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)

HER2, the erbB-2/neu proto-oncogene product, is a 185-kDa transmembrane glycoprotein related to the epidermal growth factor receptor. Overexpression of HER2 was reported in several human adenocarcinomas, including mammary and ovarian carcinomas. A family of glycoproteins, the heregulin/neu differentiation factors, was characterized and implicated as the ligands for HER2. Recently, it has been shown that HER2 alone is not sufficient to reconstitute high affinity heregulin receptors and that HER3 or HER4 may be the required components of the heregulin receptors on mammary carcinoma cells (Sliwkowski, M.X., Schaefer, G., Akita, R.W., Lofgren, J.A., Fitzpatrick, V.D., Nuijens, A., Fendly, B.M., Cerione, R.A., Vandlen, R.L., and Carraway, K.L., III (1994) J. Biol. Chem. 269, 14661-14665; Plowman, G.D., Green, J.M., Culouscou, J.-M., Carlton, G.W., Rothwell, V.M., and Buckley, W. (1993) Nature 366, 473-475). Using the Cytosensor to measure the extracellular acidification rate, we have examined the effects of recombinant human heregulin-alpha on three mammary carcinoma cell lines expressing HER2 (MDA-MB-453, SK-BR-3, and MCF-7), an ovarian carcinoma cell line expressing HER2 (SK-OV-3), and CHO-K1 and 293-EBNA cells stably transfected with HER2. By reverse transcription polymerase chain reaction and Western blotting, we found that the breast cells also express HER3 and that the ovarian line co-expresses the HER4 message. A dramatic increase in the acidification rate was observed for the mammary carcinoma cells co-expressing high levels of HER2 and HER3. In contrast, the ovarian cells expressing high levels of HER2 and low levels of HER4 or CHO-K1 and 293-EBNA cells expressing HER2 alone were not responsive to heregulin. When these same transfected cells were exposed to monoclonal anti-HER2 antibody followed by anti-IgG to cause aggregation of the HER2 molecules, an increase in the acidification rate was observed, indicating coupling of transfected HER2 to the signal transduction pathway. Transfection of HER2 into MCF-7 cells, on the other hand, gave 4-fold enhanced acidification responses. These data, together with the previously reported high affinity heregulin binding and activation of tyrosine phosphorylation in HER2 and HER3 co-transfected cells support the role of HER2 and HER3 as components of the heregulin receptor in breast cells.
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PMID:Heregulin activation of extracellular acidification in mammary carcinoma cells is associated with expression of HER2 and HER3. 767 53

The HER-2/neu proto-oncogene encodes a transmembrane receptor protein whose expression is enhanced in a number of breast and ovarian tumors and correlates with tumor aggressiveness, suggesting that it may play an important role in tumor growth. Recent evidence suggests that HER-2/neu may be a potential candidate for targeted immune intervention. In this report we show that cytotoxic T lymphocytes (CTL) expanded from tumor-associated lymphocytes with HLA-A2+ and HER-2/neu+ tumors can specifically recognize synthetic peptides corresponding to amino acids 971-980 of HER-2/neu protein. This sequence includes a potential amphiphilic area containing both Rothbard's epitode motifs and HLA-A2 anchor residues. Our study provides the first direct evidence of HER-2/neu-reactive CTL in humans. The fact that these HER-2/neu peptide-reactive CTL show significantly lower reactivity with corresponding EGF-R peptides offers new perspectives for understanding the recognition of self-antigens by tumor-reactive T cells.
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PMID:Cytotoxic T cells isolated from ovarian malignant ascites recognize a peptide derived from the HER-2/neu proto-oncogene. 769 18

Overexpression of the c-erbB-2 proto-oncogene in mammary carcinoma is frequently associated with amplification of the c-erbB-2 gene, but it also occurs from single-copy gene. Studies in mammary-derived cell lines have shown that, whether or not the gene is amplified, there is a 6- to 8-fold increase in the accumulation of c-erbB-2 mRNA per gene copy in overexpressing cells. We have recently shown that this phenomenon is due to increased activity of the c-erbB-2 promoter mediated by the binding of a novel transcription factor, OB2-1, which is present at higher levels in overexpressing cells than in low expressors. OB2-1 activity therefore represents a novel therapeutic target for the down-regulation of c-erbB-2 levels in human cells. As a prototype for this strategy, we show here that the drug sodium aurothiomalate is able to inhibit the DNA-binding activity of OB2-1 in vitro and also to interfere with c-erbB-2 promoter activity in cell-based transfection assays. In addition, endogenous c-erbB-2 immunoreactivity was reduced in cells treated with aurothiomalate as compared with the levels observed in control cells.
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PMID:Targeting gene transcription: a new strategy to down-regulate c-erbB-2 expression in mammary carcinoma. 771 Sep 40

