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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proto-oncogene HER2/neu encodes a protein tyrosine kinase (p185HER2) that is homologous to the human epidermal growth factor receptor. Amplification and/or overexpression of HER2/neu occurs in multiple human malignancies and appears to be integrally involved in progression of some breast and ovarian cancers. Because of this fact, HER2/neu is an intriguing target for specific cancer therapeutic strategies. One such strategy is active specific immunotherapy, in which the immune system is targeted at specific antigens expressed by tumor cells. We have employed a transfected cell line that secretes the extracellular domain of p185HER2 as a source of HER2-derived immunogen in a guinea pig model. The immunized animals developed a cellular immune response, as monitored by delayed-type hypersensitivity, and antisera derived from immunized animals specifically inhibited the in vitro growth of human breast tumor cells overexpressing p185HER2. These data provide support for an immunotherapeutic approach to cancers characterized by overexpression of the HER2/neu proto-oncogene.
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PMID:The extracellular domain of HER2/neu is a potential immunogen for active specific immunotherapy of breast cancer. 197 47

Cases of ductal carcinoma in situ (DCIS) and atypical ductal hyperplasia (ADH) of the breast were examined for expression of the protein product of the c-erbB-2 (neu, HER-2) oncogene using two different polyclonal antibodies via an avidin-biotin immunoperoxidase method on formalin- or Bouin'-fixed, paraffin-embedded tissue. Fifty-five percent (18/33) of DCIS and 10% (2/21) of ADH were positive. Significant c-erbB-2 expression in DCIS was generally divided on histologic grounds: ten of ten comedocarcinomas showed strong membrane staining, while only one of 14 small cell DCIS cases (micropapillary or cribiform patterns) showed immunostaining (which was weak and basilar in this single case). DCIS cases of mixed histology were strongly positive in areas of comedocarcinoma. In two of three cases of associated Paget's disease strong membrane staining was seen. The two c-erbB-2-positive ADH cases showed weak basilar staining akin to the small cell DCIS cases. Five cases of lobular neoplasia (atypical lobular hyperplasia or lobular carcinoma in situ) associated with DCIS or ADH were negative for c-erbB-2 expression. We conclude that comedocarcinoma in situ and Paget's disease frequently express the c-erbB-2 protein and are both histologically and biochemically distinct from ADH and small cell patterns of DCIS. We advocate precise subclassification of DCIS on histopathologic reports, particularly in view of reports that overexpression of the c-erbB-2 oncogene in infiltrating breast carcinomas may be associated with a poor prognosis.
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PMID:Immunohistochemical evaluation of c-erbB-2 oncogene expression in ductal carcinoma in situ and atypical ductal hyperplasia of the breast. 217 Sep 71

Head and neck squamous cell carcinomas (SCC) from 21 patients were analyzed for structurally rearranged or amplified proto-oncogenes by Southern blot hybridization. The int-2 proto-oncogene was amplified 3-5 fold in 5 (50%) of 10 laryngeal SCC and 2-3 fold in 5 (45%) of 11 nonlaryngeal SCC of the head and neck. Adjacent histologically normal tissue from the same patients had single int-2 gene copy number. Coamplification of int-2 and the epidermal growth factor receptor (c-erbB-1) gene was found in one laryngeal SCC and one SCC metastatic to the neck. No amplification or structural alterations of proto-oncogenes c-erbB-2/HER2, c-myc, H-ras-1, or K-ras-2 was detected in any of the head and neck tumors. In a survey of head and neck tumor-derived cell lines, int-2 was amplified 9 fold in a hypopharyngeal tumor cell line (FaDu), but not amplified in 3 laryngeal tumor cell lines. int-2 has been localized to the q13 band of chromosome 11. We used chromosome 11 specific probes to demonstrate that int-2 amplification was not due to complete or partial chromosome 11 duplication. int-2 amplification was localized to 11q13, but did not extend to the ets-1 locus 11q23. The results indicate that int-2 is frequently amplified in SCC of the head and neck and suggest that int-2 amplification may correlate with clinical disease progression.
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PMID:Amplification of the int-2 gene in human head and neck squamous cell carcinomas. 219 94

