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)

Amplification of HER-2(erbB-2/neu) oncogene was detected in 36 of 142 (25%) breast carcinomas (BC) RNA expression was examined in 42 carcinomas, in 10 of them overexpression was revealed. Amplification was matched by overexpression. No association was found between the increased number of HER-2(erbB-2/neu) copies and tumor size, lymph node involvement, stage of disease, age of onset, and estrogen and progesterone receptor level. HER-2(erbB-2/neu) amplification was shown to be of independent prognostic significance in the group of 32 BC patients with sufficient follow-up (more than 40 months). Six of 7 HER-2(erbB-2/neu) amplification-positive patients and only 2 of 25 HER-2(erbB-2/neu) amplification-negative ones relapsed (p < 0.00005).
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PMID:Amplification of HER-2(erbB-2/neu) oncogene as the most significant prognostic factor in a group of Russian breast cancer patients. 768 67

The HER4/erbB-4 gene has been isolated as the fourth member of the human EGFR subfamily of tyrosine kinases and has been reported to encode a receptor for NDF/heregulin. In the present study we determined the chromosomal location of the HER4/erbB-4 gene within the human genome. Using human cDNA probes in fluorescence in situ hybridization (FISH), we mapped the HER4/erbB-4 gene to human chromosome 2q33.3-34. This finding established that also the HER4/erbB-4 gene is located in close vicinity of homeobox and collagen gene loci, as is the case for the related EGFR, erbB-2/neu and erbB-3. Aberrations of this chromosomal region associated with T cell leukemias and lymphomas as well as alveolar rhabdomyosarcomas raise the possibility that HER4/erbB-4 might be activated in these tumour types.
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PMID:Localization of the human HER4/erbB-4 gene to chromosome 2. 770 Jun 49

Amplification and overexpression of the erbB-2/neu protooncogene are frequently associated with aggressive clinical course of certain human adenocarcinomas, and therefore the encoded surface glycoprotein is considered a candidate target for immunotherapy. We previously generated a series of anti-ErbB-2 monoclonal antibodies (mAbs) that either accelerate or inhibit the tumorigenic growth of erbB-2-transformed murine fibroblasts. The present study extended this observation to a human tumor cell line grown as xenografts in athymic mice and addressed the biochemical differences between the two classes of mAbs. We show that the inhibitory effect is dominant in an antibody mixture, and it depends on antibody bivalency. By using radiolabeled mAbs we found that all of three tumor-inhibitory mAbs became rapidly inaccessible to acid treatment when incubated with tumor cells. However, a tumor-stimulatory mAb remained accessible to extracellular treatments, indicating that it did not undergo endocytosis. In addition, intracellular fragments of the inhibitory mAbs, but not of the stimulatory mAb, were observed. Electron microscopy of colloidal gold-antibody conjugates confirmed the absence of endocytosis of the stimulatory mAb but detected endocytic vesicles containing an inhibitory mAb. We conclude that acceleration of cell growth by ErbB-2 correlates with cell surface localization, whereas inhibition of tumor growth is associated with an intrinsic ability of anti-ErbB-2 mAbs to induce endocytosis. These conclusions are relevant to the selection of optimal mAbs for immunotherapy and may have implications for the mechanism of cellular transformation by an overexpressed erbB-2 gene.
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PMID:Suppression and promotion of tumor growth by monoclonal antibodies to ErbB-2 differentially correlate with cellular uptake. 772 65