The c-myb proto-oncogene product (c-Myb) is a transcriptional activator that can bind to the specific DNA sequences. Although c-Myb also represses an artificial promoter containing the Myb binding sites, natural target genes transcriptionally repressed by c-Myb have not been identified. We have found that the human c-erbB-2 promoter activity is repressed by c-Myb or B-Myb in a chloramphenicol acetyltransferase co-transfection assay. Domain analyses of c-Myb suggested that Myb represses the c-erbB-2 promoter activity by competing with positive regulators of the c-erbB-2 promoter. In in vitro transcription assays, Myb proteins containing only the DNA binding domain could repress c-erbB-2 promoter activity. Two Myb binding sites in the c-erbB-2 promoter were critical for transcriptional repression by c-Myb. One of the two Myb binding sites overlaps the TATA box, and DNase I footprint analyses indicated that c-Myb can compete with TFIID. These results suggest that Myb-induced trans-repression of the c-erbB-2 promoter partly involves competition between Myb and TFIID.
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PMID:c-Myb repression of c-erbB-2 transcription by direct binding to the c-erbB-2 promoter. 772 62

The c-erbB-2 proto-oncogene encodes a transmembrane glycoprotein with tyrosine kinase activity, p185erbB-2, that has been previously localized in some developing and mature epithelia. The possible occurrence of p185 in the inner enamel epithelium of rat tooth germ was here investigated immunocytochemically. Postmitotic functional ameloblasts displayed intense p185-immunoreactivity, thus suggesting that c-erbB-2 proto-oncogene is active during odontogenesis. The expression of this gene in differentiated and functional cells of the enamel organ suggests that its role is not restricted to mitotic events but may also be important in signalling pathways related to other cell activities.
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PMID:Expression of c-erbB-2 proto-oncogene-encoded protein (p185erbB-2) in functional rat ameloblasts. 774 63

The proto-oncogene HER2/neu encodes for a 185 kDa transmembrane protein with extensive homology to the epidermal growth factor (EGF) receptor. We have previously shown a correlation between HER2/neu expression and the level of in vitro cytotoxicity of tumour-associated lymphocytes (TAL) versus autologous tumour. In addition, we have recently demonstrated that tumour-associated cytotoxic T-lymphocytes (CTL) from ovarian and breast cancer patients can recognize a HER2/neu derived peptide epitope when presented in the context of HLA-A2. Since repeated tumour stimulation of CTL enhances both proliferation and cytotoxicity against autologous tumour, we hypothesized that repeated peptide antigen stimulation would have a similar effect. To be therapeutically useful, the peptide antigen must meet the following conditions: (1) the peptide must be immunogenic and cause a proliferation of CTL to adequate therapeutic numbers, and (2) the peptide-specific CTL which are generated must be cytotoxic against autologous tumour. To test our hypothesis, T-lymphocytes isolated from the ascites of four consecutive HER2/neu+ ovarian cancer patients were initially stimulated with solid phase anti-CD3 antibody and divided into three groups: (1) treatment with recombinant interleukin-2 (IL-2) alone, (2) IL-2 plus weekly stimulation with irradiated autologous tumour cells, and (3) IL-2 plus weekly stimulation with a HER2/neu derived peptide. Peptide-stimulated and tumour-stimulated CTL showed similar increases in proliferation with both groups consistently reaching therapeutic numbers. Peptide-stimulated CTL demonstrated significantly enhanced cytotoxicity against autologous tumour in 4-h chromium release assays as compared to the IL-2 alone group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro stimulation of ovarian tumour-associated lymphocytes with a peptide derived from HER2/neu induces cytotoxicity against autologous tumour. 778 Jun 12

