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 the past 15 years, substantial progress has been made in the treatment of breast cancer, but management of women with breast cancer is still not curative in many patients. One important goal of new treatment strategies is that of defining criteria to specifically indicate therapies so that therapeutic benefit will no longer result from the indiscriminate application of treatment to all patients within a broad category of risk. This approach could be applied to paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). The taxane is one of the most active new drugs developed for women with breast cancer. A number of conventional comparative trials are ongoing to assess its role in different stages of the disease. Some of its features, however, are suitable to explore more specific and relevant questions. Possibly because of paclitaxel's documented antiangiogenic properties, its high efficacy in combination could also provide an as yet unproven survival advantage in advanced breast cancer, with the drug being administered for adequately prolonged periods of time as a single agent after initial induction of response. In addition, available evidence suggests that patients with poor prognosis associated with overexpression of c-erb B2 (HER2) have a higher probability of responding to paclitaxel than patients with HER2-negative tumors. The clarification of this possibility is a priority. Should HER2 status be a predictor of response to paclitaxel and paclitaxel-based therapy, the use of the drug could be tailored to specific patient characteristics. The ability to discriminate between paclitaxel as a therapeutic option or a therapeutic indication is one of the challenges of the future development of this important drug.
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PMID:Future directions of paclitaxel-based therapy of breast cancer. 937 3

We have analyzed serum levels of soluble HER-2/neu in 42 primary breast cancer patients prior to any therapy and studied the relationship between the overexpression and amplification of HER-2/neu in the primary tumor after surgical excision and data obtained by pathohistological staging. In addition, we have investigated the sera of 62 patients with stage IV breast cancer. Using an enzyme-linked immunosorbent assay, we observed elevated serum HER-2/neu levels in 6/42 (14.2%) preoperative patients. In 42.8% of the patients with HER-2/neu tumor expression/amplification serum levels were increased. In contrast, only 8.5% of the patients without HER-2/neu expression/amplification in the primary tumor presented with elevated serum levels. There was a significant correlation between serum concentrations of soluble HER-2/neu and tumor size (p < 0.0001) or axillary lymph node involvement (p < 0.0001). In patients with stage IV disease, 27 of 62 (43.5%) had elevated soluble HER-2/neu serum levels. A highly significant correlation between soluble HER-2/ neu and CA 15-3 (p < 0.002) was observed. The correlation of serum concentrations of HER-2/neu with estrogen and progesterone receptor status of the primary tumor was not significant in both groups. In conclusion, the measurement of serum HER-2/neu levels at diagnosis defines a small subgroup of breast cancer patients with a relatively advanced stage of disease. Its strong correlation with tumor load in patients with stage II disease and the high prevalence in patients with stage IV disease could make it a promising tool for the assessment of disease activity and biologic behavior in breast cancer.
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PMID:Tissue expression and serum levels of HER-2/neu in patients with breast cancer. 939 44

Mr 25,000 single-chain Fv (scFv) molecules are rapidly eliminated from the circulation of immunodeficient mice, yielding highly specific retention of small quantities of scFv in human tumor xenografts. We postulated that the specific retention of scFv in tumor could be enhanced by engineering significant increases in the affinity of the scFv for its target antigens. Affinity mutants of the human anti-HER2/neu (c-erbB-2) scFv C6.5 were generated by site-directed mutagenesis, which target the same antigenic epitope with a 320-fold range in affinity (3.2 x 10(-7) to 1.0 x 10(-9) M). In vitro, the Kd of each scFv correlated closely with the duration of its retention on the surface of human ovarian carcinoma SK-OV-3 cells overexpressing HER2/neu. In biodistribution studies performed in scid mice bearing established SK-OV-3 tumors, the degree and specificity of tumor localization increased significantly with increasing affinity. At 24 h after injection, tumor retention of the highest affinity scFv was 7-fold greater than that of a mutant with 320-fold lower affinity for HER2/neu. Because the rapid renal clearance of scFv may blunt the impact of improved affinity on tumor targeting, the distributions were also assayed in the absence of renal clearance (e.g., in mice rendered surgically anephric). In this model, the peak tumor retentions of the two higher affinity scFv approximated that reported previously for IgG targeting the same SK-OV-3 tumors in scid mice with intact kidneys. In contrast, the mutant with the lowest affinity for HER2/neu failed to accumulate in tumor, indicating the presence of an affinity threshold that must be exceeded for active in vivo tumor uptake. These results indicate that affinity can significantly impact the in vivo tumor-specific retention of scFv molecules.
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PMID:Increased affinity leads to improved selective tumor delivery of single-chain Fv antibodies. 945 94

