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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Betacellulin is a member of the epidermal growth factor (EGF) family. These soluble proteins are ligands for one or more of the four receptor tyrosine kinases encoded by the erbB gene family (erbB-1/epidermal growth factor receptor (EGFR), neu/erbB-2/HER2, erbB-3/HER3 and erbB-4/HER4). While evidence suggests that betacellulin is a ligand for the EGFR, the ability of betacellulin to regulate other erbB family receptors has not been analysed. Previously we engineered derivatives of the mouse Ba/F3 hematopoietic cell line to ectopically express erbB family receptors, singly and in pairwise combinations. We have stimulated this panel of cell lines with betacellulin and two other EGF family members, EGF itself and neuregulin-beta (NRG-beta). In the cell lines expressing a single erbB family receptor, betacellulin not only stimulated EGFR tyrosine phosphorylation, but it activated erbB-4 as well. Furthermore, in the double recombinant Ba/F3 derivatives, betacellulin stimulated a complex pattern of receptor phosphorylation distinct from the patterns activated by NRG-beta and EGF. Moreover, betacellulin stimulated a complex pattern of interleukin-3 independence in the Ba/F3 derivatives distinct from those activated by NRG-beta and EGF. These data identify a novel receptor for betacellulin and establish that different EGF family ligands activate distinct patterns of receptor phosphorylation and coupling to cellular signaling pathways.
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PMID:Betacellulin activates the epidermal growth factor receptor and erbB-4, and induces cellular response patterns distinct from those stimulated by epidermal growth factor or neuregulin-beta. 857 Feb 11

The neu/erbB-2/HER-2 proto-oncogene is amplified and/or overexpressed in up to 30% of mammary carcinomas and has been variably correlated with poor prognosis. The signaling activity of the encoded receptor tyrosine kinase is regulated by interactions with other type 1 receptors and their ligands. We have used a novel approach, phosphorylation-sensitive anti-Neu antibodies, to quantify signaling by Neu and epidermal growth factor receptor in a panel of frozen sections of mammary carcinoma specimens. We also determined the relationship of Neu, phosphorylated Neu (and epidermal growth factor receptor), and phosphotyrosine to the expression of Neu-related receptors (epidermal growth factor receptor, HER-3, and HER-4) and to prognostic factors (estrogen and progesterone receptor). We found that tyrosine phosphorylation of Neu (and hence signaling activity) is highly variable among mammary carcinomas. Neu and HER-4 were associated with divergent correlates, suggesting that they have profoundly different biological activities. These results have implications for etiology of mammary carcinoma for clinical evaluation of mammary carcinoma patients, and for development of Neu-targeted therapeutic strategies.
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PMID:Type 1 receptor tyrosine kinases are differentially phosphorylated in mammary carcinoma and differentially associated with steroid receptors. 857 17

The HER2/neu protooncogene encodes a transmembrane receptor tyrosine kinase of Mr185 kDa (called p185) which is structurally and functionally homologous to the epidermal growth factor receptor. Shc proteins are important downstream signal transducers of receptor tyrosine kinases. We reported here a novel finding that p66Sch was absent or nearly absent in p185-overexpressing breast cancer cells. This inverse correlation of p185 overexpression and p66Shc expression is probably specific to breast cancer cells because this phenomenon was not observed in p185-overexpressing human ovarian, lung, or oral cancer cells, or mouse fibroblast cells. In contrast, the p52Shc and p46Shc isoforms were expressed at similar levels in both p185-overexpressing and p185 basal level breast cancer cell lines. Furthermore, tyrosine phosphorylation of p52Shc and p46Shc and subsequent formation of Shc/Grb2 complex were detected in breast cancer cells in which the p185 tyrosine kinase is activated, indicating that p66Shc is not required for mediating the HER-2/neu signaling pathway in breast cancer cells.
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PMID:p66Shc isoform down-regulated and not required for HER-2/neu signaling pathway in human breast cancer cell lines with HER-2/neu overexpression. 866 Mar 24

