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 recent highlighted points in prognostic factors after breast cancer operation include: 1) the emergence of many genetic and biochemical markers, including c-erbB-2, int-2, EGFR, p53, nm23, LOH, E cadherin, s-phase fraction. The prognostic value of these factors is related to their role in cell cycle regulation, invasion/metastasis mechanisms, etc. The agents related to therapeutic effectiveness, namely p-glycoprotein, pS2, and bcl-2 may become important stratification factors when conducting clinical trials. Pathologic factors, like nodal status, however, are the most useful prognostic factors at the moment. Many newly developed prognostic factors should be examined by multivariate analysis and validated prospectively before clinical use.
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PMID:[Recent prognostic factors for breast cancer]. 912 98

The cytotoxic effects of the natural photosensitizing agent hypericin were evaluated. A dramatic difference in the sensitivity of several different human and mouse cell lines towards photoactivated hypericin (4 J cm-2) was demonstrated using a neutral red assay (e.g. A431, IC50 = 0.14 +/- 0.02 microM; HeLa, IC50 = 0.32 +/- 0.05 microM, MCF7, IC50 = 1.84 +/- 0.22 microM). Dark cytotoxicity was absent, even at high hypericin concentration (25 microM). The differential phototoxicity of hypericin did not correlate with the expression of the epidermal growth factor (EGF) receptor nor with the expression of the P170 glycoprotein in the cell. The reduction of the intracellular glutathione content did not enhance further the cytotoxic effects of photoactivated hypericin, as investigated with the A431, HeLa and MCF7 cells. Conversely, using confocal laser microscopy, it was shown that the phototoxicity correlated well with the hypericin cellular uptake.
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PMID:Differential cytotoxic effects induced after photosensitization by hypericin. 920 74

Growth factor receptors are of great interest as molecular targets for the diagnosis and treatment of cancer. Growth factor receptors are frequently over expressed on malignant cell populations since many cellular oncogenes encode either growth factors or their receptors. The wild-type epidermal growth factor receptor has a molecular weight of 170 kD and is over expressed on gliomas, bladder tumors, squamous cells carcinomas and breast carcinomas. Another growth factor oncogene, c-erbB-2, encodes a 185-kD glycoprotein found on the surface of gliomas, breast and ovarian cancers as well as other carcinomas of epithelial origin. In addition to causing over expression, oncogenic transformation also can result in genomic re-arrangements. An important example from the perspective of targeting is EGFRvIII, a deletion mutant which lacks amino acids 6-273 in the extracellular domain of the epidermal growth factor receptor. The EGFRvIII molecule (145 kD) may be of great value for targeting because it appears to be tumor-specific. Antibodies have been developed with specific reactivity with these growth factor receptors. Since these antibodies are internalized into the cell after receptor binding, it is necessary to use radiolabeling methods which residualize the radioactivity in the tumor cell after intracellular catabolism. To investigate this problem, we have evaluated the effect of radioiodination method on the in vitro and in vivo properties of an anti-EGFRvIII antibody. Methods studied were Iodogen, tyramine-cellobiose, and N-succinimidyl 5-iodo-3-pyridine-carboxylate with the last offering optimal localization in a human xenograft model.
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PMID:Growth factor receptors as molecular targets for cancer diagnosis and therapy. 920 46

