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)

We evaluated the intra- and inter-observer reproducibility of quantitative immunohistochemical (IHC) analyses using the Cell Analysis Systems (CAS) 200/486 image analyzer of Estrogen Receptor (ER), Progesterone Receptor (PR), proliferation-associated nuclear protein (Ki67), HER-2/neu (c-erbB-2) protein over-expression and cathepsin D (CD) in 20 randomly-selected invasive breast carcinomas. Qualitative analysis of IHC Epidermal Growth Factor Receptor (EGF-R) was also assessed in this study for comparative purposes. Duplicate blind assessments by the same observer showed excellent correlations for all quantitative IHC features (P < 0.001; P = 0.004 for neu). However, the immuno-quantitative analyses results between the 3 different operators showed lower correlation coefficient values, thus being less reproducible. This resulted in systematic differences and bias between the observers. This was also clear from the overall agreement between the 3 observers which was 70% for ER, 70% for PR, 56% for Ki67, 79% for c-erbB-2 and 75% for CD. The qualitative visual assessments of EGF-R, expressed as either positive or negative, showed a 75% agreement between observers and 85% intra-observer agreement (comparable to quantitative digital image processing results). The same results were obtained with kappa statistics. A further analysis of the factors causing the lack of reproducibility was performed. For quantitative IHC, segmentation of stored and retrieved digitized images was quite reproducible between and within well-trained observers. However, variation between different fields of vision of one and the same section showed large variations for most cases. Therefore, differences in sampling of fields within a section appeared to be the major cause of lack of reproducibility between observers, although segmentation differences still added slightly to the inter-observer variations. Accordingly, a strict sampling protocol of fields of vision is mandatory to obtain reproducible quantitative IHC results. It is clear from the present study that so-called random (but in fact, at convenience) selection of fields of vision for measurement is not a sufficient guarantee of adequacy of the sampling.
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PMID:Quantitative immunohistochemistry using the CAS 200/486 image analysis system in invasive breast carcinoma: a reproducibility study. 754 96

The development of human adenocarcinoma of the lung involves multiple genetic changes including activation of oncogenes and loss of tumor suppressor genes. Patients whose lung tumors contain K-ras oncogene mutation, accumulation of the protein product of the tumor suppressor gene p53, or erbB-2/neu oncoprotein overexpression have been shown to have a worse prognosis. We examined these three genetic indicators in 29 lung adenocarcinomas to determine whether these markers are present in the same tumors or if they represent molecular changes that define different subsets of patients. P53 nuclear protein accumulation and erbB-2/neu protein overexpression were determined by immunohistochemical analysis of cryostat sections of tumor specimens and corresponding normal lung tissue. K-ras mutations were detected by radiolabeled oligonucleotide probes, specific for the various twelfth codon mutations, hybridized to exon 1 of K-ras, which was amplified by the polymerase chain reaction. Increased nuclear accumulation of p53 protein was found in 11 adenocarcinomas (38%). All of the p53 positive tumors were found to show high level staining and homogeneous expression of erbB-2/neu protein. K-ras mutations were detected in seven tumors (24%), all of which overexpressed erbB-2/neu. The presence of a K-ras mutation did not correlate with p53 accumulation. In total, 93% of the tumors were found to overexpress erbB-2/neu, the highest being in one tumor with erbB-2/neu gene amplification. The presence of K-ras twelfth codon mutation was associated with increased cigarette smoking. In conclusion, erbB-2/neu overexpression is a common event in lung adenocarcinomas. Furthermore, the presence of K-ras mutation and p53 protein accumulation define separate groups of patients. The mechanisms by which these genetic alterations interact or adversely affect prognosis is unknown.
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PMID:Alterations of K-ras, p53, and erbB-2/neu in human lung adenocarcinomas. 790 43