Previously we reported that neu differentiation factor (NDF)/heregulin (HRG) elevates tyrosine phosphorylation of its receptors erbB-3, erbB-4, and erbB-2 (through heterodimer formation). We also showed that both NDF/HRG and antibodies to erbB-2 can arrest growth and induce differentiation in breast cancer cells. In this study, we report on the mechanism of NDF/HRG-induced cellular effects. We show that NDF/HRG and antibodies to erbB-2 receptors up-regulate expression of p53 by stabilizing the protein. This is accompanied by up-regulation of the p53 inducible gene, p21CIP1/WAF1, in a variety of cell lines: MCF7 and their derivatives (MCF7/HER2, MN1 and MCF-7-puro), ZR75T and LnCap cells. The induction of p21 is further enhanced when cells are treated with both NDF/HRG and DNA-damaging chemotherapeutic agents (i.e. doxorubicin). The NDF/HRG mediated induction of p21 is dependent on wildtype p53, as it fails to occur in cells expressing dominant negative p53 (MDD2). Furthermore, p21 induction is capable of inactivating cdk2 complexes as measured by Histone H1 phosphorylation assays. Finally, we show that in primary cultures of breast and other cancers, p21 is significantly induced in response to NDF/HRG treatment. Collectively, these observations suggest that the mechanism of breast cancer cell growth inhibition and differentiation via erbB receptors activation is through a p53-mediated pathway.
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PMID:Neu differentiation factor (Heregulin) activates a p53-dependent pathway in cancer cells. 870 May 12

The overexpression of the erbB-2 (HER-2, neu) gene has attracted significant interest as a molecular target for the rational design of cancer therapies. This review examines the design and preclinical testing phase for one such experimental therapy, recombinant toxins targeted to the erbB-2 protein, termed e23(Fv)PEs.
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PMID:The performance of e23(Fv)PEs, recombinant toxins targeting the erbB-2 protein. 874 May 63

Overexpression of HER-2/neu in human breast carcinomas correlates with poor prognosis, although its strength as a prognostic indicator varies widely in different reports. Variability may be due to active signalling by HER-2/neu in a subset of the tumours in which it is overexpressed. To study this hypothesis, we have developed an activation state-specific anti-HER-2/neu monoclonal antibody. In this report, we use this antibody to analyse the signalling status of HER-2/neu in a large series of invasive breast carcinomas. Overexpression of HER-2/neu was detected in 9% of 223 cases. Of the cases demonstrating overexpression, active signalling by HER-2/neu was detected in only 35%. The clinicopathological characteristics of these cases are described. This functional assay is predicted to improve the utility of HER-2/ neu as a prognostic indicator.
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PMID:Functional assay for HER-2/neu demonstrates active signalling in a minority of HER-2/neu-overexpressing invasive human breast tumours. 879 85

The immunogenicity of the idiotypic portions of two antigrowth factor receptor monoclonal antibodies (MAbs) was studied. Immunisation of allogeneic but not syngeneic mice with antihuman epidermal growth factor receptor (EGF-R) MAb MINT5 or anti-HER-2/neu MGR6 MAb elicited a detectable titre of circulating antibodies, particularly when the MAb was coupled with the keyhole limpet haemocyanin and administered together with Freund's adjuvant. The anti-Ab1 response to MAb MINT5 was slightly delayed as compared with the response obtained with MAb MGR6 and was mainly directed to the variable regions. In both cases, all anti-Ab1-positive sera specifically competed with the binding of homologous radiolabelled Ab1 to the relevant EGF-R+ or HER-2/neu+ target cells. Fusion of splenocytes from MINT5-immunised animals failed to produce MAb, whereas cell fusion was successful in generating a paratope-related MAb in the case of MGR6. The anti-MGR6 MAb-produced IdM6.4 inhibited the binding of MAb MGR6 on breast carcinoma cells, suggesting that it recognises an idiotope in or near the antigen combining site, and can be considered useful in the identification and purification of the Ab1 or its derivatives. We analysed whether a possible recognition of murine EGF-R by MAb MINT5 or a mimicry of EGF by the MAb idiotype prevented or delayed the development of an idiotypic cascade in mice. MINT5 inhibited human and murine EGF binding to the human EGF-R, whereas the anti-Ab1 response competed with MINT5 but not with murine EGF binding to A431 human epidermoid carcinoma cells. Moreover, MINT5 did not recognise the murine EGF-R. In a phase I clinical study, no detectable levels of human antimouse antibody response were observed in 5 of the 6 treated cancer patients. The ability of MAb MINT5 to block human EGF-R function, together with its low immunogenicity in patients, raise the possibility of its application in carcinoma immunotherapy.
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PMID:Anti-idiotypic response to antigrowth factor receptor monoclonal antibodies. 881 98

