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)

Selected murine monoclonal antibodies (MAb) have been shown to inhibit relevant tumor growth in vitro and in animal models. Recently, bispecific antibodies (BsMAb) have been developed which target cytolytic effector cells via one antibody binding site and tumor antigen by the other specificity. For example, the BsMAb 2B1 possesses specificity for c-erbB-2 and Fc gamma RIII, the low affinity Fc gamma receptor expressed by polymorphonuclear leukocytes (PMN), macrophages and large granular lymphocytes (LGL). The human homologue of the rat neu oncogene, c-erbB-2, has been demonstrated to be amplified in breast, gastrointestinal, lung and ovarian carcinomas. Tumor expression of c-erbB-2 has been shown to be an important prognostic indicator in breast and ovarian carcinomas. The restricted expression of the c-erbB-2 protooncogene product in normal human tissues and the wide distribution of c-erbB-2 expression in such tumors may justify attempts to use an appropriately constructed BsMAb in clinical trials. In this report we have addressed this issue by immunohistochemically evaluating the expression of c-erbB-2 oncogene product in a variety of malignant tumors utilizing 2B1 and the anti-c-erbB-2 monovalent parent of 2B1, 520C9. Among the studied neoplasms, c-erbB-2 expression was detected in 49% of primary carcinomas stained with 520C9 and in 39% of those stained with 2B1. In the group of metastatic tumors, c-erbB-2 oncoprotein was detected in 52% of cases by 520C9 and in 41% by 2B1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immunohistochemical detection of c-erbB-2 expression by neoplastic human tissue using monospecific and bispecific monoclonal antibodies. 790 24

We recently established epidermal growth factor (EGF) receptor-hyperproducing human gastric cancer xenografts in nude mice. The present study was designed to examine whether the growth of a xenograft having 1,098 +/- 276 fmol/mg protein of EGF receptor would either be stimulated by the administration of EGF or inhibited by the removal of the submandibular glands (sialoadenectomy) which contain a large amount of EGF. A miniosmotic pump containing 2 micrograms or 20 micrograms of EGF was implanted on the back of the animals in the EGF stimulation experiments. The tumor growth was stimulated by the administration of EGF (P < 0.01), and the doubling time of the tumor was reduced relative to the controls (P < 0.01). Both the mitotic indices and the bromodeoxyuridine (BrdU)-labeling indices of the tumor were higher than those of the controls (P < 0.01). Tumor growth inhibited by the sialoadenectomy (P < 0.05) while the tumor doubling time was prolonged compared with the sham-operated mice (P < 0.05). These results suggest that the growth of a human gastric cancer xenograft may be modulated by EGF.
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PMID:Stimulatory effect of EGF and inhibitory effect of sialoadenectomy on growth of an EGF receptor-hyperproducing human gastric cancer xenograft in nude mice. 798 44

Bispecific antibodies of a new category, termed "antigen forks", were constructed by crosslinking antibodies that recognized pairs of distinct tumor cell surface antigens. At concentrations of 1-100 nM, several such forks inhibited the growth of human tumor cell lines bearing both relevant antigens. The same cells were not inhibited by unconjugated component antibodies, and the active conjugates did not inhibit the growth of human cell lines that expressed lower levels of relevant antigens. The three most active antigen forks all contained monoclonal antibody 454A12, which recognizes human transferrin receptor. This antibody was conjugated respectively to antibodies 113F1 (against a tumor-associated glycoprotein complex), 317G5 (against a 42-kDa tumor-associated glycoprotein), or 520C9 (against the c-erbB-2 protooncogene product). The 317G5-454A12 fork strongly inhibited the HT-29 and SW948 human colorectal cancer cell lines, while the 113F1-454A12 and 520C9-454A12 forks strongly inhibited the SK-BR-3 human breast cancer cell line and the 113F1-454A12 fork was also effective against SW948. By designing forks against antigens of incompatible function that are co-expressed at high levels on tumor cells but not on normal tissues, it may be possible to generate reagents that inhibit tumor growth with enhanced selectivity.
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PMID:Antigen forks: bispecific reagents that inhibit cell growth by binding selected pairs of tumor antigens. 804 25