Overexpression and/or amplification of the HER2/neu gene has been shown in roughly 30% of breast cancer patients. Increased levels of HER2/neu mRNA in some breast cancer cell lines is partially caused by increased gene transcription. In MDA-MB453 human breast cancer cells, an activated trans-acting factor is involved in the increased transcription of HER2/neu by mediating its effects through a specific DNA region in the HER2/neu promoter. A methylation interference experiment showed a novel sequence for protein-DNA interactions. Three polypeptides of approximately 110, 70, and 35 kD interact with this DNA element. This region of the human HER2/neu promoter is highly conserved in the rat and mouse promoters and was shown to be capable of mediating transcriptional trans-activation in HER2/neu-overexpressing MDA-MB453 cells while having little effect in a control cell line that expresses basal levels of HER2/neu. Knowledge on interactions between this DNA element and nuclear protein factors may help us better understand the molecular mechanisms regulating HER2/neu overexpression in breast cancer cells.
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PMID:Identification of a specific DNA region required for enhanced transcription of HER2/neu in the MDA-MB453 breast cancer cell line. 883 33

PLU-1 is a novel breast cancer associated nuclear protein containing highly conserved domains including the PLU domain, putative DNA/chromatin binding motifs, and PHD/LAP domains. Here we report the cloning of the mouse homologue (Plu-1), and document its expression in adult tissues, mammary tumours and the embryo. The overall homology with human PLU-1 is 94% at the protein level, with almost 100% identity in the conserved domains, suggesting functional conservation. As with human PLU-1 the expression of Plu-1 in adult tissues is restricted, with high expression being seen only in testis, while expression in mammary tumours from c-neu transgenic mice is high. Plu-1 is also differentially expressed in the adult mammary gland. In the developing embryo Plu-1 is expressed in a temporally restricted fashion with tissue specific expression being limited to parts of the developing brain, whisker follicle, mammary bud, thymus, limbs, intervertebral disc, olfactory epithelium, teeth, eye, and stomach. The temporal and spatial expression patterns of the transcription factors Bf-1 and Pax9, recently found to bind to PLU-1 through the PLU domain overlap with Plu-1 expression during development. Thus Plu-1 appears to play an important role in mouse embryonic development which may involve interaction with Pax9 and Bf-1.
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PMID:Characterisation and developmental expression of mouse Plu-1, a homologue of a human nuclear protein (PLU-1) which is specifically up-regulated in breast cancer. 1261 14

PLU-1 is a novel breast cancer associated nuclear protein containing highly conserved domains including the PLU domain, putative DNA/chromatin binding motifs, and PHD/LAP domains. Here we report the cloning of the mouse homologue (Plu-1), and document its expression in adult tissues, mammary tumours and the embryo. The overall homology with human PLU-1 is 94% at the protein level, with almost 100% identity in the conserved domains, suggesting functional conservation. As with human PLU-1 the expression of Plu-1 in adult tissues is restricted, with high expression being seen only in testis, while expression in mammary tumours from c-neu transgenic mice is high. Plu-1 is also differentially expressed in the adult mammary gland. In the developing embryo Plu-1 is expressed in a temporally restricted fashion with tissue specific expression being limited to parts of the developing brain, whisker follicle, mammary bud, thymus, limbs, intervertebral disc, olfactory epithelium, teeth, eye, and stomach. The temporal and spatial expression patterns of the transcription factors Bf-1 and Pax9, recently found to bind to PLU-1 through the PLU domain overlap with Plu-1 expression during development. Thus Plu-1 appears to play an important role in mouse embryonic development which may involve interaction with Pax9 and Bf-1.
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PMID:Characterisation and developmental expression of mouse Plu-1, a homologue of a human nuclear protein (PLU-1) which is specifically up-regulated in breast cancer. 1451 92