The overexpression of two members of the erbB oncogene family-the epidermal growth factor receptor protein (EGF-R) and the HER-2/neu protein-in breast cancer has been investigated by numerous authors. Their exact role in breast cancer is still not defined. The simultaneous investigation of EGF-R and HER-2/neu in the same study population has only rarely been performed in breast cancer. Therefore, we analyzed the EGF-R and the HER-2/neu protein expression in 142 breast cancer specimens and 12 benign breast samples by immunohistochemistry. Results of the different expression analyses were compared with established clinicopathological parameters including estrogen and progesterone receptor status. In our study group EGF-R expression correlated with advanced tumor stage, axillary lymph node status and histological grade. HER-2/neu expression correlated with larger tumor size. Neither the evaluation of a single parameter of the erbB family nor the combination of both parameters showed a significant correlation with the disease-free and the overall survival of the individual patient with breast cancer. Only the expression of the progesterone receptor correlated with a better overall survival. Steroid hormone receptor expression and the expression of EGF-R and HER-2/ neu seem to be two independent phenomena in our samples of breast cancer. The simultaneous evaluation of EGF-R and HER-2/neu expression did not lead to new information of prognostic relevance.
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PMID:Expression analyses of epidermal growth factor receptor and HER-2/neu: no advantage of prediction of recurrence or survival in breast cancer patients. 896 Jan 38

We have developed an in vitro model to study mechanisms by which ovarian tumor cells that over-express the HER-2/neu proto-oncogene escape recognition by TCD8+. Nine tumor-specific, HLA A2-restricted TCD8+ clones were isolated from 2 ovarian tumor-specific TCD8+ lines derived from tumor-infiltrating or -associated lymphocytes. Of these, 2 clones recognized the previously defined HER-2/neu epitope E75 (a.a. 369-377) and one recognized the C85 epitope (a.a. 971-979), whereas the specificity of the remaining 6 clones was unknown. Three different tumor escape variants (EVC8, EVC22 and EVC36) were produced by co-culturing an ovarian tumor line over-expressing HER-2/neu with these autologous TCD8+ clones. Cell surface expression of HLA A2 was markedly decreased on all 3 escape variants, relative to the parental tumor line, while no significant decrease in their expression of the HER-2/neu, ICAM-1 or LFA-3 molecules was found. There was a correlation between the level of tumor-specific recognition and HLA A2 expression among the tumor clones isolated from 2 of the escape variants (EVC8 and EVC36). In contrast, high HLA A2-expressing tumor clones isolated from the EVC22 variant, or EVC22 which had regained high HLA A2 expression through IFN-gamma treatment, were not recognized by the HER-2/neu-specific TCD8+ clone C-22. No mutations were found in the cDNA or the genomic DNA derived from the PCR product corresponding to a 496 bp fragment including the region coding for the E75 epitope of the HER2/neu gene in the EVC22 variant. Collectively, this in vitro model underlines the importance of decreased expression of the HLA restriction element for escape from tumor-specific TCD8+ but also demonstrates that additional mechanisms exist.
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PMID:Mechanisms of escape from CD8+ T-cell clones specific for the HER-2/neu proto-oncogene expressed in ovarian carcinomas: related and unrelated to decreased MHC class 1 expression. 898 99

The HER-2/neu proto-oncogene encodes a 185 kDa transmembrane receptor tyrosine kinase with significant sequence homology to other members of the class I receptor tyrosine kinase family. The HER-2/neu gene is amplified and/or overexpressed in 25%-30% of human breast and ovarian cancers, and overexpression of the receptor is associated with poor prognosis. Tyrosine phosphorylation and activation of the HER-2 receptor lead to activation of specific signal transduction pathways in breast and ovarian cancer cells, including the ras/MAP kinase cascade, phosphatidylinositol 3-kinase, and phospholipase C-gamma. HER-2/neu signal transduction pathways ultimately converge on the cell nucleus, where the expression of diverse genes is induced after activation of the receptor. A more complete understanding of HER-2/neu signal transduction pathways may allow the development of specific therapeutics for the treatment of those human breast and ovarian cancers containing this alteration.
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PMID:HER-2/neu signal transduction in human breast and ovarian cancer. 900 17


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