Anti-HER2 immunoliposomes (ILs) have been constructed by conjugation of Fab' fragments of recombinant humanized monoclonal antibody rhuMAbHER2 to small sterically stabilized unilamellar liposomes, to create a targeted drug delivery vehicle for the treatment of HER2 (c-erbB-2, neu)-overexpressing cancers. Parameters affecting in vitro binding and internalization of ILs include liposome composition, Fab' linkage site and Fab' density. Anti-HER2 ILs have been constructed to optimize intracellular drug delivery. Doxorubicin (dox)-loaded ILs are highly stable and exhibit prolonged circulation in rats. In nude mice bearing HER2-overexpressing tumor xenografts, anti-HER2 ILs administered i.v. resulted in efficient tumor localization, with penetration of the ILs throughout the tumor mass and accumulation within tumor cells. In contrast, non-targeted liposomes resulted in extracellular tumor accumulation only. In multiple HER2-overexpressing human breast tumor xenograft models, treatment with dox-loaded anti-HER2 ILs produces significantly increased antitumor cytotoxicity as compared to free dox or dox-loaded non-targeted liposomes and significantly less systemic toxicity than free dox. To explore further the intracellular delivery advantages of ILs, anti-HER2 ILs bearing cationic lipids are being developed for nucleic acid delivery. These cationic immunoliposomes mediate efficient and specific transfection of target cells with reporter genes, as well as intracellular delivery of labeled oligonucleotides. Thus, anti-HER2 ILs represent an efficient and feasible strategy to achieve targeted intracellular delivery of therapeutic agents.
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PMID:Anti-HER2 immunoliposomes for targeted therapy of human tumors. 945 5

In different types of human cancer there is an overexpression of the c-erbB-2 (HER2/neu) oncogene, which is thought to be involved in tumor progression. Therefore the c-erbB-2 oncogene is an attractive target for tumor-specific gene therapy. In this report we have characterized a hammerhead ribozyme against the c-erbB-2 mRNA with high cleavage activity. To select the optimum sequence, the activity of five hammerhead ribozymes was tested in a cell-free assay. The hammerhead ribozyme recognizing the GUC sequence at position +631 to +633 of the c-erbB-2 mRNA (RZ631) efficiently cleaves in vitro transcribed fragments of the c-erbB-2 mRNA [169 to 1450 nucleotides (nt)] under multiple-turnover conditions. The ribozyme coding sequence was subsequently cloned between the A and the B box promoter sequences of the fowl adenovirus type 1 virus-associated RNA (CELO VA) gene. The in vitro activity of RZ631 was shown to be unaffected by the polymerase III promoter flanking sequences. The ability of RZ631 to inhibit the synthesis of the c-erbB-2 gene product in tumor cells was assayed by cotransfection of the ribozyme with a fusion gene of c-erbB-2 and the gene for the enhanced green fluorescent protein as a reporter. The synthesis of the fluorescent fusion protein in NIH:OVCAR-3 ovarian cancer cells was potently inhibited by RZ631, as assayed by flow cytometry. An antisense control vector, where the catalytic core was replaced by a single base, showed a weaker inhibition of expression of the c-erbB-2 derivative. The results suggest that the inhibitory effect of this c-erbB-2 ribozyme is caused by an antisense effect as well as by an additional ribozyme-mediated increase in inhibition. We conclude that this c-erbB-2 ribozyme in conjunction with a polymerase III-based expression system should be useful for the efficient downregulation of the c-erbB-2 oncogene in ovarian cancer cells.
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PMID:Selection of a high activity c-erbB-2 ribozyme using a fusion gene of c-erbB-2 and the enhanced green fluorescent protein. 947 66