Amplification and overexpression of the HER-2/neu proto-oncogene frequently coincide with an aggressive clinical course of certain human adenocarcinomas. To assess whether HER-2/neu plays a rate-limiting role in ovarian cancer, we used human SK-OV-3 ovarian cancer cells as a model. We applied a conditional mRNA depletion strategy of HER-2/neu with anti-HER-2/neu-targeted hammerhead ribozymes expressed under the control of a tetracycline-regulated promoter system. In these ovarian cancer cells, we reduced HER-2/neu mRNA, protein expression, and tumor growth in nude mice by transfection with HER-2/neu-targeted ribozymes and generated cell lines expressing different levels of HER-2/neu. Expression of the most effective ribozyme (Rz3) quenched HER-2/neu mRNA levels by >90%. Concomitantly, fluorescence-activated cell sorting analysis revealed that expression of the HER-2/neu-encoded surface glycoprotein was almost completely abrogated. In nude mice, tumor growth was dramatically inhibited in the HER-2/neu-depleted Rz3-expressing SK-OV-3 cells. Furthermore, already established tumors started to regress when Rz3 expression was activated midstream by withdrawal of the tetracycline treatment. This study supports the thesis that HER-2/neu can be rate-limiting for the malignant phenotype of ovarian cancer in a gene dose-dependent manner.
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PMID:HER-2/neu is rate-limiting for ovarian cancer growth. Conditional depletion of HER-2/neu by ribozyme targeting. 936 8

Amplification and over-expression of the HER-2/neu proto-oncogene are associated with poor prognosis in women with both node-positive and node-negative breast cancer. Therefore, the encoded surface glycoprotein represents an attractive target for cancer immunotherapies. Furthermore, the extracellular domain of HER-2/neu is released from the cell surface by proteolytic cleavage. In the present experiments, we investigated the potential biologic effects of soluble HER-2/neu with particular emphasis on its interaction with anti-HER-2/neu antibodies. A monoclonal antibody specific for the extracellular domain of HER-2/neu dose dependently inhibited the proliferation of highly HER-2/neu-expressing SK-BR-3 and BT-474 breast cancer cells but had no effect on the proliferation of weakly to moderately HER-2/neu-expressing MCF-7, HBL-100 and ZR-75-1 breast cells. Addition of SK-BR-3 or BT-474 cell supernatants with high concentrations of soluble HER-2/neu led to a neutralization of anti-HER-2/neu antibody-mediated inhibition of proliferation due to a binding of soluble HER-2/neu by the antibody, which could be demonstrated by immunoprecipitation. Furthermore, the ability of anti-HER-2/neu antibodies to mediate antibody-dependent cellular cytotoxicity (ADCC) by lymphokine-activated killer cells was assessed. Cytolysis of SK-BR-3 tumor cells was increased significantly in the presence of anti-HER-2/neu antibodies. Similar to the proliferation inhibition, ADCC was neutralized by addition of soluble HER-2/neu-containing supernatants. Our data suggest that tumors rich in HER-2/neu might thus escape certain steps of immunologic control by neutralizing biologic activities of anti HER-2/neu antibodies due to the presence of soluble HER-2/neu.
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PMID:Soluble HER-2/neu neutralizes biologic effects of anti-HER-2/neu antibody on breast cancer cells in vitro. 939 69

Small peptides, 8-10 amino acids long, derived from degradation of cytoplasmic proteins by a proteasome-proteinase complex, are usually presented and recognized by CD8+ cytolytic T lymphocytes (CTLs) associated with major histocompatibility complex (MHC) class I molecules. Recently synthetic peptides were used for the in vitro induction of tumor-specific CTLs, offering another strategy in the study of the immune-response repertoire and providing a new tool in cancer vaccination and immunotherapy. Peptides derived from otherwise normal proteins, overexpressed in many tumors as products of the protooncogene, may represent a target for an immune response. This is the case of HER-2/neu gene (also known as ErbB-2), encoding a cysteine-rich glycoprotein transmembrane receptor with tyrosine kinase activity (gp185neu). Recent data, demonstrating that HLA-A2.1-related peptides are able to stimulate in vitro CD8+ lymphocytes, Prompted us to study the binding to HLA-A2.1 molecules of several gp185 synthetic peptides containing a cystein residue and to define the relevance of this amino acid residue in the reduced or oxidated form of the sulfhydryl group. We found that monomers and their homodimers, linked by a disulfide bridge, bind to HLA-A2.1 molecules with overlapping affinity. These results suggest that additional amino acids of the nonapeptide do not prevent the binding and the HLA refolding through chemical or sterical interactions. This might be of particular relevance for the in vivo processing of cysteine-rich proteins. Because ErbB-2 molecules, as tumor-differentiation antigens in melanoma, are cysteine-rich molecules, it may be relevant to evaluate the possible role of the cystine residues interacting with the T-cell receptor. The recognition of these heterodimers by CD8+ lymphocytes will require functional in vivo studies.
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PMID:MHC-peptide binding: dimers of cysteine-containing nonapeptides bind with high affinity to HLA-A2.1 class I molecules. 940 48

