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)

Growth of epithelial ovarian cancer is influenced by several factors including transforming growth factor-alpha and transforming growth factor-beta, macrophage colony stimulating factor, tumor necrosis factor-alpha, interleukin-1 and interleukin-6, c-erb B-2 (HER-2/neu), and mutant p53. Continued expression of the epidermal growth factor receptor, new expression of c-fms, and overexpression of HER-2/neu are associated with a poor prognosis. A number of cytokines have been used to treat patients with ovarian cancer, including interferon-alpha, interferon-gamma, tumor necrosis factor-alpha, and interleukin-2. Judging from preclinical models, interferon-gamma may be more active than interferon-alpha against human ovarian cancer. Although tumor necrosis factor-alpha can stimulate proliferation of some ovarian cancers, the cytotoxic activity of tumor necrosis factor-alpha has been amplified ex vivo by inhibitors of protein synthesis. Similar heterogeneity exists with regard to interleukin-1 where stimulation or inhibition of cell proliferation has been observed. Tumor-infiltrating lymphocytes from ascites fluid contain cells capable of major histocompatibility complex-restricted and major histocompatibility complex-nonrestricted cytotoxicity. Tumor-infiltrating lymphocytes and interleukin-2 have been combined with cytotoxic chemotherapy to treat advanced or recurrent disease. Bispecific monoclonal antibodies that react both with T cells and ovarian tumor cells have produced tumor inhibition in human tumor xenografts. Immunotoxins that contain OVB3 and pseudomonas exotoxin have been evaluated in a phase I clinical trial. Dose-limiting central neurotoxicity has been observed without tumor regression. A monoclonal antibody designated OVX1 has been developed against a high-molecular-weight mucinlike molecule associated with ovarian cancers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biology and therapy with biologic agents in gynecologic cancer. 145 11

Platinum-containing regimens are very effective in the primary treatment of ovarian cancer. However, upon subsequent treatment most tumors develop multidrug resistance. The clinical application of biological response modifiers like interferon gamma (IFN gamma) in advanced ovarian cancer is therefore of increasing interest. Permanent ovarian cancer cell lines are suitable for investigating the mode of action and the potential clinical effectiveness of such response modifiers. IFN gamma is known to modulate many cellular functions. In this study it was compared for its antiproliferative and antigen-modulatory activity on the expression of tumor-associated (CA-125, HMFG, CEA) and major histocompatibility complex (MHC) class I and II antigens as well as of the epidermal growth factor (EGF) receptor on 20 newly established human ovarian carcinoma cell lines. IFN gamma in concentrations of 10, 50 and 100 U/ml was used to study its antigen-modulatory effect, and at additional 1 U/ml and 1000 U/ml to assess its antiproliferative effect on the cells. The cells were incubated with IFN for 4 days. Two cell lines showed strong antiproliferative activity even at minimal doses (up to 50 U/ml). Intermediate growth inhibition between 34% and 84% was observed in 15 cell lines with higher doses. Three lines were resistant to IFN gamma. Independent of the antiproliferative effect, IFN gamma enhanced the expression of MHC class I and MHC class II in nearly all cell lines. Upregulation was also observed for most of the tumor-associated antigens (TAA) and EGF receptor expression. A down-regulation was noticed but rarely. The fact that IFN gamma showed an antiproliferative activity on the majority of the cell lines is of clinical relevance. The in vitro modulation of cell-surface determinants by IFN gamma warrants special attention. The enhanced expression of TAA and MHC antigens can improve immunogenicity of the tumor cells and may explain the therapeutic effects observed under IFN therapy in ovarian cancer. By contrast, enhanced expression of the EGF receptor, often associated with poor patient survival rates, may be an undesirable side-effect of IFN therapy.
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PMID:Effects of interferon gamma on the proliferation and modulation of cell-surface structures of human ovarian carcinoma cell lines. 827 Jun 4

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

Transgenic mice carrying the HER-2/neu proto-oncogene under tissue-specific transcriptional control of a mammary tumor virus long terminal repeat (Tg-MMTVneu mice) spontaneously develop mammary carcinomas. HER-2/neu is a tumor antigen that can be recognized by cytotoxic T lymphocytes if tumor cells present the appropriate major histocompatibility complex (MHC) class I glycoproteins. The purpose of this work was to assess whether mammary carcinomas arising in Tg-MMTVneu mice correctly expressed MHC (H-2q) class I gene products. We analyzed by flow cytometry 51 primary tumors from 19 transgenic mice. About one-half of the tumors showed a reduced expression of class I antigens. All tumors were highly positive for membrane neu. Some mice had multiple mammary carcinomas with widely different MHC expression levels, and most mice had at least one tumor with a low expression. Treatment with gamma-interferon of carcinoma cells cultured in vitro induced a strong reexpression of H-2q antigens. Our results suggest that the immune response activated in vivo by HER-2/neu-positive tumors can lead to the emergence of escape variants characterized by a down-regulation of MHC class I products.
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PMID:Down regulation of major histocompatibility complex class I expression in mammary carcinoma of HER-2/neu transgenic mice. 971 68