One approach to development of specific cancer immunotherapy relies on the induction of cytotoxic T lymphocytes (CTL) specific for tumor-associated antigens (TAA). Induction of TAA-specific CTL could be used towards the eradication of established tumors, or to prevent their dissemination or recurrence after primary treatment. The present study identifies a set of CTL epitopes from TAA frequently found on solid epithelial tumors such as breast, lung and gastro-intestinal tumors. Specifically, HLA-A2.1 binding peptides from the MAGE2, MAGE3, HER-2/neu and CEA antigens were tested for their capacity to elicit in vitro anti-tumor CTL using lymphocytes from normal volunteers and autologous dendritic cells as antigen-presenting cells. A total of 6 new epitopes (MAGE2[10(157)], MAGE3[9(112)], CEA[9(691)], CEA[9(24)], HER2[9(435)] and HER2[9(5)]) were identified which were capable of specifically recognizing tumor cell lines lines expressing HLA-A2.1 and the corresponding TAA. In one case (CEA[9(24)]), induction of vigorous anti-tumor CTL responses required epitope engineering to increase HLA-A2.1 binding affinity. Finally, most of the newly identified epitopes (5 out of 6) were found to be highly crossreactive with other common HLA alleles of the A2 supertype (A2.2, A2.3, A2.6 and A6802), thus demonstrating their potential in providing broad and non-ethnically biased population coverage. The results are discussed in the context of the development of multi-epitope-based therapies with broad applicability for patients suffering from commonly found tumors.
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PMID:The multi-epitope approach for immunotherapy for cancer: identification of several CTL epitopes from various tumor-associated antigens expressed on solid epithelial tumors. 954 34

HER2 (erbB-2) proto-oncogene amplification and/or overexpression correlate with poor prognosis in many malignancies. The precise biological role of this oncogenic signaling pathway (which also involves the HER4 gene) in breast cancer is unclear. One property conferred by this oncogene relates to response to drug therapy. Clinical studies support an association between HER2 overexpression and resistance to alkylating agents (cisplatinum and cyclophosphamide). Data from the Cancer and Leukemia Group B 8869/8541 study indicate enhanced dose responsiveness to doxorubicin (Adriamycin) in patients who overexpress the HER2 receptor. Heregulin beta-2, a naturally occurring ligand that activates the HER2 receptor by inducing its heterodimerization with the HER4 receptor, has recently been cloned. The ability of this ligand to phosphorylate the HER2 receptor exogenously allows us to study the effect of HER2 activation on cancer cell behavior. To study the relationship between chemotherapy response and activation of HER2, MCF-7 cells expressing biologically active heregulin were assessed for response to doxorubicin and etoposide, both of which are topoisomerase IIalpha (topo IIalpha) inhibitors. Several clones show markedly increased sensitivity to these drugs. In addition, the same wild-type MCF-7 cells transfected with heregulin beta-2 under the control of an inducible promoter also show this dose-response relationship to doxorubicin after the expression of heregulin beta-2 is activated by zinc. The modulation of topo IIalpha was studied in the cell lines transfected with heregulin. topo IIalpha mRNA and protein (total protein and enzymatic decatenating activity) were found to be up-regulated in heregulin beta-2-transfected cells. Moreover, topo IIalpha promoter activity was also modestly increased in heregulin beta-2-transfected cells. Because up-regulation of topo IIalpha in vitro and in clinical specimens is associated with increased response to doxorubicin (presumptively by an increase in drug substrate), this may be the mechanism of the increased sensitivity to doxorubicin seen in heregulin beta-2-transfected cells. This implies that activation of HER2 or one of the other members of the receptor family may increase sensitivity to doxorubicin by up-regulation of topo IIalpha. This finding suggests the use of receptor/ligand expression to direct patient-specific therapeutic choices (e.g., doxorubicin versus alkylator-based regimens) and the use of biological agents (such as heregulin) in combination with certain chemotherapeutic agents to enhance response to treatment in breast cancer patients.
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PMID:Induction of sensitivity to doxorubicin and etoposide by transfection of MCF-7 breast cancer cells with heregulin beta-2. 956 96

