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)

In this study, we developed a nonviral, cationic, targeted DNA-carrier system by coupling SAINT/DOPE lipids to monoclonal antibodies. The two monoclonal antibodies used were both tumor specific, that is, MOC31 recognizes the epithelial glycoprotein EGP-2 present in carcinomas and Herceptin recognizes the HER-2/neu protein in breast and ovarian cancers. Coupling was performed under nonreducing conditions by covalent attachment. The coupling procedure appeared to be reproducible and the binding capacity of the antibody was not affected by linking them to the cationic lipid. Binding and transfection efficiency was assayed with target cells and nontarget cells. SAINT/DOPE lipoplexes as such appeared to be an effective transfection reagent for various cell lines. After coupling SAINT/DOPE to the monoclonal antibodies or F(ab)2 fragments, it was shown that the targeted MoAb-SAINT/DOPE lipoplexes preferably bound to target cells, compared to binding to the nontarget cells, especially for the Herceptin-SAINT/DOPE lipoplexes. More importantly, transfection of the target cells could also be improved with these targeted lipoplexes. In conclusion, we have shown that by using monoclonal antibody-coupled SAINT/DOPE lipoplexes cells targeted gene delivery can be achieved, and also a higher number of transfected target cells was seen.
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PMID:A nonviral carrier for targeted gene delivery to tumor cells. 1469 57

The HER-2/neu oncogene, a member of the epidermal growth factor receptor or erb gene family, encodes a transmembrane tyrosine kinase receptor that has been linked to prognosis and response to therapy with the anti-HER-2-humanized monoclonal antibody, trastuzumab (Herceptin, Genentech, South San Francisco, CA) in patients with advanced metastatic breast cancer. HER-2/neu status has also been tested for its ability to predict the response of breast cancer to other therapies including hormonal therapies, topoisomerase inhibitors, and anthracyclines. This review includes an analysis of 80 published studies encompassing more than 25,000 patients designed to consider the relative advantages and disadvantages of the various methods of measuring HER-2/neu in clinical breast cancer specimens. Southern blotting, PCR amplification detection, and fluorescence in situ hybridization assays designed to detect HER-2/neu gene amplification are compared with HER-2/neu protein overexpression assays performed by immunohistochemical techniques applied to frozen and paraffin-embedded tissues and enzyme immunoassays performed on tumor cytosols. 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 role of HER-2/neu testing for the prediction of response to trastuzumab therapy in breast cancer is reviewed along with the current studies designed to test whether HER-2/neu status can predict the response to standard and newer hormonal therapies, cytotoxic chemotherapy, and radiation. The review will also evaluate the status of serum-based testing for circulating HER-2/neu receptor protein and its ability to predict disease outcome and therapy response.
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PMID:Targeted therapy in breast cancer: the HER-2/neu gene and protein. 1476 15

The majority of cancer cells derived from epithelial tissue express Lewis-Y (LeY) type difucosylated oligosaccharides on their plasma membrane. This results in the modification of cell surface receptors by the LeY antigen. We used the epidermal growth factor (EGF) receptor family members ErbB1 and ErbB2 as model systems to investigate whether the sugar moiety can be exploited to block signaling by growth factor receptors in human tumor cells (i.e., SKBR-3 and A431, derived from a breast cancer and a vulval carcinoma, respectively). The monoclonal anti-LeY antibody ABL364 and its humanized version IGN311 immunoprecipitated ErbB1 and ErbB2 from detergent lysates of A431 and SKBR-3, respectively. ABL364 and IGN311 blocked EGF- and heregulin-stimulated phosphorylation of mitogen-activated protein kinase [MAPK = extracellular signal-regulated kinase 1/2] in SKBR-3 and A431 cells. The effect was comparable in magnitude with that of trastuzumab (Herceptin) and apparently noncompetitive with respect to EGF. Stimulation of MAPK by ErbB was dynamin dependent and contingent on receptor internalization. ABL364 and IGN311 changed the intracellular localization of fluorescent EGF-containing endosomes and accelerated recycling of intracellular [(125)I]EGF to the plasma membrane. Taken together, these observations show that antibodies directed against carbohydrate side chains of ErbB receptors are capable of inhibiting ErbB-mediated signaling. The ability of these antibodies to reroute receptor trafficking provides a mechanistic explanation for their inhibitory action.
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PMID:Antibodies directed against Lewis-Y antigen inhibit signaling of Lewis-Y modified ErbB receptors. 1487 42

c-erbB-2, proto-oncogene is amplified and overexpressed in a number of human adenocarcinomas. Overexpression of c-erbB-2 is indicated as a worse prognostic factor and associated with neoplastic progression in various organs. To investigate the therapeutic effect of Trastuzumab in gallbladder cancer, we studied HER-2/neu expression in 43 primary tumors, 12 metastatic lymph nodes and two liver metastasis, using the Hercep test. Among primary tumors, strong (3+) immunohistochemical intensity was found in two cases (4.7%), weak (2+) in two (4.7%) and negative (1+) (2.3%) in one case. This positivity rate was distinctly lower than those in previous reports. There was no tendency between clinicopathologic characteristics and HER-2 positivity in the primary gallbladder. Among 12 metastatic lymph nodes, only one specimen showed 2+ positivity where the primary lesion revealed 3+ intensity of HER-2. In two liver metastatic lesions, the expression of HER-2 was not found. Our study implied that Trastzumab may not contribute to improvement in treatment of gallbladder cancer. However, there may be a therapeutic possibility for cases with lymph node recurrence overexpressing c-erbB-2.
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PMID:Gallbladder cancers rarely overexpress HER-2/neu, demonstrated by Hercep test. 1501 Aug 78

