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)

The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with extensive homology to the epidermal growth factor receptor. HER-2/neu has been widely studied in breast cancer. The potential value of HER-2/neu status for the prediction of disease outcome and response to therapy in breast cancer is presented in the light of a series of recently published studies showing a range of impact on the outcome of patients treated with hormonal, cytotoxic and radiation therapies. This review includes the application of serum-based HER-2/neu testing and the use of antibody-based therapies directed against the HER-2/neu protein and their potential to become a new modality for breast cancer treatment.
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PMID:The HER-2/neu oncogene: prognostic factor, predictive factor and target for therapy. 1020 34

The receptors erbB-3 and erbB-4 are members of the type 1 tyrosine kinase receptor family which also comprises epidermal growth factor receptor (EGF-R) and erbB-2. ErbB-3 and erbB-4 receptors are known to bind a family of related proteins termed heregulins. In this study, we report differential expression of P185erbB-2, P160erbB-3 and P180erbB-4, and their ligand heregulin alpha, in normal bronchial epithelial, and non-small cell lung carcinoma (NSCLC) cell lines. Expression of P185erbB-2 and P160erbB-3 vary from very low to a high level in NSCLC cell lines and a low level in normal bronchial cells. In contrast, P180erbB-4 was detected only in NSCLC cell lines but not in normal bronchial cells. Heregulin alpha is expressed at intermediate levels in the normal and cancer cell lines studied. Immunoprecipitation, using antibodies to erbB-2, erbB-3 or erbB-4 receptors, coupled to phosphotyrosine Western blot analysis indicates that these three receptors are constitutively tyrosine phosphorylated in lung cancer cell lines, but only erbB-2 and erbB-3 are autophosphorylated in normal cells. These data suggest that constitutive activation of erbB-2, erbB-3 and erbB-4 receptors could be induced by heregulin alpha via an autocrine loop mechanism, and that the active forms of erbB-4 may cooperate with the other members of the EGF-receptor family in human lung carcinogenesis.
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PMID:Expression of P185erbB-2, P160erbB-3, P180erbB-4, and heregulin alpha in human normal bronchial epithelial and lung cancer cell lines. 1022 86

The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with extensive homology to the epidermal growth factor receptor. HER-2/neu has been widely studied in breast cancer. In this review, the association of HER-2/neu gene and protein abnormalities studied by Southern and slot blotting, immunohistochemistry, enzyme immunoassays, and fluorescence in situ hybridization with prognosis in breast cancer is studied in depth by review of a series of 47 published studies encompassing more than 15,000 patients. The relative advantages of gene amplification assays and frozen/fresh tissue immunohistochemistry over paraffin section immunohistochemistry are discussed. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The potential value of HER-2/neu status for the prediction of response to therapy in breast cancer is presented in the light of a series of recently published studies showing a range of impact on the outcome of patients treated with hormonal, cytotoxic, and radiation therapies. The evidence that HER-2/neu gene and protein abnormalities in breast cancer predict resistance to tamoxifen therapy and relative sensitivity to chemotherapy regimens including adriamycin is presented. The review will also evaluate the status of serum-based testing for circulating the HER-2/neu receptor protein and its ability to predict disease outcome and therapy response. In the final section, the review will briefly present preliminary data concerning the use of antibody-based therapies directed against the HER-2/neu protein and their potential to become a new modality for breast cancer treatment. The recently presented phase III clinical trial evidence that systemic administration of anti-HER2 antibodies (Herceptin®), alone and in combination with cytotoxic chemotherapy in patients with HER-2/neu overexpressing primary tumors, can increase the time to recurrence and overall response rates in metastatic breast cancer is reviewed.
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PMID:The HER-2/neu Oncogene in Breast Cancer: Prognostic Factor, Predictive Factor, and Target for Therapy. 1038 10