Class I major histocompatibility complex (MHC) molecules bind short peptides derived from proteins synthesized within the cell. These complexes of peptide and class I MHC (pMHC) are transported from the endoplasmic reticulum to the cell surface. If a clonotypic T cell receptor expressed on a circulating T cell binds to the pMHC complex, the cell presenting the pMHC is killed. In this manner, some tumor cells expressing aberrant proteins are recognized and removed by the immune system. However, not all tumors are recognized efficiently. One reason hypothesized for poor T cell recognition of tumor-associated peptides is poor binding of those peptides to class I MHC molecules. Many peptides, derived from the proto-oncogene HER-2/neu have been shown to be recognized by cytotoxic T cells derived from HLA-A2(+) patients with breast cancer and other adenocarcinomas. Seven of these peptides were found to bind with intermediate to poor affinity. In particular, GP2 (HER-2/neu residues 654-662) binds very poorly even though it is predicted to bind well based upon the presence of the correct HLA-A2.1 peptide-binding motif. Altering the anchor residues to those most favored by HLA-A2.1 did not significantly improve binding affinity. The crystallographic structure shows that unlike other class I-peptide structures, the center of the peptide does not assume one specific conformation and does not make stabilizing contacts with the peptide-binding cleft.
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PMID:Poor binding of a HER-2/neu epitope (GP2) to HLA-A2.1 is due to a lack of interactions with the center of the peptide. 1059 38

The role of major histocompatibility complex expression in cancer prognosis and pathogenesis is contradictory. The aim of the current study was to compare the expression of HLA class I molecules and of oncoproteins that may be sources of peptides presented by HLA class I antigens in non-small-cell lung cancer. For this purpose, the expression of HLA class I antigen and TAP-1 molecule (a transporter in the antigen-processing 1 transport protein) were studied with epidermal growth factor, receptor; c-erbB-2; episialin; wild-type and mutant p53; bcl-2 oncoprotein expression; and angiogenic factor expression (vascular endothelial growth factor and thymidine phosphorylase). The degree of lymphocytic stromal infiltration and of platelet-endothelial cell adhesion molecule-expressing lymphocytes was also studied. A strong association of c-erbB-2 and MUC1 (episialin) expression with HLA class I expression was observed (p = 0.005 and 0.009, respectively). Intense CD31-positive lymphocytic infiltration was also more frequent in HLA class I-positive cases (p = 0.05). Although there was no association of HLA class I expression with survival, loss of the HLA class I expression in MUC1 or c-erbB-2 overexpressing cases conferred a poorer clinical outcome (p = 0.04). Both c-erbB-2 and MUC1 are well-known targets of T-cell-mediated cytotoxicity and cell-cell or cell-matrix adhesion-regulating proteins. The authors provide evidence that the sequence of cell adhesion-disrupting oncoprotein expression, HLA class I induction, and enhanced epitope presentation followed by lymphocytic response is an important pathogenetic three-step sequence of events that define, in part, the clinical outcome in non-small-cell lung cancer.
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PMID:c-erbB-2 and episialin challenge host immune response by HLA class I expression in human non-small-cell lung cancer. 1068 43

An immunogenic peptide (GP2) derived from HER-2/neu binds to HLA-A2.1 very poorly. Some altered-peptide ligands (APL) of GP2 have increased binding affinity and generate improved cytotoxic T lymphocyte recognition of GP2-presenting tumor cells, but most do not. Increases in binding affinity of single-substitution APL are not additive in double-substitution APL. A common first assumption about peptide binding to class I major histocompatibility complex is that each residue binds independently. In addition, immunologists interested in immunotherapy frequently assume that anchor substitutions do not affect T cell receptor contact residues. However, the crystal structures of two GP2 APL show that the central residues change position depending on the identity of the anchor residue(s). Thus, it is clear that subtle changes in the identity of anchor residues may have significant effects on the positions of the T cell receptor contact residues.
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PMID:Class I major histocompatibility complex anchor substitutions alter the conformation of T cell receptor contacts. 1128 14

