with equal frequency) in a great majority of HER-2 amplified primary breast tumors and also in tumors without HER-2 amplification. Recent experimental as well as numerous, large, multi-center trials suggest that amplification (and/or deletion) of TOP2A may account for both sensitivity or resistance to commonly used cytotoxic drugs, i.e. topoII-inhibitors (anthracyclines etc.), depending on the specific genetic defect at the TOP2A locus. The understanding of HER-2 amplification and its role in the pathogenesis of cancer is expanding, and a number of therapeutic strategies targeting either the HER-2 or its signaling pathways in cancer therapy are being investigated. Combining HER-2 targeting therapies with conventional forms of cytotoxic chemotherapy, where additional diagnostic tests such as those ascertaining TOP2A status, may be helpful for the ideal selection of patients for the combination therapy of an HER-2 targeting drug together with a cytotoxic drug such as topoII-inhibitor especially in the case of TOP2A amplification.
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PMID:Simultaneous amplification of HER-2 (ERBB2) and topoisomerase IIalpha (TOP2A) genes--molecular basis for combination chemotherapy in cancer. 1710 May 65

Ependymomas are primary tumors of the central nervous system that typically originate from the walls of the cerebral ventricles or from the spinal canal. The pathogenesis of these tumors is poorly understood, and prognostic assessment based on histologic features and clinical parameters is difficult. The aim of this study was to investigate the molecular heterogeneity of ependymomas. We used cDNA microarrays and RT-PCR to examine gene expression in 47 ependymomas. We present results for five comparisons: (1) tumors from children and adults with poor versus favorable outcome, (2) tumors from children with poor versus favorable outcome, (3) tumors with high versus low proliferation indices, (4) subependymomas versus myxopapillary ependymomas, and (5) spinal versus intracranial ependymomas. For patients with an overall survival >10 years after diagnosis, we identified 27 genes associated with favorable prognosis. In contrast, overexpression of BNIP3, MRC1, EPHB3, GLIS3, CDK4, COL4A2, EBP, NRCAM, and CCNA1 genes in tumors with high proliferation indices was associated with a poor outcome. Thirty genes, including ETV6, YWHAE, TOP2A, TLR2, IRAK1, TIA1, and UFD1L were found to be highly expressed in subependymomas but not myxopapillary ependymomas. Also, 30 genes were differentially expressed in spinal versus intracranial ependymomas. There was no relationship between expression profiles and tumor grade, patient age, and patient gender. Our results provide insight into specific molecular events underlying ependymoma tumorigenesis and may contribute to more accurate diagnosis and prediction of clinical outcome.
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PMID:Ependymoma gene expression profiles associated with histological subtype, proliferation, and patient survival. 1726 49

Current choice of cancer therapy is usually empirical and relies mainly on the statistical prediction of the treatment success. Molecular research provides some opportunities to personalize antitumor treatment. For example, life-threatening toxic reactions can be avoided by the identification of subjects, who carry susceptible genotypes of drug-metabolizing genes (e.g. TPMT, UGT1A1, MTHFR, DPYD). Tumor sensitivity can be predicted by molecular portraying of targets and other molecules associated with drug response. Tailoring of antiestrogen and trastuzumab therapy based on hormone and HER2 receptor status has already become a classical example of customized medicine. Other predictive markers have been identified both for cytotoxic and for targeted therapies, and include, for example, expression of TS, TP, DPD, OPRT, ERCC1, MGMT, TOP2A, class III beta-tubulin molecules as well as genomic alterations of EGFR, KIT, ABL oncogenes.
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PMID:Molecular-based choice of cancer therapy: realities and expectations. 1730 83

HER2 and TOP2A genes, located on 17q, can be coamplified in cancer. Overexpression of both genes has been reported in high-grade, androgen-resistant prostate cancer. Both genes have not been compared in a single prostate cancer study and the frequency of TOP2A amplifications in prostate cancer is unknown. Using tissue microarrays, we did immunohistochemistry and fluorescence in situ hybridization for HER2 and TOP2A in 100 prostate cancers (41 localized and 59 advanced) and 42 cases of benign prostatic hyperplasia (BPH). Amplification was defined as a target/centromere signal ratio of > or =1.5. HER2 immunohistochemistry was scored from 0 to 3+. Percentage nuclei staining for topoisomerase IIalpha (topoIIalpha) was recorded; overexpression was defined as > or =5% cells staining. Eighteen (31%) advanced prostate cancers showed topoIIalpha overexpression; 12 (26%) showed TOP2A low-level amplification; 9 (16%) expressed HER2; and 6 (13%) showed HER2 low-level amplification. No high-level amplification of either gene (target/centromere signal ratio of > or =3.0) was detected. TOP2A coexpression and coamplification were seen in 75% and 66% of HER2-positive cases, respectively. Localized prostate cancer or BPH showed no gene amplification or topoIIalpha overexpression. Gene amplification or overexpression correlated with high stage and Gleason score. The presence of TOP2A amplification in advanced cancer was associated with androgen resistance and decreased survival by multivariate analysis. This is the first study to document low-level TOP2A amplification in prostate cancer and an association with reduced survival. TOP2A amplification may occur with or without HER2 duplication and is often associated with topoIIalpha expression. Therapies directed against topoIIalpha (and HER2) in such patients may improve survival.
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PMID:Low-level TOP2A amplification in prostate cancer is associated with HER2 duplication, androgen resistance, and decreased survival. 1736 13