The use of charged linkers in attaching radiohalogens to tumor-seeking biomolecules may improve intracellular retention of the radioactive label after internalization and degradation of targeting proteins. Derivatives of polyhedral boron clusters, such as closo-dodecaborate (2-) anion, might be possible charged linkers. In this study, a bifunctional derivative of closo-dodecaborate, (4-isothiocyanatobenzyl-ammonio)-undecahydro-closo-dodecaborate (DABI) was labeled with positron-emitting nuclide (76)Br (T 1/2 = 16.2 h) and coupled to anti-HER2/neu humanized antibody Trastuzumab. The overall labeling yield at optimized conditions was 80.7 +/- 0.6%. The label was proven to be stable in vitro in physiological and a set of denaturing conditions. The labeled antibody retained its capacity to bind to HER-2/neu antigen expressing cells. The results of the study demonstrated feasibility for using derivatives of closo-dodecaborate in indirect labeling of antibodies for radioimmunoPET.
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PMID:Radiobromination of monoclonal antibody using potassium [76Br] (4 isothiocyanatobenzyl-ammonio)-bromo-decahydro-closo-dodecaborate (Bromo-DABI). 1501 86

Overexpression of HER-2/neu in breast cancer has been associated with more aggressive disease and poor overall survival. Trastuzumab, a recombinant humanized monoclonal antibody with high affinity for the HER-2 protein, inhibits the growth of breast cancer cells overexpressing HER-2. Trastuzumab showed, as second-line treatment, 15% of objective response in metastatic breast cancer. Bone marrow metastases are detectable in 23% of the patients with advanced breast cancer at first relapse and this rate increases in patients with metastatic disease. We report a case of a complete response of bone marrow metastases from breast cancer using a 3-weekly trastuzumab schedule, in a heavily pretreated patient with severe symptomatic pancytopenia.
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PMID:Complete response of severe symptomatic bone marrow metastases from heavily pretreated breast cancer with a 3-weekly trastuzumab schedule. A clinical case. 1501 14

The aim of our study was to determine whether or not the tyrosine kinase receptor, HER2 (also known as ErbB2/Her2/neu), is overexpressed in human osteosarcomas (OS). We studied 15 biopsy and 18 resection specimens at the mRNA and protein levels. HER2 status in the OS specimens was assessed by immunohistochemistry (IHC) and quantitative Real-Time Polymerase chain reaction (PCR). In moderately immunopositive cases fluorescent in situ hybridisation (FISH) analysis was used in order to identify any possible gene amplification. 27 samples were evaluable for IHC and only 1 case showed a moderately positive membrane staining. The remaining samples showed no staining or focal cytoplasmic staining (2 samples). In the moderately positive case, FISH analysis showed no HER-2 gene amplification. There was also no overexpression of HER2 mRNA suggesting this sample was a false-positive immunostain. HER2 mRNA expression was present in all samples at a similar level to that in the breast cancer cell line, MCF7, which does not overexpress HER2 and was used as a negative control. In conclusion, this study shows that HER2 mRNA or membranous HER2 protein overexpression is absent in human OS. We noted various inconsistencies in previous published studies, with regard to methodology and the interpretation of the results based on poor methodology. We therefore conclude that the positive data with regard to HER2 overexpression reported in these previous studies is not reliable. Our results suggest that the monoclonal antibody trastuzumab (Herceptin(R)), directed against the HER2-receptor, is not likely to be an effective therapeutic agent in OS.
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PMID:Overexpression of the HER-2 oncogene does not play a role in high-grade osteosarcomas. 1509 66