The neu gene in rat neuro/glioblastoma was found to be activated by a single point mutation in the DNA sequence encoding the transmembrane region of the neu-encoded p185 protein. The human homologue of the rat neu gene, termed c-erbB-2 or HER-2, can also be activated in vitro by a similar mutation in the corresponding region. Although the human neu gene was shown to be amplified/overexpressed in a large portion of human breast and ovarian cancer, no reports indicate that the human neu gene is activated by a point mutation in human tumor. To study the possible point mutation of neu gene in human tumors, we characterized the genomic structure in the transmembrane region of human neu gene, which in turn allowed us to determine DNA sequence in this region directly following DNA amplification by polymerase chain reaction. We analyzed 7 tumor cell lines (2 breast cancer, 1 neuroblastoma, 1 rhabdomyosarcoma, and 3 glioma) and 11 tumor tissue samples (8 breast and 3 ovarian cancers). No mutation was found in the transmembrane region of human neu gene. Our results suggest that unlike the rat neuro/glioblastoma, the single point mutation in the transmembrane region of the human neu gene is a rare event in human tumors. In this study, we developed a technique for direct DNA sequencing of the transmembrane region of the human neu gene. This technique makes it possible to screen a large number of tumor samples.
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PMID:Direct sequencing analysis of transmembrane region of human Neu gene by polymerase chain reaction. 220 83

A variety of tumor characteristics can provide prognostic information useful in managing the patient with primary breast cancer. Some of these characteristics are firmly established, whereas others are observer dependent or require prospective validation. No single characteristic, however, is likely to fully define which patient with primary breast cancer is destined to relapse. This clinical dilemma--recognition of the high-risk patient--is particularly important in the management of women with node-negative breast cancer. Because most women with this early stage of disease will be cured by surgery alone, the use of adjuvant chemotherapy must be limited to high-risk subsets. Tumor size and ER status are established prognostic factors. Histologic and nuclear grade may be important, but problems of interobserver variability remain. Some studies have shown that aneuploidy or a high S-phase fraction may be independent, high-risk characteristics. Flow cytometric DNA content analysis must be applied with caution, however, because the calculation of S-phase fraction has not been standardized and because the prognostic utility of this approach has not been prospectively confirmed. For now, a prudent approach might be to gather as much prognostic information about each patient's tumor as possible. Those with several of the high-risk characteristics listed in Table 2 should receive strongest consideration for adjuvant treatment. Some of these same prognostic factors, along with several others, can be used to characterize the high-risk node-positive patient. The number of involved axillary nodes is the most important established predictor. Progesterone-receptor status is associated with both disease-free and overall survival, whereas ER status is independently related only to overall survival. Histologic grade, DNA ploidy, and S-phase fraction can also be used to help define the high-risk patient. Finally, tumors that amplify or overexpress the HER-2 gene may have a higher risk of relapse, although this finding has been questioned. Management of patients with breast cancer requires an individualized approach that is based on a careful weighing of a variety of prognostic considerations. The relative importance of these factors will require further large-scale, prospective, multiparameter studies. Although results from such studies are awaited, an understanding of the clinical heterogeneity of breast cancer must be based on a multiplicity of observations, each of which characterizes, in a limited way, the biology of this disease.
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PMID:Prognostic factors in breast cancer. 255 4

The HER2/c-erbB-2 gene encodes the epidermal growth factor receptorlike human homolog of the rat neu oncogene. Amplification of this gene in primary breast carcinomas has been show to correlate with poor clinical prognosis for certain cancer patients. We show here that a monoclonal antibody directed against the extracellular domain of p185HER2 specifically inhibits the growth of breast tumor-derived cell lines overexpressing the HER2/c-erbB-2 gene product and prevents HER2/c-erbB-2-transformed NIH 3T3 cells from forming colonies in soft agar. Furthermore, resistance to the cytotoxic effect of tumor necrosis factor alpha, which has been shown to be a consequence of HER2/c-erbB-2 overexpression, is significantly reduced in the presence of this antibody.
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PMID:p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. 256 7

Amplification, rearrangement, or overexpression of the gene for the epidermal growth factor receptor (EGFR) occurs in certain types of human neoplasia. We investigated EGFR gene structure and measured EGFR mRNA levels in human renal tumor biopsies. Seventeen renal tumors [13 renal cell carcinomas (RCCs), two Wilms' tumors, one oncocytoma, and one metastatic ganglioneuroblastoma] and their corresponding normal kidney tissues were examined for EGFR gene structural integrity by Southern blot hybridization. Twelve of these tumors (including 11 RCCs) were examined for EGFR mRNA expression levels by RNA blot hybridization. The EGFR gene was rearranged in one of 13 (8%) of the RCC specimens examined and was highly amplified in the ganglioneuroblastoma. The overall frequency of EGFR gene structure alterations in this series of renal tumors was 12%. Nine of 11 RCC specimens (82%) exhibited markedly elevated EGFR mRNA levels (approximately 2- to 6-fold). In contrast, expression of the EGFR-related protooncogene HER-2 (erbB-2) was found to be decreased in 11 RCCs and one Wilms' tumor; HER-2 gene structure, however, appeared normal in all specimens. These results indicate that overexpression of EGFR mRNA, probably due to changes in gene regulation, and underexpression of HER-2 mRNA are characteristic features of human RCC.
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PMID:Aberrant expression of epidermal growth factor receptor and HER-2 (erbB-2) messenger RNAs in human renal cancers. 257 19