Nonsmall-cell lung cancer (NSCLC) is not generally a chemosensitive tumor, and the mechanism of resistance to the relevant anticancer drugs has not been fully elucidated. Solamargine (SM), the major steroidal glycoalkaloids extracted from the Chinese herb Solanum, inhibits the growth of human tumor cells. We have previously demonstrated that SM regulates tumor necrosis factor receptors (TNFRs)- and mitochondria-mediated pathways and sensitizes NSCLC cells to initiate apoptosis. Interestingly, this investigation reveals that SM up-regulated Fas expression and down-regulated the expression of HER2, whose overexpression is associated with resistance to drugs, and promotes chemotherapy-induced apoptosis in NSCLC A549 and H441 cells. After treatment with SM, the expression of HER2 mRNA was correlated with the expression of topoisomerase IIalpha (TOP2A) mRNA. The combinatory use of low concentrations of SM with low-toxic topoisomerase II inhibitor epirubicin accelerated apoptotic cell death. Therefore, the downregulation of the HER2 and TOP2A expression by SM with epirubicin may partially explain the SM and epirubicin cytotoxicity synergy effect in NSCLC. Results of this study suggest that SM induces Fas and TNFR-induced NSCLC cell apoptosis and reduces HER2 expression. These findings provide the synergistic therapeutic interaction between SM and epirubicin, suggesting that such combinations may be effectively exploited in future human cancer clinical trials.
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PMID:Solamargine upregulation of Fas, downregulation of HER2, and enhancement of cytotoxicity using epirubicin in NSCLC cells. 1763 97

There is a long tradition for defining prognostic factors in breast carcinoma; the classic ones being lymphnode status, tumor size, malignancy grade, and hormone receptor status. More important are the detection of predictive factors, defined as factors in the tumor which predict the effect of a certain treatment. The hormone receptors are a classic example of predictive factors for determining whether patients should be offered endocrine treatment. New predictive factors are HER2 for predicting the effect of trastuzumab and TOP2A for predicting the effect of certain chemotherapies.
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PMID:[Prognostic and predictive factors for endocrine treatment in breast carcinoma]. 1795 80

We have previously demonstrated that solamargine (SM), the major steroidal glycoalkaloid extracted from Chinese herb Solanum plants, reveals down-regulation of HER2 and up-regulation of Fas and tumor necrosis factor receptor (TNFR) expressions, triggers the mitochondria-mediated cell apoptosis pathway, and sensitizes human nonsmall cell lung cancer (NSCLC) H441 and A549 adenocarcinoma cells to chemotherapy. The present study shows that SM enhances HER2 expression in NSCLC large cell carcinoma H661 and small cell lung cancer (SCLC) H69 cells and may increase the susceptibility of the cells to trastuzumab, the humanized anti-HER2 antibody. The combinational treatment of SM and trastuzumab synergistically augments and inhibits H661 and H69 cell proliferation. After treatment with SM, coexpression of HER2 and topoisomerase IIalpha (TOP2A) H661 and H69 cells is more sensitive to the TOP2 inhibitor, epirubicin. The combinatory use of low concentrations of SM with the low-toxic epirubicin accelerated greater apoptotic cell death than each drug did alone in H661 and H69 cells. Relevant studies have shown that HER2 overexpressing cancer cells are more resistant than HER2 low-expressing cells to the chemotherapeutic agent and tumor necrosis factor-induced apoptosis. These investigations have indicated that HER2 overexpression does not suffice to induce intrinsic and pleomorphic drug resistance. The data presented herein suggest that the expression of HER2 did not influence the SM-induced apoptosis of different types of lung cancer cells and that the SM up-regulation of HER2 and TOP2A expressions simultaneously augmented trastuzumab and epirubicin-induced deaths of lung cancer H661 and H69 cells.
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PMID:Solamargine enhances HER2 expression and increases the susceptibility of human lung cancer H661 and H69 cells to trastuzumab and epirubicin. 1807 28


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