Peripheral pulmonary adenocarcinomas (PPAs) often demonstrate a bronchioloalveolar component, with or without glandular differentiation. PPAs can be nondescript, mucinous, or show features of Type II pneumocytes. Particularly, mucinous lung carcinomas can resemble gastrointestinal metastases. Previous reports suggested that patterns of keratins 7 (K7) and 20 (K20) differ in pulmonary tumors versus enteric metastases. These studies, however, often failed to specify the precise morphotypes of PPA. Thus, we undertook this evaluation of PPAs with different histologic images. Thirty-nine cases were retrieved from institutional files; all were confirmed as primary tumors by clinicopathologic and radiographic review. Cases were classified as Type I (mucinous) bronchioloalveolar carcinoma (BAC1); Type II (nonmucinous) bronchioloalveolar carcinoma (BAC2); conventional PPA with BAC1-like areas (PPA1); or conventional PPA with BAC2-like foci (PPA2). Immunostains were performed for K7, K20, carcinoembryonic antigen, CA19-9, tumor-associated glycoprotein-72, surfactant apoprotein-A, and the c-erbB-2 peptide. BAC1 and PPA1 failed to express surfactant apoprotein-A, and BAC2 also consistently lacked K20, whereas 28% of PPA2 lesions were labeled for K20. All of the other determinants, however, were seen in variable proportions in each subgroup of PPA. Primary BAC1 and PPA1 resembled enteric adenocarcinomas immunophenotypically; on the other hand, BAC2 demonstrated a pattern of protein expression similar to that of Type II pneumocytes. PPA2s are a diverse group of neoplasms, and a subset of PPA2 does show K20 reactivity, as would be expected in metastatic enteric carcinomas. Thus, immunohistochemical data on PPAs must be interpreted carefully and only in clinicopathologic context. With respect specifically to primary pulmonary mucinous tumors, there still seems to be no uniformly reliably marker that will always allow the exclusion of metastatic enteric tumors.
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PMID:Peripheral pulmonary adenocarcinomas with bronchioloalveolar features: immunophenotypes correlate with histologic patterns. 964 95

Erythrocyte production in mammals is known to depend on the exposure of committed progenitor cells to the glycoprotein hormone erythropoietin (Epo). In chimeric mice, gene disruption experiments have demonstrated a critical role for Epo signaling in development beyond the erythroid colony-forming unit (CFU-e) stage. However, whether this might include the possible Epo-specific induction of red blood cell differentiation events is largely unresolved. To address this issue, mechanisms of induced globin expression in Epo-responsive SKT6 cells have been investigated. Chimeric receptors containing an epidermal growth factor (EGF) receptor extracellular domain and varied Epo receptor cytoplasmic domains first were expressed stably at physiological levels in SKT6 cells, and their activities in mediating induced hemoglobinization were assayed. While activity was exerted by a full-length chimera (EE483), truncation to remove 7 of 8 carboxyl-terminal tyrosine sites (EE372) markedly enhanced differentiation signaling. Moreover, mutation of a STAT5 binding site in this construct (EE372-Y343F) inhibited induced globin expression and SKT6 cell hemoglobinization, as did the ectopic expression of dominant-negative forms of STAT5 in parental SKT6 cells. As in normal CFU-e, SKT6 cells also were shown to express functional receptors for stem cell factor (SCF). To further define possible specific requirements for differentiation signaling, effects of SCF on SKT6 cell hemoglobinization were tested. Interestingly, SCF not only failed to promote globin expression but inhibited this Epo-induced event in a dose-dependent, STAT5-independent fashion. Thus, effects of Epo on globin expression may depend specifically on STAT5-dependent events, and SCF normally may function to attenuate terminal differentiation while promoting CFU-e expansion.
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PMID:Erythropoietin receptor and STAT5-specific pathways promote SKT6 cell hemoglobinization. 969 97