c-erb B2/neu has been demonstrated to be a transforming oncogene in both rodent and human prostatic epithelial cells. To understand the potential role of neu in human prostatic cancer progression, we used a transfer procedure to determine whether neu amplification/overexpression leads to increased tumor growth and metastasis. We chose an androgen-independent human prostatic epithelial cell line, PC-3, as the target for gene transfer. PC-3 cells were cotransfected with pSVneu-T (a point-mutated rat neu oncogene construct) and pSV2neo, and single-cell cloned. Fifty cell clones were isolated and characterized, of which two neu-transfected clones (N17 and N35) and a neo control clone (C32) were studied extensively with respect to neu gene integration, levels of neu mRNA and protein expression, anchorage-independent growth, and tumorigenic and metastatic potential. Results showed that: 1) Clone N35 contained 70 copies of the neu oncogene and a high level of neu mRNA transcripts. It acquired increased anchorage-independent growth potential in vitro and increased tumorigenicity in vivo. 2) Clone N17 contained 10 copies of the neu oncogene and a low level of neu mRNA transcripts. It did not acquire additional capability for anchorage-independent growth and tumorigenic potential as compared to the controls. 3) Despite an increased level of neu mRNA transcripts present in clone N35, there was no corresponding increase of the steady-state levels of neu protein in this particular clone. 4) When administered subcutaneously, none of the cell clones tested, including the control neomycin-resistant clone, acquired metastatic potential. However, clone N35 exhibited marked metastatic potential when administered orthotopically; this cell clone was found to disseminate widely to the lymph nodes, kidney, skeletal muscle, lung, liver, and bone. 5) When neu-transfected cell subclones from N35-induced primary and metastatic lymph node, kidney, and bone tumors were analyzed for cytoskeletal, extracellular matrix, and cell adhesion protein expression, the bone metastatic subclone exhibited increased levels of vimentin and collagen IV and decreased levels of cytokeratin and ICAM-1. These results, taken together, suggest that neu transfection induces secondary changes, which, rather than neu protein per se, are responsible for the acquisition of tumorigenic and metastatic potential of prostate cancer cells when an appropriate host microenvironment is present.
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PMID:Transfected neu oncogene induces human prostate cancer metastasis. 860 95

Previously, a panel of mouse monoclonal antibodies (mAbs) to several tumor-associated antigens was chemically crosslinked to an IgG1 anti-human transferrin receptor antibody, 454A12. We called this new class of bispecific antibodies (BmAbs) "antigen forks" and showed that these antigen forks inhibited but did not completely prevent tumor cell growth. We speculated that the conjugates acted by heterologously crosslinking two antigens in a manner that interfered with the functions of one or both. The most effective BmAbs all shared one specificity for the human transferrin receptor. A monoclonal antibody to this receptor has been shown by others to reduce tumor cell growth when used with the iron chelator deferoxamine. When we combined our antigen forks with deferoxamine, two of five BmAbs synergized with deferoxamine to arrest tumor cell count at or below input levels. The most effective BmAbs were 317G5/454A12 (3/4) and 520C9/454A12 (5/4). mAb 317G5 recognizes a 42-kDa tumor-associated glycoprotein, and mAb 520C9 recognizes the c-erbB-2 protooncogene product. BmAb 3/4 was most effective against colorectal cancer cell line HT-29, and BmAb 5/4 was most effective against breast cancer cell line SK-BR-3. When deferoxamine and BmAb were replaced by fresh medium after a 6- or 7-day treatment period, no regrowth of tumor cells was observed during the next 4 days, although regrowth was seen if either deferoxamine or BmAb was used alone. Our results show that BmAbs with specificities for transferrin receptor and certain tumor-associated antigens effectively inhibit tumor growth in vitro. When used in combination with deferoxamine, such BmAbs may have therapeutic potential for the treatment of cancer.
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PMID:In vitro tumor growth inhibition by bispecific antibodies to human transferrin receptor and tumor-associated antigens is augmented by the iron chelator deferoxamine. 876 64

The HER-2/neu proto-oncogene is frequently amplified or overexpressed in human breast and ovarian cancers, and is significantly correlated with shorter survival. We have previously reported that the adenovirus type 5 early region 1A (E1A) gene product can repress HER-2/neu overexpression by repressing HER-2/neu promoter activity, and suppress the tumorigenic potential of HER-2/neu-overexpressing ovarian cancer cells. To examine E1A tumor suppressor function in breast cancer, we transduced E1A in vitro by adenovirus into both HER-2/neu-overexpressing and low expressing human breast cancer cell lines. In HER-2/neu-overexpressing cells, E1A greatly inhibited tumor cell growth in vitro. However, in HER-2/neu low expressing cancer cell lines, E1A had no significant effect on cell growth in culture medium. To test the therapeutic efficacy of E1A, we used both adenovirus-mediated and cationic liposome-mediated E1A gene delivery systems in an orthotopic breast cancer animal model. An advanced breast cancer model was established by inoculation of HER-2/neu-overexpressing human breast cancer cells in mammary fat pad and treated by local injections of either replication-deficient adenovirus expressing E1A, Ad.E1A(+) or a liposome-E1A DNA complex. As controls, mice bearing tumors were also treated with Ad.E1A(-) which is virtually the same adenovirus as Ad.E1A(+) except that E1A is deleted, a liposome-E1A frame-shift mutant DNA complex, or just PBS. In mice bearing a HER-2/neu-overexpressing breast cancer cell line, E1A delivered either by adenovirus or liposome significantly inhibited tumor growth and prolonged mouse survival compared with the controls. In fact, 60-80% of E1A-treated mice lived longer than 2 years versus only 0-20% of control mice (P<0.05). Western blot analysis showed that E1A protein was expressed in tumor tissue and immunohistochemical analysis showed that HER-2/neu p185 protein expression was suppressed. Taken together, our results indicated that both adenovirus and cationic liposome delivery systems were effective in transfering E1A gene for tumor suppression in a HER-2/neu-overexpressing breast cancer model.
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PMID:The tumor suppression activity of E1A in HER-2/neu-overexpressing breast cancer. 905 54

