Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To assess the importance of Neu activation during mammary tumorigenesis, altered receptors harboring in-frame deletions within the extracellular domain were expressed in transgenic mice. Females from several independent lines develop multiple mammary tumors that frequently metastasize to the lung. Tumor progression in these strains was associated with elevated levels of tyrosine-phosphorylated Neu and ErbB-3. Consistent with these observations, a survey of primary human breast tumors revealed frequent co-expression of both erbB-2 and erbB-3 transcripts. The ability of altered Neu receptors to induce mammary tumorigenesis in transgenic mice prompted us to examine whether similar mutations occurred in ErbB-2 during human breast cancer progression. Interestingly, an alternatively spliced form of erbB-2, closely resembling spontaneous activated forms of neu, was detected in human breast tumors. The ErbB-2 receptor encoded by this novel transcript harbors an in-frame deletion of 16 amino acids in the extracellular domain and can transform Rat-1 fibroblasts. Together, these observations argue that co-expression of ErbB-2 and ErbB-3 may play a critical role in the induction of human breast tumors, and raise the possibility that activating mutations in the ErbB-2 receptor may also contribute to this process.
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PMID:Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer. 1020 69

Breast cancers arising in women with and without a germline mutation in the BRCA1 or BRCA2 gene display different histological features, which suggests unique mechanisms of molecular pathogenesis: We used a molecular pathological analysis to define the genetic abnormalities relevant to these specific pathogeneses. Tumor material was studied from 40 women with breast cancer diagnosed before 40 years of age, sampled from a population-based study and stratified by BRCA1 and BRCA2 germline mutation status. Cases were not selected for family history or ethnic origin, and none were known to be genetically related. Thus, germline mutation itself is likely to impact on the molecular pathogenesis of these tumors, with no substantial influence due to modifying genetic or environmental factors. Breast cancers occurring in BRCA1 mutation carriers had significantly higher levels of p53 expression, including the preinvasive (carcinoma in situ) stage of disease, compared with cancers occurring in BRCA2 mutation carriers or women with no detectable germline mutation. These cancers also had a higher proliferation rate as measured by Ki-67 antibody. Expression of the prognostic factors c-erbB-2, cyclin D1, and estrogen receptor was significantly less common in BRCA1 mutation carriers. Lower levels of cyclin D1 were also found in cancers from BRCA2 mutation carriers compared with non-mutation carriers. Direct p53 mutation analysis revealed mutations in 18% of all of the early-onset breast cancers within the study and included rare insertion and deletional mutations in cancers from BRCA1 mutation carriers. Our data indicate that a BRCA1 breast cancer phenotype may be recognized by an exceptionally high proliferation rate and early and frequent p53 overexpression but infrequent selection for overexpression of several other prognostic factor proteins known to be involved in breast oncogenesis. In contrast, breast cancers arising in BRCA2 mutation carriers have a more heterogeneous phenotypic profile.
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PMID:Distinct molecular pathogeneses of early-onset breast cancers in BRCA1 and BRCA2 mutation carriers: a population-based study. 1021 14

Prostate cancer is the most frequent malignancy and the second leading cause of cancer deaths among males in the Western world. The clinical course of the disease is highly complex, and genetic factors underlying tumorigenesis are poorly understood. The challenge that lies ahead is to identify the important gene(s) that causes adenocarcinoma of the prostate. Chromosomal findings by cytogenetic and molecular methods, including Southern blotting, microsatellite analysis, fluorescence in situ hybridization, and comparative genomic hybridization, revealed a high frequency of chromosomal aberrations of heterogeneous nature, including: -1, +1, -1q, +4, -6q, -7, +7, -8, -8p, -8q, +i(8q), -9, -9p, -10, +10, +11, -12, -13q, -16, -16q, +16, -17, +17, +17q, -18, +18, -18q, +19p, +20q, +X, -Xq, -Y, and +Y. Specific chromosomal regions of alterations were 1q24-25, 2cen-q31, 5cen-q23.3, 6q14-23.2, 7q22-q31, 8p12-21, 8p22, 8q24-qter, 10q22.1, 10q23-25, 11p11.2, 16q24, 17p13.1, 18q12.2, and Xq11-12. Recently, a predisposing gene for early onset has been localized on 1q42.2-43. The losses of heterozygosity at specific chromosomal loci from chromosomes 5q, 6q, 7q, 8p, 8q, 10q, 13q, 16q, 17p, 17q, and 18q are generally correlated with poor prognosis in advanced tumor stage. In addition, an abnormal function of known tumor suppressor genes from these regions have been observed in prostate cancer. Although, the amplification of the androgen receptor gene at Xq11-13 and HER-2/neu gene at 17q11.2-q12 are novel findings, no single gene has been implicated in harboring prostate cancer. Frequent inactivation of PTEN/MMAC1 tumor suppressor gene at 10q23, MXI-1 at 10q25, KAI-1 at 11p11.2, Rb at 13q14.2, and p53 at 17p13.1 and deregulation of c-myc oncogene at 8q24 have recently been the subject of intense scrutiny and debate.
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PMID:Chromosomal basis of adenocarcinoma of the prostate. 1043 55