The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with extensive homology to the epidermal growth factor receptor. The association of HER-2/neu gene and protein abnormalities with prognosis in breast cancer is presented by considering a series of 52 published studies including more than 16,000 patients. The relative advantages and disadvantages of Southern blot testing, polymerase chain reaction amplification, and fluorescence in situ hybridization assays designed to detect HER-2/neu gene amplification are compared with HER-2/neu protein overexpression assays performed with immunohistochemical techniques applied to frozen and paraffin-embedded tissues and enzyme immunoassays performed on tumor cytosols. The importance of HER-2/neu protein overexpression in ductal carcinoma in situ, and HER-2/neu protein status in uncommon breast diseases in female patients and breast cancer in male patients are also considered. The potential value of HER-2/neu protein status for the prediction of response to therapy in breast cancer is presented for standard hormonal therapy, cytotoxic chemotherapy, and radiation therapy. Also evaluated is the status of serum-based testing for circulating HER-2/neu receptor protein and its ability to predict disease outcome and therapy response. Finally, preliminary data concerning use of antibody-based therapies directed against HER-2/neu protein and their potential use in breast cancer treatment are considered.
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PMID:HER-2/neu (c-erb-B2) gene and protein in breast cancer. 1039 1

The neu (c-erbB-2) proto-oncogene encodes a tyrosine kinase receptor that is overexpressed in 20 to 30% of human breast tumors. Herein, cyclin D1 protein levels were increased in mammary tumors induced by overexpression of wild-type Neu or activating mutants of Neu in transgenic mice and in MCF7 cells overexpressing transforming Neu. Analyses of 12 Neu mutants in MCF7 cells indicated important roles for specific C-terminal autophosphorylation sites and the extracellular domain in cyclin D1 promoter activation. Induction of cyclin D1 by NeuT involved Ras, Rac, Rho, extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38, but not phosphatidylinositol 3-kinase. NeuT induction of the cyclin D1 promoter required the E2F and Sp1 DNA binding sites and was inhibited by dominant negative E2F-1 or DP-1. Neu-induced transformation was inhibited by a cyclin D1 antisense or dominant negative E2F-1 construct in Rat-1 cells. Growth of NeuT-transformed mammary adenocarcinoma cells in nude mice was blocked by the cyclin D1 antisense construct. These results demonstrate that E2F-1 mediates a Neu-signaling cascade to cyclin D1 and identify cyclin D1 as a critical downstream target of neu-induced transformation.
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PMID:Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. 1061 Dec 46

Overexpression of the c-erbB-2/HER-2/neu protooncogene which encodes for the tyrosine kinase receptor p185neu, has been observed frequently in cisplatin resistant human tumors, such as colorectal, breast, and non-small-cell lung cancers, and is known to induce resistance to cisplatin (CDDP) in vitro. To confirm a direct relationship between erbB-2 expression and CDDP resistance, we examined the role of erbB-2 in the cellular sensitivity to cisplatin using erbB-2 transfected HAG-1 human gallbladder adenocarcinoma cell lines. Three out of four cell lines, which stably expressed ErbB-2 protein (p185neu), did not show CDDP resistance but acquired sensitivity to cisplatin, compared to non-transfected cells. This chemosensitivity appears to be inversely correlated with the abundance of p185neu. Although the mechanism still remains unclear, these results suggest that sensitivity to CDDP in erbB-2 expressed cells may vary, depending on the cell type.
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PMID:Expression of activated c-erbB-2 oncogene induces sensitivity to cisplatin in human gallbladder adenocarcinoma cells. 1069 35

Epidermal growth factor (EGF) stimulates the growth of various types of cells via its cell surface tyrosine kinase receptor. The EGF receptor (EGF-R) has an oncogenic potential when overexpressed in a wide range of tumor cells. Geldanamycin (GA) and herbimycin (HA), specific inhibitors of the cytosolic chaperone HSP 90 and its endoplasmic reticulum homologue GRP 94, were shown to accelerate degradation of the EGF-R and of its homologue p185(c-)(erbB-2). Here we compared the effects of GA and HA on intracellular degradation and maturation of EGF-R. By using an inhibitor of proteasomal degradation, we learned that GA, but not HA, blocks processing of newly synthesized EGF-R. The effects of GA and HA on receptor degradation are mediated by the cytosolic portion of EGF-R and could be conferred to the erythropoietin receptor (EPO-R), by employing the respective chimera. Neither HA nor GA affected stability of newly synthesized EGF-R lacking the cytosolic domain (Ex EGF-R), but GA caused intracellular retention of this mutant. Taken together, our results imply that GA has two distinct targets of action on the EGF-R, one for promoting its degradation and another for mediating its intracellular retention. Apparently, degradation of the EGF-R mediated by GA or HA requires the presence of the EGF-R cytosolic domain, whereas intracellular retention in the presence of GA is coupled to the extracellular domain of the EGF-R.
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PMID:Intracellular retention and degradation of the epidermal growth factor receptor, two distinct processes mediated by benzoquinone ansamycins. 1080