HER2/neu-derived peptides inducing MHC class II-restricted CD4+ T helper lymphocyte (Th) responses, although critical for tumour rejection, are not thoroughly characterized. Here, we report the generation and characterization of CD4+ T cell clones specifically recognizing a HER-2/neu-derived peptide (776-788) [designated HER2(776-788)]. Such clones yielded specific proliferative and cytokine [gamma-interferon(IFN)-gamma] responses when challenged with autologous dendritic cells (DCs) loaded with HER2(776-788). By performing blocking studies with monoclonal antibodies (MAbs) and by using DCs from allogeneic donors sharing certain HLA-DR alleles, we found that HER2(776-788) is a promiscuous peptide presented, at least, by DRB5*0101, DRB1*0701 and DRB1*0405 alleles. One TCRV beta 6.7+ clone recognized the HLA-DRB5*0101+ FM3 melanoma cell line transfected with a full length HER-2/neu cDNA. Moreover, this clone recognized the HER-2/neu+ SKBR3 breast cancer cell line induced to express HLA-DR, thus demonstrating that HER2(776-788) represents a naturally processed and presented epitope. Our data demonstrate that helper peptide HER2(776-788) represents a promiscuous epitope binding to at least three HLA-DR alleles, thus offering a broad population coverage. The use of antigenic peptides presented by major histocompatibility complex (MHC) class II in addition to those presented by class I may improve the therapeutic efficacy of active immunization.
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PMID:Peptide HER2(776-788) represents a naturally processed broad MHC class II-restricted T cell epitope. 1172 Apr 40

Dendritic cells (DCs) are powerful antigen-presenting cells that process antigens and present peptide epitopes in the context of the major histocompatibility complex molecules to generate immune responses. DCs are being studied as potential anticancer vaccines because of their ability to present antigens to naive T cells and to stimulate the expansion of antigen-specific T-cell populations. We investigated an antitumor vaccination using DCs modified by transfer of a nonsignaling neu oncogene, a homologue of human HER-2/neu, in a transgenic model of breast cancer. BALB-neuT mice develop breast cancers as a consequence of mammary gland-specific expression of an activated neu oncogene. We vaccinated BALB-neuT mice with bone marrow-derived DCs transduced with Ad.Neu, a recombinant adenovirus expressing a truncated neu oncoprotein. The vaccine stimulated the production of specific anti-neu antibodies, enhanced interferon-gamma expression by T cells, and prevented or delayed the onset of mammary carcinomas in the mice. Over 65% of vaccinated mice remained tumor free at 28 weeks of age, whereas all of the mice in the control groups developed tumors. When challenged with a neu-expressing breast cancer cell line, vaccinated tumor-free animals had delayed tumor growth compared with controls. The antitumor effect of the vaccine was specific for expression of neu. Studies showed that CD4+ T cells were required in order to generate antitumor immunity. Importantly, the effectiveness of the vaccine was not diminished by preexisting immunity to adenovirus, whereas the protection afforded by vaccination that used direct injection of Ad.Neu was markedly reduced in mice with anti-adenovirus antibody titers. DCs modified by recombinant adenoviruses expressing tumor-associated antigens may provide an effective antitumor vaccination strategy.
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PMID:Vaccination by genetically modified dendritic cells expressing a truncated neu oncogene prevents development of breast cancer in transgenic mice. 1552 Feb 11

Peptides derived from pathogens or tumors are selectively presented by the major histocompatibility complex proteins (MHC) to the T lymphocytes. Antigenic peptide-MHC complexes on the cell surface are specifically recognized by T cells and, in conjunction with co-factor interactions, can activate the T cells to initiate the necessary immune response against the target cells. Peptides that are capable of binding to multiple MHC molecules are potential T cell epitopes for diverse human populations that may be useful in vaccine design. Bioinformatical approaches to predict MHC binding peptides can facilitate the resource-consuming effort of T cell epitope identification. We describe a new method for predicting MHC binding based on peptide property models constructed using biophysical parameters of the constituent amino acids and a training set of known binders. The models can be applied to development of anti-tumor vaccines by scanning proteins over-expressed in cancer cells for peptides that bind to a variety of MHC molecules. The complete algorithm is described and illustrated in the context of identifying candidate T cell epitopes for melanomas and breast cancers. We analyzed MART-1, S-100, MBP, and CD63 for melanoma and p53, MUC1, cyclin B1, HER-2/neu, and CEA for breast cancer. In general, proteins over-expressed in cancer cells may be identified using DNA microarray expression profiling. Comparisons of model predictions with available experimental data were assessed. The candidate epitopes identified by such a computational approach must be evaluated experimentally but the approach can provide an efficient and focused strategy for anti-cancer immunotherapy development.
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PMID:Candidate epitope identification using peptide property models: application to cancer immunotherapy. 1554 72


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