A series of novel nonviral vectors targeting the HER-2/neu gene product human epidermal growth factor receptor-2 (HER2) were constructed and evaluated in breast cancer cell lines to optimize vector formulation for receptor-specific gene transfer. These vectors were DNA/polycation complexes (polyplexes) prepared by mixing, at varying ratios, plasmid DNA carrying a luciferase reporter gene to HerPEI, which is a conjugate of linear polyethylenimine (PEI), a cationic polymer, and trastuzumab (Herceptin), a HER2-specific monoclonal antibody. Transfection studies were carried out in both HER2 overexpressing Sk-Br-3 and HER2 low-expressing MDA-MB-231 breast cancer cells. The HerPEI polyplexes showed significantly greater transfection activity up to 20-folds than nonderivatized PEI-based polyplexes in the Sk-Br-3 cells. The transfection efficiency of targeted polyplexes was dependent on the trastuzumab:PEI ratio and can be blocked by excess free trastuzumab, suggesting HER2-mediated gene delivery. In contrast, no significant difference in transfection activities was observed between HER2-targeted and nontargeted polyplexes in the HER2 low-expressing MDA-MB-231 cells. The transfection efficiency of HerPEI polyplexes was retained in serum-containing medium. In summary, HerPEI polyplexes have shown promising HER2 receptor-specific gene transfer properties and warrant further evaluation as a tumor-targeted vector for gene therapy.
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PMID:Tumor-targeted gene delivery via anti-HER2 antibody (trastuzumab, Herceptin) conjugated polyethylenimine. 1519 62

Human papillomavirus (HPV) type 16 is causally associated with a subset of oral cancers, predominantly those cancers arising in the oropharynx (OP). Increased HPV16 E6 and E7 oncogene expressions are responsible for the malignant transmission in these cancers. ErbB-2 is the family member most closely implicated in human cancer, where it is overexpressed in about 30% of carcinomas including head and neck squamous cell carcinoma. Coexpressions of E6/E7 and ErbB-2 downregulate E-cadherin and catenin expression, therefore induces metastatic process. Trastuzumab is a humanized monoclonal antibody that recognizes the ErbB-2 protein receptor and breakthrough in the treatment of metastatic breast cancer in combination with chemotherapeutic agents. This antibody is also in clinical testing for adjuvant treatment of breast cancer. We propose that trastuzumab as an adjuvant treatment may decrease process of tumor metastasis in oropharyngeal cancer patients who completed primary treatment (surgery and/or radiotherapy) and show expression of both HPV16 E6/E7 and erbB-2 oncoproteins. In vitro and in vivo studies with trastuzumab in these subgroup of patients may support our hypothesis.
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PMID:Adjuvant targeted therapy with trastuzumab may decrease metastatic capacity in specific group of oropharyngeal cancer patients: downregulation of E-cadherin-catenin complex by cooperative effect of erbB-2 and human papillomavirus type 16 E6/E7 protooncogenes. 1523 90

HER2 overexpression has been associated with anti-estrogen resistance in human breast cancer, and it has been suggested that the combined treatment of an anti-HER2 antibody plus tamoxifen has enhanced anti-cancer efficacy in breast cancer. The detailed anti-proliferative interactions between trastuzumab and tamoxifen were analyzed with the isobologram and Chou and Talalay methods, which assess the presence of synergy, addition or antagonism. We used the breast cancer cell lines that are estrogen receptor (ER)-positive and HER2-positive. We also analyzed the molecular changes on the HER2 and (ER) signaling pathways that are induced by trastuzumab plus tamoxifen. In terms of cancer cell proliferation, the simultaneous combination of trastuzumab and tamoxifen on BT-474 cells was more growth inhibitory (44%) than the treatment with trastuzumab (24%) or tamoxifen (31%) alone. Isobologram analysis of simultaneous trastuzumab plus tamoxifen exposure showed, however, that there were antagonistic interactions at an effect level of 30% (IC30). Using Chou and Talalay analysis we also observed antagonistic interactions at lower levels of cell kill, although there were additive effects at highest levels of cell kill. Trastuzumab followed by tamoxifen showed antagonism at all effects levels. Tamoxifen followed by trastuzumab showed antagonism at lower levels of cell kill, and additivity at higher levels of cell kill. Similar interactions were observed using T47D cells. The molecular effects of the combined treatment with trastuzumab plus tamoxifen on the levels of HER2 and ER signaling showed that, with respect to HER2 protein levels, trastuzumab downregulated HER2 by 27%, tamoxifen upregulated HER2 by 40%, and the combination of trastuzumab plus tamoxifen did not induce changes in HER2 respect to control. With respect to HER2 mRNA, trastuzumab upregulated HER2 mRNA to 367%, tamoxifen to 166%, and the combination to 401%. With respect to HER2 phosphorylation, trastuzumab upregulated HER2 phosphorylation to 352%, tamoxifen to 202% and the combination to 633%. Epidermal growth factor receptor levels were not changed by trastuzumab or tamoxifen alone, and were upregulated to 138% by the combination. The protein levels and activity of extracellular recptor kinase were not modified by trastuzumab, tamoxifen or the combination. Finally, estrogen receptor protein and mRNA levels were downregulated to about 50% by trastuzumab, tamoxifen or the combination. Taken together, our results show that in ER-positive breast cancer cells overexpressing HER2, trastuzumab plus tamoxifen have antagonistic interactions when used in combination, and that this antagonism may be related with an increase in HER2 signaling pathways that occurs when tamoxifen is added to trastuzumab.
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PMID:Trastuzumab plus tamoxifen: anti-proliferative and molecular interactions in breast carcinoma. 1531 65


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