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)

We, and others, have demonstrated an in utero origin for translocations associated with childhood leukemia, with latency periods in some cases exceeding 10 years. The mechanism of generation of most of the translocations is thought to be aberrant repair following abortive apoptosis, rather than V(D)J recombination or exposure to topoisomerase II inhibitors. Folate supplementation may prevent some of the chromosome breakage leading to translocation formation. Translocations t(8;21) and t(12;21) have been shown to occur in the normal population (before birth) at a frequency that is 100-fold greater than the risk of developing the corresponding leukemia. In most instances, additional genetic changes are required for progression to leukemia. Tyrosine kinase receptor (RTK) mutations, which give cells a survival/proliferative advantage, are proposed to act cooperatively with fusion genes, leading to transformation. However, translocations and cooperating RTK mutations have not been identified for all leukemia subtypes, particularly in acute myeloid leukemia. The core binding transcriptional pathway is frequently targeted by translocation in utero. We propose that this pathway is highly sensitive during fetal hematopoiesis and may be targeted by mechanisms other than translocation. For each leukemia subtype it is important to characterize the corresponding leukemic stem cell, which is thought to be the initial target for translocation. This would help to elucidate the molecular pathways involved in the progression from preleukemic clone harboring a translocation to fully disseminated leukemia.
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PMID:Prenatal origin of chromosomal translocations in acute childhood leukemia: implications and future directions. 1505 23

New strategies for improving treatment of patients with breast carcinoma have focused on the HER2 oncoprotein with regard to response to traditional therapy regimes and the effect of a new drug specifically directed against the protein. Furthermore, the status of the topoisomerase IIalpha (TOP2A) gene has been suggested as a predictive marker of anthracycline treatment. In this study of 120 tumours, immunohistochemically detected HER2 overexpression with HercepTest has been compared to the HER2 gene amplification investigated with a new HER2 probe for fluorescence in situ hybridization (FISH). In addition, the HercepTest was evaluated as a screening tool for choosing cases for FISH investigation of TOP2A gene aberrations. The HercepTest score 3+ identified HER2 gene amplification in 27 of 30 amplified tumours (sensitivity of 0.90) with a false-negative rate of 0.10 and a false-positive rate of 0.06. TOP2A gene amplification or deletion was found in 20 cases. Sixteen (80%) of these carcinomas were in the HercepTest 3+ group, but four tumours had alterations in the TOP2A gene with normal HER2 status. Traditionally, in the FISH technique the result has been based on counting 60 cells. However, we found that a much less time-consuming method of counting 60 signals gave equally good results.
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PMID:Amplification of HER2 and TOP2A and deletion of TOP2A genes in breast cancer investigated by new FISH probes. 1506 18

In this study, we examined alterations in the apoptotic response of tamoxifen (TAM)-resistant breast cancer cells. We used an in vitro selection approach for TAM resistance by means of long-term culture of MCF-7 breast cancer cells with increasing concentrations of TAM. The apoptotic response to TAM was determined by means of ELISA measurement of apoptotic DNA-histone complexes in cytoplasm and by Annexin-V staining. MCF-7(LT) cells isolated after 5 months of long-term treatment with TAM exhibited a significantly reduced apoptotic response to this drug, even if administered in high concentrations up to 20 microM. This reduced apoptotic response was also observed after treatment with the topoisomerase II inhibitor etoposide, a pro-apoptotic antineoplastic drug. Microarray experiments comparing the transcriptome of MCF-7(LT) and wild-type cells revealed both the down-regulated expression of several genes coding for pro-apoptotic proteins and the up-regulation of genes coding for apoptosis inhibitors. Further experiments to determine expression changes of the receptor tyrosine kinases HER2 and epidermal growth factor receptor did not reveal any alterations in MCF-7(LT) if compared to wild-type cells. Our findings suggest that long-term treatment with TAM in vitro does not necessarily change the expression of receptor tyrosine kinases, but can modulate the expression of apoptotic key genes impairing the apoptotic response of MCF-7 breast cancer cells.
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PMID:Tamoxifen long-term treatment in vitro alters the apoptotic response of MCF-7 breast cancer cells. 1549 41

