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)

Ligand-induced dimerization of growth factor receptors is crucial for stimulation of their intrinsic protein tyrosine kinase activity promoting receptor autophosphorylation by an intermolecular mechanism. Moreover, the suppressive and negative dominant action of defective epidermal growth factor receptor (EGFR) was shown to be caused by formation of inactive heterodimers with normal EGFR leading to diminished biological signaling. In this report we explore the structural requirements and functional significance of heterodimerization between EGFR and HER2. HER2 (also called c-erbB-2 or neu) is a member of the EGFR family whose natural ligand is still unknown. We show that in response to EGF, wild type EGFR and various EGFR mutants were able to undergo heterodimerization with HER2. Addition of EGF to transfected cells co-expressing HER2 with a kinase negative point mutant of EGFR (K721A) stimulated heterodimer formation, tyrosine phosphorylation of K721A and HER2, and tyrosine phosphorylation of one of their known substrates, phospholipase C gamma. However, the binding of EGF to transfected cells co-expressing HER2 together with another EGFR mutant CD533 (a deletion mutant lacking most of the cytoplasmic domain of EGFR) caused heterodimerization and inhibition of tyrosine kinase activity. It appears therefore that EGF-induced heterodimerization of EGFR and HER2 can promote either stimulatory or inhibitory influences on kinase activity. We propose that the nature of receptor interactions on the cell surface can either activate or inhibit the initiation of growth factor-controlled cellular signaling.
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PMID:Heterodimerization of c-erbB2 with different epidermal growth factor receptor mutants elicits stimulatory or inhibitory responses. 134 15

Oncogene amplification is found in many human tumors, and its detection may have important prognostic value. However, analysis of gene amplification may be hampered by inadequate tissue or poor DNA quality. We have previously described a polymerase chain reaction (PCR)-based procedure called differential PCR that can detect variations in gene dosage using miniscule amounts of tumor DNA [Frye, R.A., Benz, C.C. & Liu, E. (1989). Oncogene, 4, 1153-1157]. We now report the optimization of this technique for the analysis of oncogene amplification in paraffin-embedded archival tissues. We find that differential PCR is able to detect amplification of the HER2 (c-erbB-2) and the epidermal growth factor receptor (EGFR) genes and can be used to arrive at a semiquantitative estimate of gene dosage. Furthermore, our approach can determine gene amplification in samples in which the DNA is significantly degraded. Using differential PCR on paraffin-embedded tissues from cases previously investigated by standard DNA extraction and dot-blot procedures, good correlation between the two methods was found. Approaches are described to overcome technical problems posed by factors that affect the differential PCR, including the method of DNA extraction and extreme fragmentation of the DNA (less than 200 base pairs). Furthermore, the resulting analytical algorithm reported herein has proved effective in detecting oncogene amplification in archival breast cancer specimens from standard pathology laboratories. Thus, differential PCR will be particularly helpful in the analysis of tumor specimens that are archived, small in size or rare in occurrence.
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PMID:Analysis of gene amplification in archival tissue by differential polymerase chain reaction. 134 62

Amplification and overexpression of the HER2 (c-erbB-2) oncogene was assessed in paraffin-embedded specimens from 27 in situ carcinomas of the breast and from 122 stage II breast cancers. Gene amplification detected in these archival tissues by differential polymerase chain reaction (PCR) was found in 48% of in situ carcinomas and in 21% of stage II lesions (chi 2 = 7.62, p less than or equal to 0.01). In addition, the level of gene amplification correlated with the level of HER2 oncoprotein expression as measured by immunohistochemistry for both in situ cancers (p less than or equal to 0.025) and stage II cancers (p less than or equal to 0.0005). This high incidence of HER2 gene amplification with accompanying overexpression in non-invasive breast tumors suggests that perturbations of the HER2 oncogene are among the earliest and most common genetic lesions in human breast cancer.
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PMID:The HER2 (c-erbB-2) oncogene is frequently amplified in in situ carcinomas of the breast. 134 63

Protein-tyrosine phosphatase (PTPase) activity in frozen human mammary primary carcinoma tissue sections has been quantitated using a modified histochemical assay. The improved method features the assay of PTPase activity in 12-microns sections of air-dried unfixed tissues, and the use of [2-(N-morpholino)-ethanesulfonic acid] (MES) buffer to prepare stable reaction solutions. Tissue samples from 53 primary human mammary carcinomas were assayed for PTPase activity, and immunohistochemically stained for c-erbB-2 protein-tyrosine kinase expression. Elevated levels of PTPase activity were found in 68% of the tumors compared with the level of activity found in normal human mammary tissues. PTPase activity was co-localized with pathology definitive for carcinoma. Excessive activity was demonstrated throughout the cell, with high activity evident in the cell cytoplasmic membrane and the nucleus. Coexistence of elevated expression of c-erbB-2 and increased PTPase activity was present in 53% of the tumors. In contrast, 15% displayed low c-erbB-2 expression and high PTPase activity, and 24% displayed high c-erbB-2 expression and low PTPase activity. No statistically significant association was found between increased PTPase activity and either c-erbB-2 overexpression or grade and stage of disease in primary human mammary tumors.
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PMID:Histochemical staining of protein-tyrosine phosphatase activity in primary human mammary carcinoma: relationship with established prognostic indicators. 134 18

203 tumor specimens from 175 patients were studied. Amplification of ERBB-2 was detected in 14 out of 63 (22%) cases of breast carcinoma, in 1 out of 23 patients with ovarian cancers, in 1 out of 19 cases of colon carcinoma and in 1 out of 27 patients with thyroid cancer. We failed to find more than one copy of ERBB-2 in 34 patients with lung cancers, 6 with sarcomas and 3 with melanomas. There was tendency toward correlation between ERBB-2 amplification and lymph node involvement in patients with breast carcinoma. Thus, the oncogene ERBB-2 is often amplified in human tumors, but breast cancer is characterized by an especially high frequency of ERBB-2 amplification.
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PMID:Amplification of ERBB-2 (HER-2/NEU) oncogene in different neoplasms of patients from USSR. 134 30