The relative expression of mucin antigens MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, and MUC7 and glycoprotein antigens KSA, carcinoembryonic antigen, prostate-specific membrane antigen (PSMA), HER-2/neu, and human chorionic gonadotropin-beta on different cancers and normal tissues is difficult to determine from available reports. We have compared the distribution of these antigens by immunohistology on a broad range of malignant and normal tissues. MUC1 expression was most intense in cancers of breast, lung, ovarian, and endometrial origin; MUC2 was most intense in cancers of colon and prostate origin; and MUC5AC was most intense in cancers of breast and gastric origin. MUC4 was intensely expressed in 50% of cancers of colon and pancreas origin, and MUC3, MUC5B, and MUC7 were expressed in a variety of epithelial cancers, but not so intensely. KSA was intensely and uniformly expressed on all epithelial cancers; carcinoembryonic antigen was expressed in most cancers of breast, lung, colon, pancreas, and gastric origin; and PSMA was expressed only in cancers of prostate origin. Human chorionic gonadotropin-beta was expressed on the majority of sarcomas and cancers of breast, lung, and pancreas origin, although intense staining was not seen. Staining on normal tissues was restricted to one or many normal epithelial tissues ranging from MUC3, MUC4, and PSMA, which were expressed only on epithelia of pancreas, stomach, and prostate origin, respectively, to MUC1 and KSA, which were expressed on most normal epithelia. Expression was restricted to the secretory borders of these epithelia while stroma and other normal tissues were completely negative. These results plus the results of the two previous papers (S. Zhang et al, Int. J. Cancer, 73: 42-49, 1997; S. Zhang et al., Int. J. Cancer, 73: 50-56, 1997) in this series provide the basis for selection of multiple cell surface antigens as targets for antibody-mediated attack against these cancers.
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PMID:Selection of tumor antigens as targets for immune attack using immunohistochemistry: protein antigens. 982 29

We have recently demonstrated an association between distant metastasis and the expression of the extracellular matrix glycoprotein tenascin-C (Tn-C) in the invasion border of small axillary node-negative breast carcinomas. Our purpose was to assess the relationship between the expression of Tn-C in the tumour invasion border and several histopathological and biological variables and to compare their usefulness in predicting local and distant disease recurrences. The original patient group consisted of 143 women with axillary node-negative breast cancer (one bilateral) treated with breast-conserving surgery and post-operative radiotherapy, and followed for a median of 8 years. Because of the small number of recurrences an additional group of 15 similarly treated women with recurrent breast cancer was also studied. The size of the tumour, its histology, including a possible intraductal component, and grade were re-evaluated. The expression of erbB-2, p53, Ki-67 and Tn-C was evaluated by immunohistochemistry. Ploidy and S-phase fraction (SPF) were assessed by flow cytometry. The only statistically significant prognostic factor for local recurrence was Tn-C expression in the invasion border. For metastasis Ki-67 positivity, tumour size and Tn-C expression in the invasion border were statistically significant, but Ki-67 positivity was the only independent prognostic factor. Tn-C expression in the invasion border was associated with a higher proliferation rate measured by Ki-67 and SPF, which is consistent with the suggested growth-promoting activity of Tn-C. Tn-C may be a useful marker in selecting patients for adjuvant therapies to reduce the rate of both local and distant cancer recurrences.
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PMID:Tenascin-C expression in invasion border of early breast cancer: a predictor of local and distant recurrence. 983 85


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