In the wake of recent progress in understanding the genetic pathways involved in the development of brain tumors, a major goal is to correlate molecular data with clinical outcome, survival, and response to treatment modalities. This is of particular importance among the pediatric population. Reliable prognostic factors could potentially permit a tailoring of therapy in that only patients with the most aggressive tumors would receive the most intense treatments. A survey of publications about prognosis-related molecular features among pediatric brain tumors revealed 74 series, of which 46 presented statistically significant outcome-associated parameters as defined by a p value <0.05. Most investigations revealing significant prognosis-related features were performed on medulloblastomas (34 publications), followed by astrocytic tumors (6 publications) and ependymomas (5 publications). Promising approaches and molecular markers include gene expression profiles, DNA ploidy, loss of heterozygosity and chromosomal aberrations as detected by CGH and FISH (1q, 17p, 17q), as well as oncogenes/ tumor suppressor genes and their proteins (TP53, PTEN, c-erbB2, N-myc, c-myc), growth factor and hormonal receptors (PDGFRA, VEGF, EGFR, HER2, HER4, ErbB-2, hTERT, TrkC), cell cycle genes (p27) and cell adhesion molecules, as well as factors potentially related to therapeutic resistance (multi-drug resistance, DNA topoisomerase IIalpha, metallothionein, P-glycoprotein, tenascin). This review discusses the predictive potential of molecular markers for clinical outcome and their influence on therapeutic decision-making among children with brain tumors.
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PMID:Prognosis-related molecular markers in pediatric central nervous system tumors. 1562 58

Brain tumors account for approximately 20% of all childhood cancers, and are the leading cause of cancer morbidity and mortality among children. Although numerous demographic, clinical and therapeutic parameters have been identified over the past few years that have significant prognostic bearing for some pediatric brain tumors, predicting the clinical course and outcome among children with central nervous system tumors is still difficult. A survey of publications on prognosis-related histopathological and immunohistochemical features among pediatric brain tumors revealed 172 series, of which 91 presented statistically significant outcome-associated parameters as defined by a P value of less than 0.05. Most investigations revealing significant prognosis-related markers were performed on medulloblastomas (30 publications), ependymomas (25) and astrocytic tumors (18). In total, 16 cohorts consisted of more than 100 cases (5 on ependymomas, 3 each on medulloblastomas and astrocytic tumors). On the other hand, there were also 13 series with fewer than 20 cases (5 on medulloblastomas). Potentially prognostic histopathological markers vary among different entities and consist of assessment of necroses, mitoses, differentiation, vascular proliferation, and growth pattern, whereas immunohistochemical features include proliferation markers (Ki-67, MIB-1), expression of oncogenes/tumor suppressor genes and their proteins (TP53, c-erbB2), growth factor and hormonal receptors (VEGF, EGFR, HER2, HER4, ErbB-2), cell cycle genes (p27, p14ARF) and cell adhesion molecules, as well as factors potentially related to therapeutic resistance (DNA topoisomerase IIalpha, metallothionein, P-glycoprotein, tenascin). This review discusses the prognostic potential of histopathological and immunohistochemical markers that can be investigated by the practicing neuropathologist as part of the routine diagnostic workload, and scrutinizes their benefit for predicting therapy response and patient outcome among children with brain tumors.
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PMID:Prognosis-related histomorphological and immunohistochemical markers in central nervous system tumors of childhood and adolescence. 1564 46

