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)

Intrinsic or acquired resistance to chemotherapy is responsible for failure of current treatment regimens in breast cancer patients. The Y-box protein YB-1 regulates expression of the P-glycoprotein gene mdr1, which plays a major role in the development of a multidrug-resistant tumor phenotype. In human breast cancer, overexpression and nuclear localization of YB-1 is associated with upregulation of P-glycoprotein. In our pilot study, we analyzed the clinical relevance of YB-1 expression in breast cancer (n = 83) after a median follow-up of 61 months and compared it with tumor-biologic factors already used for clinical risk-group discrimination, i.e., HER2, urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1). High YB-1 expression in tumor tissue and surrounding benign breast epithelial cells was significantly associated with poor patient outcome. In patients who received postoperative chemotherapy, the 5-year relapse rate was 66% in patients with high YB-1 expression. In contrast, in patients with low YB-1 expressions, no relapse has been observed so far. YB-1 expression thus indicates clinical drug resistance in breast cancer. Moreover, YB-1 correlates with breast cancer aggressiveness: in patients not treated with postoperative chemotherapy, those with low YB-1 expression are still free of disease, whereas the 5-year relapse rate in those with high YB-1 was 30%. There was no significant correlation between YB-1 expression and either HER2 expression or uPA and PAI-1 levels. Risk-group assessment achieved by YB-1 differed significantly from that by HER2 or uPA/PAI-1. In conclusion, YB-1 demonstrated prognostic and predictive significance in breast cancer by identifying high-risk patients in both the presence and absence of postoperative chemotherapy, independent of tumor-biologic factors currently available for clinical decision making.
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PMID:Y-box factor YB-1 predicts drug resistance and patient outcome in breast cancer independent of clinically relevant tumor biologic factors HER2, uPA and PAI-1. 1177 77

The tall-cell variant (TCV) of papillary thyroid carcinoma (PTC), characterized by tall cells bearing an oxyphilic cytoplasm, is more clinically aggressive than conventional PTC. RET tyrosine kinase rearrangements, which represent the most frequent genetic alteration in PTC, lead to the recombination of RET with heterologous genes to generate chimeric RET/PTC oncogenes. RET/PTC1 and RET/PTC3 are the most prevalent variants. We have found RET rearrangements in 35.8% of TCV (14 of 39 cases). Whereas the prevalences of RET/PTC1 and RET/PTC3 were almost equal in classic and follicular PTC, all of the TCV-positive cases expressed the RET/PTC3 rearrangement. These findings prompted us to compare RET/PTC3 and RET/PTC1 in an in vitro thyroid model system. We have expressed the two oncogenes in PC Cl 3 rat thyroid epithelial cells and found that RET/PTC3 is endowed with a strikingly more potent mitogenic effect than RET/PTC1. Mechanistically, this difference correlated with an increased signaling activity of RET/PTC3. In conclusion, we postulate that the correlation between the RET/PTC rearrangement type and the aggressiveness of human PTC is related to the efficiency with which the oncogene subtype delivers mitogenic signals to thyroid cells.
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PMID:Potent mitogenicity of the RET/PTC3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma. 1178 18

Sixty-one heterozygotes harboring the germline V804L mutation of the RET protooncogene were identified in five independent families. A total of 31 subjects underwent surgery. Histology identified C cell hyperplasia in 30 cases, isolated in 12 and associated with medullary thyroid carcinoma (MTC) in 18. Six patients with MTC had lymph node metastases. Among the 14 patients with basal detectable calcitonin (CT) level, 12 had MTC and 2 had isolated C cell hyperplasia. In most individuals carrying 804 RET mutation, C cell disease displayed late onset and an indolent course; a pentagastrin test was negative in the majority of heterozygotes during the first 2 decades and was positive in only half of them during the third and fourth decades of life. Interestingly, concomitant somatic M918T was detected in a 12-yr-old girl with MTC and was likely to be responsible for both the early clinical appearance and the aggressiveness of the disease. Our data show that in these gene carriers, surgery may be postponed to the fourth decade of life or until the pentagastrin stimulation test becomes positive. Indeed, our data should be confirmed on a larger series of V804L carriers, but may offer a balanced strategy to keep under control and prevent development of the full disease phenotype.
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PMID:Familial medullary thyroid carcinoma: clinical variability and low aggressiveness associated with RET mutation at codon 804. 1193

