Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007097 (carcinoma)
 152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enhanced levels of disulfide-linked dimers of the neu oncogene product have been suggested to be associated with the transformed state [Weiner DB, Liu J, Cohen JA, Williams WV, Greene MI: Nature 338:230-231, (1989)]. We, therefore, investigated the properties of the dimeric forms of p185HER-2/neu from the human breast carcinoma cell line, SK-BR-3. We found disulfide-linked dimers as well as noncovalently associated dimers that were detected by cross-linking with bis(sulfosuccinimidyl) suberate (BS3). However, the disulfide-linked dimers did not exist in intact cells, since they were eliminated when the cells were lysed in the presence of the alkylating agent, sodium iodoacetate. Moreover, the disulfide-linked dimeric molecules were not the activated form of p185HER-2 since they incorporated about the same level of phosphate in an in vitro kinase reaction as the monomeric molecules. In contrast, the noncovalent dimers appeared to be present on the surface of intact cells and were phosphorylated at levels at least tenfold higher than monomers in an in vitro kinase reaction.
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PMID:Disulfide-linked and noncovalent dimers of p185HER-2 in human breast carcinoma cells. 137 5

Immunocytochemical assays were performed on cell cultures as well as on a wide range of human tissues using a monoclonal antibody, MAb 83D4, produced by a murine hybridoma generated by immunization with a cell suspension from a paraffin block of human breast carcinoma tissue. Frozen breast tissue samples (n = 49) were compared to fixed and paraffin-embedded samples (n = 62). Paraffin sections (n = 194) from a variety of human tissues were compared to breast immunoreactivity. Immunoprecipitates, resulting from positive reactions between 83D4 and Avidin Biotin Peroxidase, were evaluated by computer-assisted microcytophotometry (SAMBA). In some frozen breast samples (n = 27), 83D4 antigen distribution was correlated with tumor cell DNA index, ploidy balance, growth fraction (Ki67), hormone receptor (ER, PR) antigenic sites, NORsAg and oncoprotein pHER-2/neu cell content. MAb 83D4 reacted with 3 breast cancer cells lines (MCF7, T47D and H466B) but not with normal epithelial breast cells in culture. The immunostaining in frozen paraffin sections from breast were similar. Like most normal tissues, normal breast did not react with 83D4. Cellular MAb 83D4 antigen concentration increases with the degree of malignancy but is independent of DNA nuclear content, ER, PR, growth fraction and pHER-2neu in cancers. These results suggested that routine immunohistochemical procedures using MAb 83D4 could facilitate the grading of breast cancer, in particular by allowing detection of microvascular invasions in the breast as well as at a distance and of blood-born micrometastases, especially in bone marrow.
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PMID:Monoclonal antibody 83D4 immunoreactivity in human tissues: cellular distribution and microcytophotometric analysis of immunoprecipitates on tissue sections. 156 69

The human breast carcinoma cell line SK-BR-3, expresses the neu oncogene product, p185, which is a receptor tyrosine kinase. Using a double monoclonal antibody capture enzyme-linked immunosorbent assay for p185, activity was detected in conditioned media from cultures of SK-BR-3 cells. Two monoclonal antibodies specific for the extracellular domain of p185/neu immunoprecipitated a protein with a molecular mass of approximately 105 kDa. p105 was further shown to compete with p185 for binding to monoclonal antibodies and pulse-chase experiments indicate that it was generated by post-translational processing. Peptide maps showed that p105 and p185 are related polypeptides. Since p105 is close to the predicted size for the extracellular domain of p185/neu, we propose that SK-BR-3 cells specifically process and release this portion of the receptor into the medium. The release of the extracellular domain may have implications in oncogenesis and its detection could prove useful as a cancer diagnostic.
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PMID:The extracellular domain of p185/neu is released from the surface of human breast carcinoma cells, SK-BR-3. 167 Oct 42