We sought to identify the frequency of amplification of the topoisomerase IIalpha gene (TOP2A) in pancreatic cancer and determine the usefulness of TOP2A immunolabeling in screening for TOP2A and human epidermal growth factor receptor (HER)2/neu amplification. We examined 55 pancreatic adenocarcinoma specimens for TOP2A immunolabeling and identified TOP2A protein expression in all specimens with a nuclear labeling index (NLI; positive nuclei/total nuclei x 100) of 5% to 80%. Normal pancreatic ductal epithelium, proposed to give rise to pancreatic adenocarcinoma, did not demonstrate detectable TOP2A expression. In a subset of specimens selected for fluorescence in situ hybridization analysis of TOP2A and HER2/neu amplification using a recently developed multicolor probe, 7 of 8 lesions with an NLI of 25% or more demonstrated TOP2A amplification, in contrast with 2 of 14 lesions with a TOP2A NLI of less than 25%. In 8 of 9 TOP2A-amplified cases, coamplification of HER2/neu was present, suggesting a potential relationship between TOP2A and HER2/neu in pancreatic adenocarcinoma. We propose that TOP2A immunolabeling be used in conjunction with a newly developed multicolor probe to screen patients with pancreatic adenocarcinoma to determine the best potential therapeutic modalities, such as TOP2A inhibitors, trastuzumab, or both.
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PMID:A subset of pancreatic adenocarcinomas demonstrates coamplification of topoisomerase IIalpha and HER2/neu: use of immunolabeling and multicolor FISH for potential patient screening andtreatment. 1576 77

Clinical and in vitro evidence supports the concept that human epidermal growth factor receptor-2 ( HER2 ) gene amplification prediction of response to anthracycline-based chemotherapy in breast cancer is not a direct effect of HER2 overexpression, but the result of coamplification of topoisomerase II-alpha ( TOP2A ). We investigated the relationship of TOP2A to HER2 genomic alterations by fluorescence in situ hybridization (FISH) and the correlations with polysomic states for chromosome 17 (CEP17). One hundred thirty-eight cases of breast cancer HER2 gene amplified by 2-color FISH ( HER2 /CEP17) were reevaluated with a 3-color probe set ( HER2 /CEP17/ TOP2A ) to investigate the frequency of coamplification and deletion of TOP2A . TOP2A was never amplified in the absence of HER2 amplification and was coamplified with HER2 in 68 (50%) of 137 cases; HER2 gene copy number was higher than the TOP2A copy number ( P < .01). Of the 137 cases with HER2 amplification, 23 (16%) showed a monoallelic deletion of TOP2A . Of the 43 cases not amplified for HER2 , 27 (63%) were CEP17 eusomic, 13 (30%) polysomic, and 3 (7%) monosomic. Of the HER2 nonamplified cases, 2 (5%) showed monoallelic deletion of both the HER2 and TOP2A . The current study demonstrates the complex interrelationship between the HER2 and TOP2A genes in breast cancer. The clinical implications of TOP2A amplification and deletion in breast cancer need to be further defined. If TOP2A gene dosage can be confirmed to correlate with tumor responsiveness to anthracycline-based therapy in the clinical setting, FISH testing for TOP2A status may be warranted to aid in the selection of the most appropriate therapy.
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PMID:The incidence of topoisomerase II-alpha genomic alterations in adenocarcinoma of the breast and their relationship to human epidermal growth factor receptor-2 gene amplification: a fluorescence in situ hybridization study. 1589 95

In the past 30 years, important advances have been made in the knowledge of breast cancer biology and in the treatment of the disease. However, the translation of these advances into clinical practice has been slow. With the advent of molecular-based medicine, it is hoped that the bridge between the bench and the bedside will continue to be shortened. Because breast cancer is a heterogeneous disease with wide-ranging subsets of patients who have different prognoses and who respond differently to treatments, the identification of patients who need treatment and the definition of the best therapy for an individual have become the priorities in breast cancer care. This article will review the crucial role of prognostic and predictive factors in achieving these goals. A critical review of classical and newer individual molecular markers, such as hormone receptors, HER2, urokinase-type plasminogen activator and plasminogen activator inhibitor 1, cyclin E, topoisomerase II, and p53, was performed, and the preliminary results obtained using the new gene expression profiling technology are described along with their potential clinical implications.
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PMID:Bringing molecular prognosis and prediction to the clinic. 1589 74