Several studies have shown that some organochlorine compounds act like estrogen in certain animals and in vitro cell culture systems, and therefore, there is a possibility that they could promote the process of tumorigenesis in breast cancer cells. In our previous study, two representative organochlorines, 1,1,1-trichloro 2-o-chlorophenyl-2'-p-chlorophenyl ethane (o,p'-DDT) and beta-1,2,3,4,5,6-hexachlorocyclohexane (beta HCH), were found to directly activate the protein tyrosine kinase of Neu (c-erbB-2 proto-oncogene product) immunoprecipitates isolated from MCF-7 breast cancer cells. In the current study, we also found that 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) at 1 nM and alpha-HCH isomers at 100 nM could also significantly activate protein tyrosine kinase of Neu immunoprecipitates in a cell-free system. We also found that organochlorines result in an increase of Neu protein tyrosine kinase after intact cell treatment in estrogen-depleted medium. This Neu kinase activation by beta-HCH (100 nM) was blocked when the cells were pretreated with Neu mRNA antisense oligonucleotide (p < 0.07, Student's t-test). Endogenously added alpha-, beta-, and gamma-HCH, o,p'-DDT, 2,2'-dichlorobiphenyl (2,2'-PCB), and 2,4,5-T at 100 nM were found to promote foci formation in postconfluent cultures of this cell line. This stimulatory effect caused by 17beta-estradiol, o,p'-DDT, and beta-HCH on foci formation was inhibited by coincubation with Neu monoclonal antibody (p < 0.05). Those two events induced by organochlorines (i.e., Neu kinase activation and foci formation) seemed causally correlated.
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PMID:Correlation between the activation of Neu tyrosine kinase and promotion of foci formation induced by selected organochlorine compounds in the MCF-7 model system. 1048 16

The Epidermal Growth Factor receptor (EGFr) was one of the first oncogenes identified, and it, or its ligands Epidermal Growth Factor (EGF) and Transforming Growth Factor a (TGFa) are overexpressed in most clinical tumours. As EGF and TGFa are potent mitogens, it appeared that inhibition of EGFr signaling would be a viable anti-proliferative strategy. Screening found several classes of EGFr inhibitor, one of which, the indolinethiones was developed. The SAR, in common with that of other first generation tyrosine kinase (TK) inhibitors was flat, and potency was poor. Rescreening in presence of a thiol, to remove chemically reactive species, identified only two leads, a pyridopyrimidine and a quinazoline. These were developed into a very broad class of EGFr inhibitors, with great potency and selectivity for EGFr, but poor physicochemical properties, and little if any in vivo anti-tumour activity. Meanwhile the complex role of other members of the EGFr TK family in oncogenesis, was becoming apparent, suggesting that the whole EGFr family should be inhibited. The difficulty of finding potent compounds with acceptable pharmacokinetics also suggested that irreversible inhibitors of the TK might produce better in vivo profiles. Modeling suggested that the unusual Cys773 residue might be reached from the 6/7-positions of quinazoline and pyridopyrimidine inhibitors. Inhibitors with acrylamides at these positions proved to be irreversible alkylating agents for both EGFr and erbB-2 with cellular inhibitory activities in the low nanomolar range, and very potent in vivo antitumour activity. Optimized inhibitors had exceptionally potent oral antitumour activity, with negligible cytotoxicity.
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PMID:The rationale and strategy used to develop a series of highly potent, irreversible, inhibitors of the epidermal growth factor receptor family of tyrosine kinases. 1049 54

The amplification and overexpression of the erbB-2 oncogene and its involvement in tumorigenesis makes this receptor an appropriate target for specific agents directed towards tumor cells. The purpose of this study was to evaluate the in vitro effect of the bacterially produced recombinant immunotoxin scFv(FRP5)-ETA on the protein synthesis and adenosine triphosphate (ATP) reduction in oral squamous cell carcinoma (OSCC) cells. This agent recognizes the erbB-2 receptor and inhibits protein synthesis in receptor-overexpressing cells. OSCC cells were selected for this study, and amplification and expression levels of the erbB-2 receptor were determined. Cell suspensions were cultured for 6 d with various concentrations of scFv(FRP5)-ETA (1-1000 ng/ml). A431 and MDA-MB468 cell lines were used as controls. Chemosensibility of tumor cells was measured by [3H]leucine incorporation assay and by an ATP luminescence assay. In OSCC cells with amplification and overexpression of erbB-2 inhibition, up to 92% of protein synthesis and 90% of ATP reduction was observed when cells were exposed to 1,000 ng/ml immunotoxin. In OSCC cells showing a deletion of erbB-2 and in erbB-2-negative MDA-MB468 cells, protein synthesis was inhibited by 22% and 8%, respectively. These results indicate that the effectiveness of a recombinant immunotoxin targeting erbB-2 receptors in OSCC cells depends on the level of erbB-2 amplification and expression, that it is highly specific for tumor cells expressing these receptors, and that a dose-dependency can be observed.
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PMID:Chemosensitivity testing of oral cancer cells treated with a p185neu-specific agent. 1051 98