In breast cancer the membrane expression of HER2 receptor protein encoded by the HER2 proto-oncogene seems to have an ever growing clinical significance. In tissue cultures and animal experiments it was shown that the HER2 gene amplification induces malignant transformation and intensifies the aggressiveness of the tumour cells. Correlating with the so called pheno-and genotypic prognostic markers, the overexpression of HER2 in breast cancer predicts also poor prognosis and indicates enhanced potential for metastatisation. In some of the so called precancerous proliferations and "in situ" carcinomas we demonstrated the enhanced membrane staining of the HER2 receptor protein. In these cases we frequently observed DNA aneuploidy,the presence of p53 mutational protein and CD44v6 glycoprotein. The immunohistochemical studies of HER2 protein in invasive carcinomas have revealed, an interrelationship between the grade of differentiation, histological type, aggressiveness and biological behaviour of the "in situ" and invasive carcinomas. In clinical studies trastuzumab, a humanized monoclonal antibody recognizing extracellular domain of HER2 receptor protein, has proved to be effective in HER2 overexpressing metastatic breast cancer either as monotherapy or in combination with chemotherapeutical agents. The DAKO "HercepTest" is a semiquantitative, standardised method for the determination of HER2 overexpression.
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PMID:[Expression of HER2 in breast cancer] 1205 Jul 66

Neuroblastoma is a neural crest-derived tumor of childhood with a serious prognosis; only 20% of patients with stage 4 disease survive 5 years from diagnosis. Mechanisms involved in neuroblastoma development are unclear, but the engagement of many neuroblastoma-related gene(s) is suggested by specific chromosomal alterations. Most prominent among these is the amplification of the MYCN oncogene and the deletion of the 1p36 region. Other genetic aberrations have been discovered over the years such as deletions of 11q and 14q and gain of 17q. Although tumor aggressiveness greatly depends on the most frequent genetic abnormalities, to date no neuroblastoma-related gene has been discovered. Neuroblastoma usually occurs sporadically, but 1.5% of all diagnosed cases show familial recurrence with an autosomal dominant inheritance and incomplete penetrance. A comparison between hereditary and sporadic neuroblastomas led Knudson and Strong to gather that the two-hit hypothesis, proposed for retinoblastoma, could be applied to neuroblastoma. To determine if the 1p36 region harbors a predisposition gene for familial neuroblastoma, we carried out linkage analysis at 1p36 loci in two families with recurrent neuroblastoma. Similarly, we analyzed loci of chromosome 16, where a predisposition locus was recently mapped. We also analyzed markers located close to several candidate genes (RET, NF1, GDNF, GFRA1, EDNRB, and EDN3) involved to a different extent in other neurocristopathies. Our findings indicate that the candidate chromosomal regions and genes analyzed are not in linkage with neuroblastoma.
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PMID:Linkage analysis in families with recurrent neuroblastoma. 1209 31

Inflammatory breast cancer (IBC) is a rare but particularly aggressive form of primary breast cancer. In contrast to noninflammatory breast cancer (non IBC), the molecular alterations underlying IBC are poorly known. We postulated that the kind and frequency of these alterations might differ between IBC and non IBC and account for its particular aggressiveness. We investigated allelic losses associated with primary breast cancer (on chromosome arms 1p, 3p, 6p, 6q, 7q, 8p, 9p, 11p, 11q, 16q, 17p and 17q) by analyzing 71 microsatellite markers in 66 cases of IBC. Loss of heterozygosity (LOH) was frequent, with a mean fractional allelic loss (FAL) index of 52%. Relative to published data on non IBC, allelic loss was particularly frequent at 3p21-p14, 6p, 8p22, 11q, 13q14 and 17q21, suggesting the presence of genes that are markedly altered in IBC. In contrast, the DNA amplification levels of ERBB2, MYC and CCND1, as measured by real-time quantitative PCR, did not differ between IBC and non IBC.
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PMID:Evidence of chromosome regions and gene involvement in inflammatory breast cancer. 1244 4