Chromatin in interphase nuclei exhibits a topology that is associated with the transcriptional state of cells. We examined the spatial, intranuclear distribution of chromosome 17 and the ERBB-2 (HER2/neu) sequence thereon, relative to that of DNase-hypersensitive chromatin (DHC), in breast tumour cells exhibiting different levels of expression of ERBB-2. These sequences were specifically associated with the nuclear periphery, within a band of DHC. The remainder of the chromosome 17 mass showed no preferential position within the nucleus. The peripheral placement of ERBB-2 sequences is associated with a specific conformation of chromosome 17. We propose that the conformational organization of chromosome territories might represent a fundamental control mechanism in gene expression.
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PMID:A specific conformation of the territory of chromosome 17 locates ERBB-2 sequences to a DNase-hypersensitive domain at the nuclear periphery. 960 77

We undertook a study to analyze the expression of urokinase-type plasminogen activator (u-PA) protein in colorectal cancer (CRC) and to compare it with c-erbB-2 (HER2/neu) and nm23 protein expression. Paraffin-embedded specimens from 58 patients with CRC were retrospectively collected. Immunohistochemical staining of u-PA, c-erbB-2, and nm23 was quantitatively evaluated using a color video image analysis (color VIA) technique. No correlation was found between u-PA expression and tumor stage, age, sex, or tumor site. Although there was no evidence from our data that the level of u-PA in the primary tumors could predict risk of liver metastasis or survival duration, CRC showing overexpression of u-PA (above 85 pixels) had a worse prognosis (P = 0.013). There were significant positive correlations among all three u-PA, c-erbB-2, and nm23 proteins (u-PA vs. c-erbB-2, P = 0.003; u-PA vs. nm23, P < 0.001; c-erbB-2 vs. nm23, P = 0.001), suggesting that, in vivo, all proteins interact or are similarly regulated.
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PMID:Correlates of urokinase-type plasminogen activator in colorectal cancer: positive relationship with nm23 and c-erbB-2 protein expression. 961 57

We established an RT-PCR method to measure the amount of a 2.3-kb alternatively spliced mRNA of the human c-erbB-2/HER-2 proto-oncogene relative to the 4.6-kb full-length transcript. For the first time, we demonstrated production of c-erbB-2 extracellular domains via alternative splicing in breast cancer tissues, lymph node and bone marrow micrometastases. In 15 c-erbB-2-positive primary breast tumor samples, we found two significantly distinct subgroups: 6/15 had a low level of the extracellular fragment, and 9/15 showed an average 4.4-fold higher amount of the alternatively spliced mRNA. Additionally, six lymph nodes and six bone marrow aspirates from metastatic breast cancer patients were analyzed: 5/6 lymph nodes and 6/6 bone marrow aspirates were found to produce elevated relative amounts of the truncated fragment. The results demonstrate that our method is suitable for sensitive detection of c-erbB-2-positive micrometastasis and strongly suggest that the alternatively spliced c-erbB-2 variant is involved in the development of micrometastasis in breast cancer.
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PMID:Differential expression of alternatively spliced c-erbB-2 mRNA in primary tumors, lymph node metastases, and bone marrow micrometastases from breast cancer patients. 964 24


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