E-Cadherin has been shown to be an invasion tumor suppressor gene, but few epidemiological studies have revealed relationships between loss of E-cadherin expression and invasive tumor growth and/or metastasis. The adhesive function of E-cadherin is dependent on the integrity of the catenin components which link E-cadherin to the actin filaments. In order to achieve a better correlation between the loss of cell adhesion and metastasis in cancer, we decided to investigate both E-cadherin and the catenins. 157 archival primary mammary carcinomas were immunohistochemically studied using antibodies against E-cadherin, alpha-, beta- and gamma-catenin. The following results were obtained: (a) Independent of the presence of E-cadherin, loss of expression of one or multiple catenins was noted; (b) loss of E-cadherin and alpha-catenin expression was more pronounced in lobular-type than ductal-type carcinomas; c) axillary lymph node metastases were completely lacking only in the group where expression of E-cadherin, alpha- and beta- catenin was preserved: d) no correlation between expression of c-erbB-2 and E-cadherin or one of the catenins was found. The results demonstrate for the first time that consideration of both the expression of E-cadherin and of the three catenins is useful in evaluation of the metastatic potential of mammary carcinomas.
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PMID:Expression of E-cadherin and catenins in invasive mammary carcinomas. 906 80

ErbB-2 is an orphan receptor that belongs to a family of tyrosine kinase receptors for either epidermal growth factor (EGF) or Neu differentiation factor (NDF/neuregulin). Because overexpression of the erbB-2 proto-oncogene is frequently associated with an aggressive clinical course of certain human adenocarcinomas, the encoded protein is an attractive target for immunotherapy. Indeed, certain monoclonal antibodies (mAbs) to ErbB-2 effectively inhibit tumor growth in animal models and in clinical trials, but the underlying mechanism is incompletely understood. To study this question, we generated a large battery of mAbs to ErbB-2, that were classified epitopically. Whereas most antibodies stimulated tyrosine phosphorylation of ErbB-2, their anti-tumor effect correlated with its accelerated endocytic degradation. One group of tumor-inhibitory mAbs (Class II mAbs) was elicited by the most antigenic site of ErbB-2, and inhibited in trans binding of NDF and EGF to their direct receptors. The inhibitory effect was due to acceleration of ligand dissociation, and it resulted in the reduction of the ability of ErbB-2 to transactivate the mitogenic signals of NDF and EGF. These results identify two potential mechanisms of antibody-induced therapy: acceleration of ErbB-2 endocytosis by homodimerization and blocking of heterodimerization between ErbB-2 and growth factor receptors.
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PMID:A subclass of tumor-inhibitory monoclonal antibodies to ErbB-2/HER2 blocks crosstalk with growth factor receptors. 916 Aug 90

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

The 9E3/CEF4 gene codes for a chemokine that is highly homologous to human interleukin-8 and melanoma growth-stimulating activity/groalpha. These chemokines belong to a family of molecular mediators that are importantly involved in inflammation, wound healing, tumor development, and viral entry into cells. On the chorioallantoic membrane the 9E3 protein is chemotactic for monocyte/macrophages and lymphocytes and is angiogenic. In cultured chicken embryo fibroblasts, which have many of the properties of wound fibroblasts, the gene is stimulated by a variety of agents including oncogenes, growth factors, phorbol esters, and thrombin. The strong stimulation of 9E3 by thrombin in culture correlates well with the observation that in young chicks this gene is stimulated to very high levels in fibroblasts upon wounding and remains high throughout wound repair. Activation of 9E3 by thrombin: (i) occurs very rapidly, one minute exposure to thrombin is sufficient to initiate the signals necessary for gene activation; (ii) is independent of mitogenesis; (iii) operates through the proteolytically activated receptor for thrombin; (iv) is mediated by tyrosine kinases, including c-src and the epidermal growth factor (EGF) receptor, rather than Ser/Thr kinases such as protein kinase C and protein kinase A. Inhibition of either c-src or the EGF receptor tyrosine kinase inhibits the stimulation of 9E3 by thrombin. We show here for the first time that activation of the EGF receptor through a cell-surface receptor that does not have tyrosine kinase activity can lead to expression of an immediate early response gene which encodes for a secreted protein, a chemokine. This rapidly activated tyrosine kinase pathway may be a general stress response by which in vivo a localized cell population reacts to emergency situations such as viral infection, wounding, or tumor growth.
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PMID:Thrombin aivation of the 9E3/CEF4 chemokine involves tyrosine kinases including c-src and the epidermal growth factor receptor. 947 78


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