Therapy-related myeloid leukemia (t-AML) is a distinctive clinical syndrome occurring after exposure to chemotherapy (CT) or radiotherapy (RT). We studied 306 consecutive patients referred to the University of Chicago with cytogenetic analyses. Since 1972, 141 males and 165 females with a median age of 51 years (range: 3-83 years) at primary diagnosis and 58 years (range: 6-86 years) at secondary diagnosis were analyzed. Patients had received various cytotoxic agents including alkylating agents (240 patients, 78%) and topoisomerase II inhibitors (115 patients, 39%). One hundred and twenty-one (40%) had received CT alone, 43 (14%) had received RT alone, and 139 (45%) had received both modalities. At diagnosis of t-AML, 282 (92%) had clonal abnormalities involving chromosome 5 (n=63), chromosome 7 (n=85), both chromosomes 5 and 7 (n=66), recurring balanced rearrangements (n=31), or other clonal abnormalities (n=39); 24 had a normal karyotype. Abnormalities of chromosomes 5 and/or 7 accounted for 76% of all cases with an abnormal karyotype. Seventeen patients had developed t-AML after autologous stem cell transplantation, but no unique pattern of cytogenetic abnormalities was observed. Patients presenting with acute leukemia were more likely to have a balanced rearrangement than those presenting with myelodysplasia (28% versus 4%, p<0.0001). Shorter latency was observed for patients with balanced rearrangements (median: 28 months versus 67 months; p<0.0001). Median survival after diagnosis of t-AML was 8 months; survival at 5 years was less than 10%. To gain insights into the molecular basis of this disease, we performed gene expression profiling of CD34+ hematopoietic progenitor cells from t-AML patients. We found distinct subtypes of t-AML that have characteristic gene expression patterns. Common to each of the subgroups are gene expression patterns typical of arrested differentiation in early progenitor cells. Leukemias with a -5/del(5q) have a higher expression of genes involved in cell cycle control (CCNA2, CCNE2, CDC2), checkpoints (BUB1), or growth (MYC), and loss of expression of the gene encoding interferon consensus sequence-binding protein (ICSBP). A second subgroup of t-AML is characterized by down-regulation of transcription factors involved in early hematopoiesis (TAL1, GATA1, and EKLF) and overexpression of proteins involved in signaling pathways in myeloid cells (FLT3) and cell survival (BCL2). Establishing the molecular pathways involved in t-AML may facilitate the identification of selectively expressed genes that can be exploited for the development of targeted therapies.
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PMID:Therapy-related myeloid leukaemia: a model for leukemogenesis in humans. 1593 16

The myelodysplastic syndromes (MDS) are receiving unusual attention recently as great strides have been made in understanding the biology. Recognition that excessive cytokine-induced apoptosis plays a significant role in the cytopenias of the majority of patients opened the doors to anti-cytokine therapy, with thalidomide being used with success in approximately 20% patients. Other therapies that have emerged include the thalidomide analog lenalidomide which is particularly beneficial for 5q- patients as well as a subset of non-5q- patients with low or intermediate-1 risk MDS. Other targeted therapies include vitamins, agents that are cytoprotective, differentiation inducers, anti-angiogenic, or immune modulatory. In addition, inhibitors of proteasome, methylation, histone deacetylation, farnesylation, receptor tyrosine kinases, topoisomerase, and matrix mettaloproteinases have yielded encouraging responses in subsets of patients. Specific therapies have also been developed for genetic abnormalities that lead to fusion genes (TEL-PDGFR-beta, or FIP1L1-PDGFR-alpha), or abnormal proteins due to mutations/functional inactivation (FLT3), dysregulated expression (EVI-1). In a short span of ten years, the field has evolved from having no effective therapy to offer the majority of MDS patients save chemotherapy, to having one FDA approved drug, several on the way to approval, and a number of novel agents producing exciting clinical results. This chapter summarizes the novel targets and targeted therapies in the rapidly evolving therapeutic landscape of MDS.
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PMID:Translational research in myelodysplastic syndromes. 1602


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