The c-erbB-2 proto-oncogene encodes a transmembrane protein tyrosine kinase receptor of 185 kDa (p185) and has been associated with several types of human cancers. In human breast cancer, overexpression of p185 occurs in 15-30% of cases, correlates with poor prognostic factors and characterizes breast cancers with a more aggressive behavior. Overexpression of p185 is usually associated with c-erbB-2 amplification, though it may occur independently and thus define subpopulations of breast cancers which might be of clinical interest. p185 expression is usually detected by immunohistochemistry (IHC) and few studies have been carried out to evaluate the p185 content of breast cancers with an ELISA technique. In this context, we showed, in 106 breast cancer samples, that p185 was expressed at high levels in 13.2%, intermediate levels in 55.7% and negative ones in 31.1% of cases. All p185 positive samples showed a c-erbB-2 oncogene amplification while none of the p185 negative samples and only 4% of p185 imtermediate samples had an amplification of c-erbB-2. p185 expression is significantly correlated with the negativity of estrogen and progestrone receptors, with high levels of cathepsin D and in some conditions with axillary nodal involvement. Thus, using the p185 ELISA assay, the c-erbB-2 status of breast cancers can be defined and moreover a subset can be discriminated which is characterized by intermediate levels of p185 and absence of c-erbB-2 amplification. The quantitative approach towards p185 in breast cancers affords the possibility of identifying more appropriately patients with high or low risk and thus permits adaptation of therapeutic regimens.
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PMID:Relevance of p185 HER-2/neu oncoprotein quantification in human primary breast carcinoma. 1109 92

The G protein-coupled thrombin receptor can induce cellular responses in some systems by transactivating the epidermal growth factor (EGF) receptor. This is in part due to the stimulation of ectoproteases that generate EGF receptor ligands. We show here that this cannot account for the stimulation of proliferation or migration by thrombin of Swiss 3T3 cells. Thrombin has no direct effect on the activation state of the EGF receptor or of its downstream effectors. However, thrombin induces the subcellular clustering of the EGF receptor at filamentous actin-containing structures at the leading edge and actin arcs of migrating cells in association with other signaling molecules, including Shc and phospholipase Cgamma1. In these thrombin-primed cells, the subsequent migratory response to EGF is potentiated. Thrombin did not potentiate the EGF-stimulated EGF receptor phosphorylation. Thus, in Swiss 3T3 cells the G protein-coupled thrombin receptor can potentiate the EGF tyrosine kinase receptor response when activated by EGF, and this appears to be due to the subcellular concentration of the receptor with downstream effectors and not to the overall ability of EGF to induce receptor transphosphorylation. Thus, the EGF receptor subcellular localization which is altered by thrombin appears to be an important determinant of the efficacy of downstream EGF receptor signaling in cell migration.
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PMID:Activation of endogenous thrombin receptors causes clustering and sensitization of epidermal growth factor receptors of swiss 3T3 cells without transactivation. 1126 44

Described herein is the design and synthesis of indazolylaminopyridopyrimidines and quinazolines as inhibitors of the class 1 tyrosine kinase receptor family. Data is presented for N(4)-(1-benzyl-1H-indazol-5-yl)-N(6),N(6)-dimethylpyrido[3,4-d]pyrimidine-4,6-diamine 3B. This compound inhibited EGFr and c-erbB-2 enzymes selectively over other kinases. It inhibited the proliferation of a range of tumour cell lines in vitro and the growth of BT474 xenografts in SCID mice.
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PMID:Indazolylamino quinazolines and pyridopyrimidines as inhibitors of the EGFr and C-erbB-2. 1137 64


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