Separate mechanisms for oncogenesis and metastasis have been postulated. We show here that prolonged and invasive cell migration, a key mechanism in cancer metastasis, is linked to c-erbB-2 signaling. Cell lines with c-erbB-2 and EGFR expression and transphosphorylation activity display a high transendothelial invasiveness in an endothelial-extracellular matrix model mimicking a capillary vessel wall in vitro. Tyrosine-phosphorylated c-erbB-2 receptors and EGFR are localized predominantly in areas of the cell with high membrane extension activity. On the molecular level, there is a subtle cross talk between the transmembrane signaling molecule c-erbB-2 and the actin cytoskeleton at multiple levels, including the generation of the second messenger PIP2 and the mobilization of the actin-regulatory protein gelsolin. Our data strongly suggest that c-erbB-2, especially in a heterodimer with EGFR, is closely involved in signaling pathways, inducing alterations in cell morphology that are required for a human breast cancer cell to become motile and conceivably metastatic.
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PMID:c-erbB-2/EGFR as dominant heterodimerization partners determine a motogenic phenotype in human breast cancer cells. 1054 77

A number of receptor systems have been implicated to play an important role in the development and progression of many human cancers. The epidermal growth factor (EGF) receptor tyrosine kinase family has been found to consistently play a leading role in tumor progression. Indeed, in human breast cancer cases the prognosis of a patient is inversely correlated with the overexpression and/or amplification of this receptor family. Furthermore, downstream signaling components such as the Src kinases, PI3'K, and the Ras pathway display evidence of deregulation that can accelerate tumor progression. The transgenic mouse system has been ideal in elucidating the biological significance of this receptor family in mammary tumorigenesis. Molecular events involved in mammary tumorigenesis such as ligand binding, receptor dimerization, and the activation of downstream pathways have been addressed using this system. Although there are many molecular steps that appear to drive each stage of tumor development, the EGF receptor family appears to play a causal role in the progression to a transformed phenotype.
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PMID:The role of the epidermal growth factor receptor family in mammary tumorigenesis and metastasis. 1057 13

The study was carried out on 53 patients who had thyroid cancer with various degree of differentiation. We studied the expression of bcl-2, a-erbB-2, p53, and p21 ras protein. The protein encoded by bCL-2 proto-oncogene is implicated in the prolongation of cell survival by blocking programmed cell death, i.e. apoptosis. The role of p53 and bcl-2 genes in the regulation of apoptosis has important implications in oncogenesis. Wild-type p53 is thought to promote apoptosis, whilst mutant p53 has a similar effect on apoptosis as bcl-2 that is inhibition of programmed cell kinase activity. C-erb-2 protein overexpression is currently being evaluated as a potential risk factor in breast cancer patients? The ras gene family codes for a 21 kD protein (p21), which binds guanine nucleotides and possesses GTPase activity. Through this mechanism, the ras p21 protein participates in the control of cell proliferation, possibly as a signal transducer from cell surface receptors to the nucleus. Activation of ras genes has been implicated in neoplastic transformation of cells. The aim of our study is to evaluate the expression of these markers in thyroid carcinomas. All immunohistochemical study was performed in paraffin-embedded tissues pathology specimen. Any well differentiated tumor in our study was positive for bcl-2 protein. C-erb-2 immunostaining was present in tumor samples in 60% of cases. In most cases, specific membrane staining as well as a weak cytoplasmic positivity of tumor cells were seen. Immunoreactivity for p53 was positive only in 10% of cases. By immunostaining, p21 protein was expressed in 55% of the 53 tumors tested, with different degree of expression. Only some poorly differentiated tumours were positive for bcl-2, furthermore all markers tested were strongly positive in these tumours. In conclusion, our results indicate that bcl-2, c-erbB-2, p53, and p21 ras protein are differently expressed in thyroid carcinomas in relation to the degree of aggressiveness and differentiation.
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PMID:Expression of bcl-2, c-erbB-2, p53, and p21 (waf1-cip1) protein in thyroid carcinomas. 1060 83

Primary fallopian tube carcinoma is a rare form of female cancer and the genetic basis of its carcinogenesis remains unclear. Eighteen cases of primary fallopian tube adenocarcinoma were studied. Immunohistochemical staining for p53, HER-2/neu and c-myc genes were performed. Overexpression of p53 was detected in 12 cases (67%), HER-2/neu in 16 cases (89%), and c-myc in 11 cases (61%). The potential relevance of overexpression of the three genes with clinicopathological features was examined, but no significant correlation was found. The high incidence of p53, HER-2/neu and c-myc overexpression in fallopian tube adenocarcinoma suggests these genes may play a role in its tumorigenesis.
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PMID:Overexpression of p53 and HER-2/neu and c-myc in primary fallopian tube carcinoma. 1062 73


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