Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The S100-related calcium-binding protein S100A4 (p9Ka) is expressed at a low level in rat mammary epithelial cells from normal mammary gland and benign mammary tumors. In transgenic mice, expressed rat S100A4 transgenes co-operate with the activated c-erbB-2 oncogene, neu, to form metastatic mammary tumors. Elevated levels of S100A4 (p9Ka) in cultured benign rat or mouse mammary epithelial cells are associated with the induction of metastatic capability. A cis-acting sequence related to the consensus recognition sequence of GC-factor, 1,300 base pairs upstream of the start site of transcription of the rat S100A4 gene, acts as a cis-acting inhibitor of transcription of the S100A4 (p9Ka) gene in a low S100A4 (p9Ka)-expressing benign rat mammary epithelial cell line, but not in highly expressing rat mammary epithelial cell lines. There is an inverse relationship between the level of S100A4 (p9Ka) mRNA and the level of GC-factor mRNA in a range of rat mammary cell lines. The results suggest a novel mechanism for regulating the expression of the mRNA encoding an S100 protein.
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PMID:Transcriptional down-regulation of the metastasis-inducing S100A4 (p9Ka) in benign but not in malignant rat mammary epithelial cells by GC-factor. 924 9

Elevated levels of the calcium-binding protein S100A4 have been causally linked to the metastatic spread of breast cancer cells in several in vitro and in vivo model systems and, more recently, correlated with patient death in a series of human breast cancer specimens. In transgenic mice expressing MMTV-neu transgenes in mammary gland, additional expression of S100A4 transgenes results in an enhanced metastatic capability. Despite this phenotypic difference arising from elevated S100A4, it is now shown that the primary breast tumours in all mice examined are histopathologically very similar and resemble those human tumours associated with elevated c-erbB-2. Using a panel of genes identified by suppression subtractive hybridization of cDNAs from individual primary tumours and a metastasis, some cDNAs were found to exhibit a differential pattern of expression associated with the expression of S100A4 protein (including osteopontin, S100A9, claudin 2 and several Expressed Sequence Tags sequences). Whilst confirming differential expression of these genes, it was demonstrated that individual primary tumours of matched transgenic status, histology and grade exhibit some degree of heterogeneity at the mRNA level by reverse Northern and Northern hybridizations. This intertumour heterogeneity of mRNA level was confirmed by cDNA array analysis and suggests that even in a transgenic model, which exhibits far less variation than the human disease, there may be multiple mechanisms of disease progression.
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PMID:Examination of tumour histopathology and gene expression in a neu/S100A4 transgenic model of metastatic breast cancer. 1463 31

Elevated levels of the calcium-binding protein S100A4 are associated with poor patient survival in breast cancer patients and induce metastasis in rodent models. To investigate the effects of S100A4 on different components of the metastatic process, epithelial cells lines have been isolated from nonmalignant tumours in neu transgenic mice and from malignant tumours in neu/S100A4 double transgenic mice. Additional cell lines expressing both Neu and S100A4 have also been derived by transfection of rat S100A4 cDNA into tumour cell lines cloned from neu single transgenic mice. Using these cells in transfilter migration assays, it has been shown that increases in either motility or invasive properties correlate with each other and with the level of S100A4 protein. Injection of three of the cell lines separately into the mammary fat pads of nude mice showed that elevated levels of S100A4 correlated with the degree of metastasis to the lungs. In contrast, changes in cell proliferation and cell-substrate adhesion did not correlate with S100A4 levels. Neither motility nor invasiveness correlated with proteolytic degradation of gelatin as measured by zymography. Thus, the results suggest that the main effect of increases in S100A4 levels in metastasis is to generate increased cell motility and invasion and that this latter change is not dependent upon an increased ability to degrade the intercellular matrix.
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PMID:S100A4 regulates cell motility and invasion in an in vitro model for breast cancer metastasis. 1471 Feb 37

Her2/neu (Her2) is a tyrosine kinase belonging to the EGF receptor (EGFR)/ErbB family and is overexpressed in 20-30% of human breast cancers. We sought to characterize Her2 signal transduction pathways further by using MS-based quantitative proteomics. Stably transfected cell lines overexpressing Her2 or empty vector were generated, and the effect of an EGFR and Her2 selective tyrosine kinase inhibitor, PD168393, on these cells was characterized. Quantitative measurements were obtained on 462 proteins by using the SILAC (stable isotope labeling with amino acids in cell culture) method to monitor three conditions simultaneously. Of these proteins, 198 showed a significant increase in tyrosine phosphorylation in Her2-overexpressing cells, and 81 showed a significant decrease in phosphorylation. Treatment of Her2-overexpressing cells with PD168393 showed rapid reversibility of the majority of the Her2-triggered phosphorylation events. Phosphoproteins that were identified included many known Her2 signaling molecules as well as known EGFR signaling proteins that had not been previously linked to Her2, such as Stat1, Dok1, and delta-catenin. Importantly, several previously uncharacterized Her2 signaling proteins were identified, including Axl tyrosine kinase, the adaptor protein Fyb, and the calcium-binding protein Pdcd-6/Alg-2. We also identified a phosphorylation site in Her2, Y877, which is located in the activation loop of the kinase domain, is distinct from the known C-terminal tail autophosphorylation sites, and may have important implications for regulation of Her2 signaling. Network modeling, which combined phosphoproteomic results with literature-curated protein-protein interaction data, was used to suggest roles for some of the previously unidentified Her2 signaling proteins.
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PMID:Phosphoproteomic analysis of Her2/neu signaling and inhibition. 1678 28

Pleomorphic adenoma (PA) is known to occasionally progress to carcinoma, but the mechanisms of its malignant transformation have not been fully elucidated. S100P, an EF-hand calcium-binding protein, has recently been proposed as an initiator of carcinogenesis in some kinds of epithelial tumors. In this study, we aimed to elucidate the potential role of S100P in tumorigenesis and stepwise progression of carcinoma ex pleomorphic adenoma (CXPA) with ductal differentiation. In 31 ductal type CXPAs (8 in situ, 5 intracapsular, and 18 extracapsular) and 28 PAs (21 conventional and 7 atypical) of the salivary gland, we examined the protein expression of S100P, androgen receptor (AR), HER2/neu, p53, and Ki-67 by immunohistochemistry. HER2 expression, p53 expression, and the Ki-67 labeling index were higher in CXPAs than in atypical PAs and conventional PAs, whereas the AR expression level was relatively high even in atypical PAs. S100P overexpression was significantly more prevalent in CXPAs (27 cases; 87.1%) than in atypical PAs (2 cases; 28.6%) and conventional PAs (1 case; 4.8%) (P<0.05). High prevalence of S100P expression was observed in each intraductal, extraductal-intracapsular, and extracapsular component of CXPAs. In addition, equivalent, high-level S100P expression was observed in all histologic subtypes of the malignant component of CXPAs. These results indicate that S100P may play an important role in malignant transformation of ductal cells of PA, and that immunohistochemical staining for S100P would be a useful diagnostic marker for identifying the early phase of CXPA, in combination with AR, HER2, p53, and Ki-67.
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PMID:S100P expression in ductal type of carcinoma ex pleomorphic adenoma. 2131 6