C-erbB-2(HER-2/neu) proto-oncogene is mainly expressed in epithelial tissue and activated due to its amplification. Amplification of the C-erbB-2 proto-oncogene has been associated with poor prognosis in human ovarian cancer. Our study was to examine whether amplification is more frequently observed in ovarian cancer, or it is associated with poor prognosis of human ovarian cancer in China. The DNA of ovarian cancers was extracted and consequently digested with restriction endonuclease EcoRI, electrophoresed in 0.8% agarose gels and blotted onto nitrocellulose filter with Southern transferring method. It was then hybridized with a 32P-labelled C-erbB-2 probe and subsequently underwent autoradiography. The result has shown that the C-erbB-2(HER-2/neu) gene was amplified in 8 of 26 human ovarian cancers (30.8%). The clinical data showed that all of the 8 cases with the amplified C-erbB-2 were in their advanced stage (III-IV). Five of the patients died from 2 to 4 months after operation. These data suggest that amplification of the C-erbB-2 gene may play a role in the pathogenesis of ovarian carcinoma; it is frequently observed in advanced ovarian cancer and is associated with poor prognosis for these patients.
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PMID:Amplification of the C-erbB-2(HER-2/neu) proto-oncogene in ovarian carcinomas. 780 42

In order to evaluate the involvement of cerbB-2 oncogene in the etiology and progression of breast cancer, DNA samples from 157 primary human mammary carcinomas were subjected to Southern and dot blot analyses for the presence of c-erbB-2 protooncogene alterations. None of 157 carcinomas analyzed showed c-erbB-2 rearrangement. Amplification of the c-erbB-2 was found in 28.6% (45/157) of the samples. Gene expression could be analyzed in only 97 of these tumors. High levels of c-erbB-2 transcripts were detected in 25.7% (25/97) of the tumor RNA preparations. Although there was a good correlation between c-erbB-2 overexpression and gene amplification, a significant proportion of the tumors showed overexpression in the absence of gene amplification or gene amplification without overexpression. A significant correlation between c-erbB-2 proto-oncogene alterations with the number of positive lymph nodes and tumor necrosis was found, suggesting that c-erbB-2 genetic alterations have a biological importance in the etiology of breast cancer.
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PMID:c-erbB-2 DNA amplification and mRNA expression in human primary breast tumors and its relationship to other prognostic factors. 781 45

A single missense mutation in the human erbB-2 proto-oncogene (HER2N) efficiently transforms cultured NIH/3T3 fibroblasts. The transforming allele (HER2VE) contains a glutamic acid residue at position 659, instead of a valine, in the transmembrane region of the growth factor receptor. Receptor action is dependent on oligomerization. We have investigated the ability of erbB-2 gene variants with mutations in the intracellular tyrosine kinase domain to revert the transformed phenotype of cells. These variants most likely form hetero-oligomers with the transforming oncogene. Two receptor variants were constructed and introduced into cells expressing the oncogenic form of the human erbB-2 gene, HER2VE. The mutant HER2N delta contains a deletion of a large part of the kinase domain including the ATP binding site. This mutant had no effect on the growth of transformed cells, although it was found to interact with HER2VE. HER2N delta is phosphorylated in the presence, but not in the absence of HER2VE. A second mutant was constructed, HER2VEK753A, which contains both a mutation in the transmembrane region and a mutation in the ATP binding site of the kinase domain. This mutant led to a reversion of the transformed phenotype and significantly decreased growth in soft agar of HER2VE transformed cells. A concomitant increase in phosphorylated receptors was observed. These results indicate that an intact kinase domain is required for the oncogenic action of HER2VE and that transformation parameters can be suppressed by kinase domain mutants.
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PMID:NIH/3T3 cells transformed with the activated erbB-2 oncogene can be phenotypically reverted by a kinase deficient, dominant negative erbB-2 variant. 782 11

Adenocarcinomas of the proximal stomach including the gastroesophageal junction are extremely virulent cancers which are increasing rapidly in incidence. Stage-for-stage proximal gastric cancers have a worse prognosis than do tumors of the body or antrum of the stomach. To further explore biological differences based on site, we studied 80 patients with locally advanced primary tumours of the proximal (n = 40) and distal stomach (n = 40) for amplification of the HER-2/neu proto-oncogene. None of 40 patients with proximal lesions had overexpression of HER-2/neu, whereas four of 40 (10%) distal adenocarcinomas had a 16-24-fold gene amplification (P = 0.04). In the adenocarcinomas from two patients, gene rearrangements were found in addition to amplification. HER-2/neu gene product p185 over-expression was found only in the amplified cases. All four patients with distal tumors and amplification had rapid progression of disease (median survival: 4.3 months). While it is unclear why HER-2/neu amplification is seen only in distal tumors, these data further support the hypothesis that biological differences between proximal and distal lesions are present. As is the case for other tumours, HER-2/neu amplification is associated with a poor prognosis for the individual patient.
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PMID:Amplification of HER-2/neu gene in human gastric adenocarcinomas: correlation with primary site. 785 55


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