Normal tissues, primary tumors, and metastases of mammary and salivary glands and oral/laryngeal mucosa have been analyzed with Northern-blots employing 32P-labeled RNA probes for the expression of the neu oncogene. Neu oncogene expression of a mRNA species of 4.6 kilobases was found in all normal salivary (five) and mammary glands (four) as well as in two normal or inflamed samples of tongue mucosa. This expression was regarded as baseline activity of the neu gene for the respective tissues and was used as standard for the evaluation of benign and malignant tumors. None of 14 squamous cell carcinomas of the oral and laryngeal mucosa showed enhanced neu transcription level. Five fibroadenomas, one benign variant of phylloid tumor, one carcinosarcoma, and one of two proliferative fibrocystic diseases of the breast showed lacking or normal baseline expression of the neu oncogene, as did one monomorphous cystadenolymphoma of the parotid gland. In contrast, four parotid pleomorphic adenomas and one salivary gland adenocarcinoma showed enhanced neu expression. For mammary adenocarcinomas, increased neu oncogene expression concerned ten of 34 cases--all being variants of ductal carcinomas--and all metastases analyzed (six) deriving from three primaries. One adenoid cystic carcinoma also showed enhanced neu expression. Neu overexpression may reflect accidents of genomic reconstitutional events occurring regularly within the differentiation pathway of epithelial/myoepithelial cells. This assumption was supported by further immunohistochemical analysis which showed stainings of myoepithelial and myoepithelia-like cell populations in tumors, especially pleomorphic adenomas and adjacent normal-looking tissues.
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PMID:Comparative investigation of c-erbB2/neu expression in head and neck tumors and mammary cancer. 167 62

Lobular carcinoma in situ (LCIS) has uncertain malignant potential; biologic markers that will identify patients at risk for a poor clinical outcome have been sought actively. Amplification of the c-erbB-2 protooncogene has been correlated with poor prognosis in invasive mammary carcinoma, and immunohistochemical evaluation for expression of the oncogene protein has been correlated with gene amplification. The authors retrospectively evaluated 62 cases of lobular neoplasia for expression of the c-erbB-2 gene product on formalin-fixed, deparaffinized sections, using two monoclonal anti-erbB-2 (p185) antibodies (c-neu Ab3 and m-erb) and one polyclonal anti-erbB-2 antibody (pAb 1) by the avidin-biotin-peroxidase method. All 62 cases were negative with the pAb 1 antibody; one of 62 cases was weakly positive with the c-neu Ab3 in a membranous pattern. Expression of c-erbB-2 gene product was identified on adjacent invasive ductal carcinoma in one case and in adjacent ductal carcinoma in situ in another. None of 15 cases if infiltrating lobular carcinoma was positive with either of the two anti-c-erbB-2 antibodies. Strong positivity was found on benign epithelium in one case, demonstrating epitheliosis. In summary, evidence of expression of the c-erbB-2 gene product was found in one of 57 cases of LCIS and none of 15 cases of invasive lobular carcinoma. This suggests that, in contrast to reported data concerning intraductal and invasive ductal carcinoma, c-erbB-2 oncogene amplification and/or overexpression does not play a significant role in the progression of lobular breast neoplasia.
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PMID:C-erbB-2 oncogene protein in in situ and invasive lobular breast neoplasia. 167 30

A partially agonistic monoclonal antibody, 4D5, known to bind to the extracellular domain of p185HER2 and shown to inhibit long term growth of p185HER2-overexpressing breast cancer cells, was used to study signal transduction and phosphotyrosyl protein substrates associated with this receptor. Normal breast epithelial cells and breast carcinoma cells expressing low levels of p185HER2 were not affected by 4D5. HER2/neu-overexpressing breast cancer cells (BT-474 and SK-Br-3) exposed to 4D5 exhibited rapid phosphorylation of both p185HER2 and an associated 56-kDa phosphotyrosyl protein (ptyr56). Paralleling the 4D5- stimulated phosphorylation of p185HER2 and ptyr56 was a 5-10-fold induction of c-fos mRNA and phosphatidylinositol 4-kinase activity and a 2-fold induction of inositol 1,4,5-trisphosphate 3'-kinase activity. The increased phosphatidylinositol 4-kinase activity immunoprecipitated with p185HER2 and also co-eluted with ptyr56 from an antiphosphotyrosine immunoaffinity column. These results indicate that short term (less than 6 h) 4D5 activation of p185HER2 in overexpressing breast cancer cells produces agonistic-like signaling typical of homologous tyrosine kinase growth factor receptors such as epidermal growth factor receptor. The data also suggest that ptyr56 represents a novel phosphorylated substrate associated with 4D5-stimulated p185HER2.
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PMID:p185HER2 signal transduction in breast cancer cells. 167 43

Diagnosis- and/or prognosis-related alterations of (proto) oncogenes may be detected in neuroblastoma (N-myc), carcinoma of breast and ovary (HER2/neu), NHL (c-myc, bcl-2), CML (c-abl/bcr), and some other neoplasias. A wide variety of methods for the detection of gene alterations can be applied. The methods of detection have to be chosen according to the expected mechanisms of oncogene activation, the availability of adequately prepared tissue, and the technical standard of the laboratory. The sensitivity, specificity, and quantitation of morphological techniques (immunohistochemistry and in situ hybridization) is restricted and their results have to be interpreted most carefully. Whenever possible, at least two different techniques should be used, preferably on two different levels, i.e. RNA/DNA and protein. Furthermore, the combination of morphological and non morphological methods should be aspired.
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PMID:[Oncogenes and oncogene products--possibilities and significance of their detection]. 170 8