Angiogenesis, a process related to tumor growth and malignancy, is stimulated by several growth factors. Among these is vascular endothelial growth factor (VEGF), which acts on endothelial cells by binding with 2 specific receptors, VEGFR1 and VEGFR2. Recent studies have demonstrated that VEGF expression is correlated with microvessel density (MVD) and tumor progression. Digestive endocrine tumors are heterogeneous neoplasms exhibiting variable biological aggressiveness and behavior that often are not predictable on morphologic grounds alone. The aims of this study were to evaluate the expression of VEGF, VEGFR1, and VEGFR2 in digestive endocrine tumors and to examine its correlation with MVD and malignancy. A total of 84 specimens from endocrine neoplasms and normal gut and pancreatic tissue were immunohistochemically studied using specific antibodies directed against VEGF, VEGFR1, VEGFR2, endothelial antigens, and gastroenteropancreatic hormones. Ultrastructural immunocytochemistry was performed to identify the cellular localization of VEGF and the VEGFRs. In normal tissues, VEGF immunoreactivity was detected in G cells and PP cells. Ultrastructurally, VEGF was localized within secretory granules. The VEGFRs were not significantly expressed by normal endocrine cells. VEGF-immunoreactive (IR) cells were detected in 40 of 83 tumors, mainly G cell and enterochromaffin cell neoplasms. VEGFR1-IR cells were found in 44 of 82 tumors, and VEGFR2-IR cells were found in 55 of 82 tumors, with no predilection for any specific tumor type. The expression of VEGF and its receptors did not correlate with MVD or malignancy. These results suggest that in normal tissues, endothelial functions may be regulated by VEGF produced by some endocrine cells and that a VEGF/VEGFR binding mechanism may be involved in tumorigenesis, but not in tumor progression and aggressiveness.
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PMID:Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathologic features. 1260 62

The natural history and survival of breast cancer are extremely variable although the advances and improvement in treatment in recent years led to a lower mortality. In fact, in spite of the administration of systemic adjuvant therapy, women with metastatic lymph nodes at diagnosis have a risk of disease progression at 5 years of 40-50%. The disease heterogeneity and the intrinsic tumor cell resistance to therapies are determining factors of the problem. The role of parameters as tumor size, grading, vascular spread, axillary lymph node status, are well defined. However the increasingly early diagnosis and changes in clinical practice have led to the need for non morphologic parameters as estrogen and progesteron receptors, cell proliferation index, labelling index, growth factors tumor-dependent genes (p53, HER2), cell cycle regulators (cyclins). Specific cellular and molecular alterations are studied to identify diagnosticoinstrumental images (MRI) of tumor angiogenesis, the cause of the different tumor aggressiveness. In the surgical and consequently clinico-oncologic approach there is the problem of the interpretation and prognostic role of sentinel lymph node when it is positive for micrometastasis only, if diagnosed by immunohistochemistry.
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PMID:Biological factors and therapeutic modulation in breast cancer radiotherapy. 1269 49

Since the establishment of a protocol for molecular analysis of hereditary medullary thyroid carcinoma (MTC) in southern Brazil, in 1997, 17 independent families with RET germline mutation have been identified. Because neither molecular diagnosis nor the pentagastrin test were available before the establishment of this protocol, we had the opportunity to observe a large number of patients in whom the disease has evolved naturally without medical intervention, namely prophylactic thyroidectomy. We observed a wide spectrum in terms of clinical presentation and natural course of the disease even among genetically related individuals. Sixty-nine individuals from 12 different families presented a codon 634 mutation, the most prevailing missense mutation in our series. The specific mutations identified were C634Y (n = 49), C634R (n = 13), and C634W (n = 7). Individuals with the C634R mutation presented significantly more distant metastases at diagnosis than subjects with the C634Y or C634W mutations (54.5% vs. 19.4% vs. 14.3%, respectively, P = 0.03). Further analysis of the estimated cumulative frequency of lymph node and/or distant metastases by Kaplan-Meier curves showed that the appearance of lymph nodes and metastases occurred later in patients with C634Y than in those with C634R (P = 0.001). Our results suggest that specific nucleotide and amino acid exchanges at codon 634 might have a direct impact on tumor aggressiveness in MEN 2A syndrome.
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PMID:RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. 1278 68

Multiple endocrine neoplasia Type 2 is a rare familial cancer syndrome transmitted in an autosomal dominant manner. It is characterized by the association of medullary thyroid carcinoma with pheochromocytoma and hyperparathyroidism. Medullary thyroid carcinoma, present in virtually all patients, is the principal cause of death. In 1993, germline mutations in the RET proto-oncogene were identified as the underlying cause of the syndrome. Genetic screening of at-risk family members can now be performed with high specificity and sensitivity. The ability to determine gene carrier status at a preclinical stage is of great value as it allows early prophylactic thyroidectomy. The specific RET codon mutation correlates with clinical variants of the syndrome, age at onset and aggressiveness of medullary thyroid carcinoma. This review will focus on mutational spectrum, genotype-phenotype correlations and clinical decisions based on genetic information.
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PMID:Molecular diagnosis of multiple endocrine neoplasia Type 2. 1462 4


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