The etiology of human breast cancer is poorly understood and no specific marker of transformation has been identified. Amplification of HER-2/neu, as reported in a comprehensive study by Slamon et al, was found to be the most powerful predictor of disease-free and overall survival after the status of the axillary lymph nodes. Our study examines the HER-2/neu oncogene in 61 primary human breast cancers at both the DNA level (by Southern blotting) and the protein level (by immunohistochemical methods). Of the 61 tumors analyzed in our study, 17 (28%) had amplification of HER-2/neu. There was no significant correlation of HER-2/neu amplification with age, tumor diameter or hormone receptor status; however, amplification and overexpression of HER-2/neu was significantly correlated with the status of the axillary lymph nodes (P = 0.02). Of 16 patients with amplification of HER-2/neu, 14 (88%) had positive regional nodes. One of the two node negative cases with amplified HER-2/neu had bone marrow micrometastasis. Overall, 16 out of 17 (94%) tumors of the patients having amplified HER-2/neu had metastatic disease at the time of diagnosis. In summary, HER-2/neu amplification is associated with early tumor dissemination in primary human breast cancer and may be a marker of poor prognosis.
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PMID:HER-2/neu amplification and overexpression in primary human breast cancer is associated with early metastasis. 134 94

Amplification and/or overexpression of the erbB-2 gene have been demonstrated in 20-30% of adenocarcinomas of the breast, ovary, lung, and stomach and are associated with aggressive clinical course and poor prognosis. Interference with erbB-2 function by the use of monoclonal antibodies is a promising approach to the treatment of these diseases. In this study we demonstrate that a combination of two anti-erbB-2-specific antibodies inhibited the growth of human gastric tumor cells in vitro. This combination antibody therapy also inhibited the growth of human tumor cell lines growing as xenografts in nude mice and was able to dramatically reduce established tumors. This is the first reported observation of tumor regression induced by anti-erbB-2 monoclonal antibodies. Treatment was not curative in that tumors regrew after 6 weeks. Treatment with either single antibody alone did not inhibit cell growth or tumor formation. Pulse chase and tyrosine kinase activity experiments were used to investigate the activity of the erbB-2 gene product (gp185erbB-2). The formation of complexes by two antibodies was found to interfere with receptor function and mimic some properties of a typical receptor ligand. Selective interference of the erbB-2 receptor by combination antibody therapy may be advantageous for the treatment of human cancers.
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PMID:Therapy of an animal model of human gastric cancer using a combination of anti-erbB-2 monoclonal antibodies. 134 49

The HER-2/neu oncogene (a member of the Erb-like oncogene family) is distinct from but closely related to the c-erb B gene which encodes the epidermal growth factor receptor (EGFr). HER-2/neu gene amplification was found in a large number of mammary carcinomas and there was a strong correlation between this phenomenon and poor prognosis. In our study HER-2/neu oncogene expression was determined in 16 malignant ovarian tumors, 2 ovarian lymphomas and 5 normal ovaries. The HER-2/neu gene was found both in normal ovaries and malignant tumors, without any apparent difference among the various histological types. In all the specimens examined, HER-2/neu expression did not seem to be related to EGF binding capacity.
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PMID:Preliminary evaluation of HER-2/neu oncogene and epidermal growth factor receptor expression in normal and neoplastic human ovaries. 134 8

The expression of oncogene products related to cell growth (c-erbB-2, c-myc, ras p21, EGFR) was investigated in benign (15 cases) and malignant breast lesions (20 cases) by means of immunohistochemistry using the avidin-biotin-peroxidase technique with polyclonal and monoclonal antibodies. The aim of this study was to evaluate the relationship between the staining positivity and various morphological and biological features, such as tumour type, grading, hormone receptor status and cell kinetic parameters. In benign breast lesions, as expected, the kinetic parameters were low, both for Ki-67 and LI. All the specimens showed a diploid condition (the DI being equal to 1) and we found a limited degree of immunoreactivity for all the growth factors and oncogene products. In breast cancer we studied the distribution of immunohistochemical positivity for EGFR, c-erbB-2, c-myc, ras p21 and Ki-67, which was related to age, nodal status, ER and PgR receptor status, LI, DI and histopathological grading. A significant positive correlation was found both between ras p21 expression and nodal status and ER-ICA positivity. We observed a strong correlation between LI and Ki-67 and an inverse relation between Ki-67 and ER expression. These findings suggest the importance of studying the relationship between prognostic factors which may provide preoperative prediction in the biological behaviour of breast cancer, not only on biopsy specimens, but also on fine needle aspirates.
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PMID:Preliminary study on oncogene product immunohistochemistry (c-erbB-2, c-myc, ras p21, EGFR) in breast pathology. 134 7

The amplification grade of oncogene c-erbB-2 was examined by the polymerase-chain-reaction-method in DNA's of 56 primary mammary carcinomas. 26 (46.4%) of these showed the amplified oncogene c-erbB-2. In the strongly amplified cases, the expression of the c-erbB-2 oncoprotein was verifiable immunohistochemically. Between the progesterone receptor status (PR) and the amplified c-erbB-2 oncogene there was a statistically proven dependency. No correlation was observed between the amplified c-erbB-2 oncogene and the epidermal growth-factor receptor (EGFR).
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PMID:[C-erbB-2 oncogene amplification in breast cancer in correlation to steroid and epidermal growth factor receptor]. 135 Jan 29


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