The ERBB2 (also called HER2, neu, and c-erbB-2) gene product, which encodes a growth factor receptor, was implicated in the malignancy of human adenocarcinomas. An antibody directed to the rat oncogenic receptor has been previously shown to have an antitumor effect in model systems. In an attempt to extend this observation to the protooncogenic human receptor and also to understand the underlying mechanism, we generated a panel of monoclonal antibodies specific to the extracellular portion of the ERBB2 protein. The effects of the antibodies on tumor growth were compared with their cellular and biochemical actions in vitro. Surprisingly, opposing in vivo effects were observed: although some antibodies almost completely inhibited the growth in athymic mice of transfected murine fibroblasts that overexpress Erbb-2, other antibodies either accelerated tumor growth or resulted in intermediate responses. When tested on cultured human breast carcinoma cells or ERBB2 transfectants, the tumor-stimulatory antibody was found to induce significant elevation of tyrosine phosphorylation of the ERBB2 protein. In contrast, only partial correlation was observed between the capacity to restrict tumor growth and the effects of the antibodies on receptor degradation and cellular proliferation in vitro. This suggests that the antitumor antibodies affect both receptor function and host-tumor interactions. Our results may help establish experimental criteria for the selection of specific antibodies for use either alone or in conjunction with other molecules as pharmacological antitumor agents.
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PMID:Mechanistic aspects of the opposing effects of monoclonal antibodies to the ERBB2 receptor on tumor growth. 171 84

We assayed rat colon tumors induced by N-methyl-N-nitrosourea (MNU) for transforming oncogenes by the NIH 3T3 transfection and nude mouse tumorigenicity assays. Transfection of DNA from 3 of 3 adenomas and 3 of 5 carcinomas induced transformed foci on NIH 3T3 cells. DNA from 2 of 3 primary foci also possessed focus-forming activity, and rat-specific sequences were observed in secondary focus DNAs. Furthermore, NIH 3T3 cells transfected with DNA from a carcinoma and from a primary focus derived from it, both positive in the focus-forming assay, induced tumors in nude mice. We found no evidence for rat H-ras, K-ras, or N-ras sequences in the DNA of any of 16 primary foci derived from 6 rat tumors; thus, in contrast to other animal tumor models induced by MNU, activation of the ras genes does not appear to predominantly occur in MNU-induced rat colon tumors. We also did not observe, in any of these foci, sequences corresponding to the rat neu, raf, fms, met, or hst genes, thus indicating that none of these is the transforming oncogene in our model. These results suggest that an as yet unidentified transforming oncogene may be activated in rat colon tumors induced by MNU.
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PMID:Detection of transforming oncogenes in rat colon tumors induced by direct perfusion with N-methyl-N-nitrosourea. 173 Jan 34

We performed immunohistochemical analyses of 568 breast/cancer specimens using Ki-67, a monoclonal antibody specific for a nuclear antigen present in proliferating cells. The specimens were divided into three groups (I-III) according to the proportion of Ki-positive cells detected. These findings were compared with features of tumor extension as well as with certain prognostic variables. There was no detectable correlation between Ki-67 reactivity and either tumor size or node involvement. In contrast, a statistically significant correlation was found between Ki-67 reactivity and tumor grading, in that G-I tumors had small growth fractions, while a high proportion of G-III tumors exhibited strong (group III) Ki-67 positivity. When growth fractions were compared with biochemical receptor status, a significant difference was detected between tumors with negative and positive findings for receptors. The same co-variation was observed with respect to the overexpression of neu-protein P185, with most neu-positive carcinomas being strongly positive for Ki-67 (group III). In the relapse cases examined, there was a close correspondence between Ki-67 reactivity and the duration of the disease-free period. Long-term observation of patients with primary breast carcinoma revealed that, with regard to overall survival, the less reactive groups I and II differed significantly from group III. With respect to disease-free survival, no difference was detectable between Ki-groups II and III, but when these two groups together were compared with group I, a significant trend emerged. Similar results for both overall and disease-free survival were obtained for subgroups of pT2 and G-II carcinomas as well as for receptor expression.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immunohistochemical evaluation of growth fractions in human breast cancers using monoclonal antibody Ki-67. 175 57


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