Functional characterization of oncogene products that induce cellular transformation has progressed rapidly in recent years. However, less is known about the mechanism(s) by which the transformed cells may escape destruction by host immune defenses and form tumors. A recently described oncogene that has an important association with aggressive human breast carcinoma is "HER2," for human epidermal growth factor receptor 2. The oncogene has also been called NGL and human c-erbB-2 (ERBB2). In this paper we show that amplification of HER2 oncogene expression can induce resistance of NIH 3T3 cells to the cytotoxic effects of recombinant tumor necrosis factor alpha (rTNF-alpha) or macrophages. Resistance is accompanied by an increased dissociation constant for rTNF-alpha binding to high-affinity receptors on the HER2-transformed NIH 3T3 cells. The resistance phenotype is independent of transformation since NIH 3T3 cells transformed by the activated human homologue of the Harvey-ras oncogene (HRAS) retain high-affinity binding sites for rTNF-alpha as well as sensitivity to its cytotoxic effects. These results suggest that HER2 may potentiate tumorigenesis by inducing tumor cell resistance to host defense mechanisms.
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PMID:Amplified expression of the HER2/ERBB2 oncogene induces resistance to tumor necrosis factor alpha in NIH 3T3 cells. 289 23

The rat neu oncogene encodes a cell surface glycoprotein, p185, that possesses tyrosine kinase activity. The p185 polypeptide exhibits structural similarity to the epidermal growth factor receptor (EGFR) at both the deduced amino acid and nucleic acid level. However, the neu oncogene and the gene encoding the EGFR have been shown to reside on distinct chromosomes. Comparative analysis of the sequences of the normal neu cDNA and of the neu cDNA from neuroblastomas has revealed a single point mutation leading to a valine-to-glutamic acid substitution in the transmembrane anchoring domain. This mutation converts the neu gene to a transforming gene in rodents. In humans, the gene is called ERBB2 (also NGL and HER2), and amplification and over-expression of its products have been detected in certain tumors. The rat embryonal fibroblast cell line (Rat-1) appears to express both EGFR and cellular p185 polypeptides. We have found that EGF stimulates the phosphorylation of p185 in these cells at tyrosine as well as serine and threonine residues in a specific and dose-dependent manner. This activity occurs even though radiolabeled EGF cannot bind to immunopurified p185. The EGF effect is apparently unique since platelet-derived growth factor, insulin, and transforming growth factor beta all fail to phosphorylate p185 at tyrosine. The EGF-induced effect requires interaction of the EGFR and its cognate ligand because cell lines that lack EGFR cannot be shown to phosphorylate p185, even when exposed to large amounts of EGF. Oncogenic rodent p185 and the human p185 homologue ERBB2 that is overexpressed in human breast tumor cells also can be shown to become phosphorylated on tyrosine residues by the action of EGF. Collectively, these data demonstrate that EGF mediates phosphorylation of p185 at tyrosine as well as serine/threonine through cellular kinases by a receptor-specific mechanism.
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PMID:Phosphorylation process induced by epidermal growth factor alters the oncogenic and cellular neu (NGL) gene products. 289 89

The HER2/neu protooncogene was found to be amplified in 6 of 109 primary adenocarcinoma tumors. No HER2/neu amplification was found in 29 other primary nonadenocarcinomatous tumors. In two colon tumors, in addition to the amplification, DNA rearrangement of HER2/neu gene was also observed. The rearrangement was explored in detail in one tumor and it was shown to be confined to the 3' region of the gene. Moreover, this tumor expressed an aberrant HER2/neu polypeptide with a molecular weight of 190,000, which is larger by approximately 5,000 than the molecular weight of the normal HER2/neu protein. The aberrant HER2/neu protein was immunoprecipitated with site-specific antibodies against a synthetic peptide from the COOH-terminal end of the normal HER2/neu protein; it also displayed intrinsic protein tyrosine kinase activity leading to self-phosphorylation.
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PMID:Sporadic amplification of the HER2/neu protooncogene in adenocarcinomas of various tissues. 334 25


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