Amplification of the neu/erbB-2/HER-2 gene and/or overexpression of its receptor tyrosine kinase product, p185neu/erbB-2 (p185), occurs in 15-40% of primary human breast tumors and is variably correlated with poor patient prognosis. Variability in predictive accuracy likely results from activation of p185 by agonist(s) in only a subset of tumors in which it is overexpressed, which may greatly affect outcomes. As a first step toward evaluating this hypothesis, we previously produced a polyclonal antibody that specifically recognizes the activated, tyrosine-phosphorylated forms of p185 and the closely related epidermal growth factor receptor (L. Bangalore et al., Proc. Natl. Acad. Sci. USA, 89: 11637-11641, 1992). We now describe the production of a mAb, PN2A, that specifically recognizes tyrosine-phosphorylated p185 and bears no cross-reactivity with closely related receptors. Furthermore, we demonstrate its reactivity in immunohistochemical staining of paraffin-embedded, formalin-fixed tumor samples. In a series of five p185-overexpressing human tumors examined thus far, PN2A reactivity was detected in two, indicating that p185 is phosphorylated and hence actively signaling in a subset. This reagent will facilitate both clinical and research analyses of p185 activity. Furthermore, this work serves as a prototype for similar analyses of other tyrosine phosphoproteins.
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PMID:Activation state-specific monoclonal antibody detects tyrosine phosphorylated p185neu/erbB-2 in a subset of human breast tumors overexpressing this receptor. 772 65

The overexpression of the growth factor receptor p185neu/c-erbB-2 has been observed in a number of human adenocarcinomas and is mechanistically linked to neoplastic growth. Monoclonal antibodies raised against extracellular domains of the p185neu/c-erbB-2 receptor oncoprotein have been utilized to inhibit the pathway of neu-induced tumor development. Our laboratory has demonstrated a direct effect of anti-p185neu/c-erbB-2 antibodies which requires receptor ligation. This induced aggregation causes the downmodulation of cell-surface expression and eventual degradation of p185neu/c-erbB-2 protein. In cells transformed by the neu oncogene, the result of antibody-induced p185neu/c-erbB-2 receptor modulation is the reversion of the malignant phenotype. We are exploiting the direct efficacy of this monoclonal antibody by developing small molecules (peptides and organic mimietics) based on anti-p185neu/c-erbB-2 antibody structure that can mediate similar receptor binding and biological effects.
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PMID:Biological studies and potential therapeutic applications of monoclonal antibodies and small molecules reactive with the neu/c-erbB-2 protein. 773 25

Recently, a family of growth factors has been described that activates erbB-2 receptors. These factors, known as the neu differentiation factors (NDF) or heregulins (HRG), induce tyrosine phosphorylation of erbB-2 receptors as a result of their direct interaction with either erbB-3 or erbB-4 receptors. Although it is known that expression of erbB-2 receptors has relevance in human breast cancer progression, how erbB-2, -3 and -4 receptors regulate mammary epithelial cell proliferation is not known. Therefore, experiments were carried out to study the mitogenic activity of NDF/HRG on the human mammary epithelial cell line MCF-10A which can be cultured continuously under serum-free conditions. MCF-10A cells, like primary cultures of normal human mammary epithelial cells, express an absolute requirement for exogenous epidermal growth factor (EGF) and insulinlike growth factor I (IGF-I) for growth. The results of these experiments indicate that NDF/HRG can induce tyrosine phosphorylation of p185erbB-2 in MCF-10A cells and is mitogenic for these cells. This is consistent with the coexpression of erbB-2 and erbB-3 mRNA that we have observed in MCF-10A cells. In addition, we found that NDF/HRG can substitute for either EGF or IGF-I to stimulate proliferation of these cells. The ability to substitute for both EGF and IGF-I is a unique property of NDF/HRG and is not shared by other members of the EGF or IGF family of growth factors, nor by other factors that we have studied. A striking isoform specificity was also observed which indicated that the beta-isoforms of NDF/HRG were greater than ten times more mitogenic than the alpha-isoforms. We also examined the mitogenic activity of NDF/HRG on MCF-10A cells that overexpress the erbB-2 receptor as a result of infection with a retroviral vector containing the human c-erbB-2 gene (MCF-10AerbB-2 cells). These studies indicated that MCF-10AerbB-2 cells have increased sensitivity to the mitogenic effects of NDF/HRG and that these cells are responsive to the alpha-isoforms of NDF/HRG at physiological concentrations. Thus, NDF/HRG is a dual specificity growth factor for human mammary epithelial cells, and the responsiveness of the cells to NDF/HRG is influenced by the level of expression of erbB-2 receptors.
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PMID:Mitogenic activity of neu differentiation factor/heregulin mimics that of epidermal growth factor and insulin-like growth factor-I in human mammary epithelial cells. 777 1

The human c-erbB-2 oncogene is homologous to the rat neu oncogene, both encoding transmembrane growth factor receptors. Overexpression and point mutations in the transmembrane domain of the encoded proteins in both cases have been implicated in cell transformation and carcinogenesis. In the case of the neu protein, it has been proposed that these effects are mediated by conformational preferences for an alpha-helix in the transmembrane domain, which facilitates receptor dimerization, an important step in the signal transduction process. To examine whether this is the case for c-erbB-2 as well, we have used conformational energy analysis to determine the preferred three-dimensional structures for the transmembrane domain of the c-erbB-2 protein from residues 650 to 668 with Val (nontransforming) and Glu (transforming) at position 659. The global minimum energy conformation for the Val-659 peptide from the normal, nontransforming protein was found to contain several bends, whereas the global minimum energy conformation for Glu-659 peptide from the mutant, transforming protein was found to be alpha-helical. Thus, the difference in conformational preferences for these transmembrane domains may explain the difference in transforming ability of these proteins. The presence of higher-energy alpha-helical conformations for the transmembrane domain from the normal Val-659 protein may provide an explanation for the presence of a transforming effect from overexpression of c-erbB-2. In addition, docking of the oncogenic sequences in their alpha-helical and bend conformations shows that the all-alpha-helical dimer is clearly favored energetically over the bend dimer.
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PMID:Conformation of the transmembrane domain of the c-erbB-2 oncogene-encoded protein in its monomeric and dimeric states. 777 61

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

Shc is a ubiquitously expressed Src homology 2 (SH2) domain protein that can transform fibroblasts and differentiate PC12 cells in a Ras-dependent fashion. Shc binds a variety of tyrosine-phosphorylated growth factor receptors presumably via its carboxyl-terminal SH2 domain. We cloned a fragment of Shc when screening a bacterial expression library with tyrosine-phosphorylated epidermal growth factor (EGF) receptor. Surprisingly, this fragment encodes the amino terminus of Shc, a region that has no significant similarity to an SH2 domain. When expressed as a glutathione S-transferase fusion protein, this amino-terminal domain binds to autophosphorylated EGF receptor, as well as HER2/neu and TrkA receptors. This fragment acts like an SH2 domain in that it does not bind non-phosphorylated EGF receptor or EGF receptor with all tyrosine phosphorylation sites mutated or deleted. Our data define a novel domain in Shc that has the potential to interact with growth factor receptors and other tyrosine-phosphorylated proteins.
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PMID:A region in Shc distinct from the SH2 domain can bind tyrosine-phosphorylated growth factor receptors. 779 94

The c-erbB-2 (HER-2, neu) oncogene has been implicated frequently in many human tumors. This oncogene codes for a 185-kDa protein that functions as a transmembrane growth factor receptor. Overexpression of the normal protein or point mutations in the transmembrane domain of the protein have been shown to have a transforming effect. Molecular structure studies of the transmembrane domain provide a plausible explanation for this transforming effect in both cases and relate this to the process of receptor dimerization in the membrane, degradation of the protein with release of the extracellular domain (ECD) into the extracellular environment, and aberrant signal transduction. The release of the ECD into the extracellular environment provides a potential biomarker for the study of signal transduction at the molecular level in vivo. The ECD can be quantitated immunologically in the serum of individuals with cancers associated with p185 overexpression and in individuals at risk for the development of such cancers and can be used to distinguish these individuals from normal, healthy controls. Identification of such individuals by their serum ECD levels combined with specific chemotherapeutic/chemoprophylactic interventions could allow for improvement treatment and prevention of c-erbB-2-related cancers.
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PMID:The c-erbB-2 protein in oncogenesis: molecular structure to molecular epidemiology. 784 90


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