Most breast cancers are "lipogenic", defined by high fatty acid synthase (FAS) content and dependence on fatty acid synthesis for growth and survival. S14 (Spot 14; THRSP) is a nuclear protein that activates genes required for fatty acid synthesis. The S14 gene is amplified in approximately 15% of breast cancers, but clinical correlates of its expression were unknown. We analyzed 131 breast cancers by immunohistochemistry for S14 and FAS. Staining was graded 0, 1, or 2+, and scores were correlated with traditional tumor markers, histological features, and outcome. S14 and FAS staining were related to tumor size (p=0.05 for S14, p=0.038 for FAS), but not to stage. S14 but not FAS scores correlated with tumor grade in both DCIS (p=0.003) and invasive cases (p<0.001). Invasive cases (pooled node - and +) with weak S14 staining (n=21) showed no recurrence over 3000 d follow-up, including 10 cases with lymph node involvement, whereas 32% of 67 strongly-staining tumors recurred (log rank p<0.0001). S14 scores did not cosegregate with sex steroid receptors, Her2/neu, or cyclin D1. Low level S14 expression is associated with prolonged disease-free survival in invasive cases, including those with nodal metastasis. High-level expression of S14 identifies a subset of high-risk breast cancers that is not specified by analysis of sex steroid receptors, Her2/neu, or cyclin D1, and provides a molecular correlate to histologic features that predict recurrence.
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PMID:Expression of "Spot 14" (THRSP) predicts disease free survival in invasive breast cancer: immunohistochemical analysis of a new molecular marker. 1655 28

The recently identified TGF-beta-inducible early gene 3 (Tieg3) belongs to the gene family of Sp1/Klf-like transcription factors and is upregulated immediately after TGF-beta treatment. To explore the molecular mechanisms of Tieg3-mediated transcriptional control, GAL4-based luciferase assays were performed in order to determine regulatory domains within the Tieg3 protein. Using EGFP-fusion proteins, we monitored the intracellular localization and mapped putative nuclear localization signals (NLS). We provide evidence that the amino-terminus of Tieg3 is essential to repress the transcription and that the loss of the mSin3A interacting domain (SID) disrupts the repressive effects of Tieg3 in the oligodendroglial cell line OLI-neu. Herein we also demonstrate that the zinc finger containing DNA-binding domain (DBD) alone is able to activate the transcription of a reporter gene. Sequence analysis of the zinc finger region revealed no similarities to known activation domains. Analysis of the subcellular localization disclosed Tieg3 as a nuclear protein. Further, we identified the DBD as being essential for the nuclear localization of Tieg3. We detected two closely located putative bipartite NLS within the second and third zinc finger, which are conserved among the members of the Tieg family of proteins. Together these results may help to increase the understanding of Tieg3-mediated transcriptional control and to characterize this TGF-beta-induced Sp1/Klf-like transcription factor.
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PMID:Functional domains of the TGF-beta-inducible transcription factor Tieg3 and detection of two putative nuclear localization signals within the zinc finger DNA-binding domain. 1725 42

Mechanisms that result in HER2/neu over-expression in breast cancer were examined by studying breast cancer cell lines that express much higher levels of HER2/neu mRNA than normal breast tissue while maintaining a near normal HER2/neu gene copy number. Nuclear run-on experiments indicate that the breast cancer cell lines MDA-MB453, BT483 and BT474 have an increased HER2/neu gene transcription rate. By using HER2/neu promoter-CAT constructs, we show that the enhanced HER2/neu transcription rate in MDA-MB453 is due to activation of the gene in trans. We have localized a 13-bp element on the gene promoter that is required for the increased transcription rate and have demonstrated sequence specific interaction of this fragment with a nuclear protein complex. We have also shown that in BT474 cells, transcriptional upregulation is mainly due to gene amplification and does not fully account for the levels of HER2/neu mRNA, demonstrating that deregulation of HER2/neu expression at the post-transcriptional level significantly contributes to HER2/neu overexpression in BT474 cells. Our results suggest that multiple activations of the HER2/neu gene are involved in HER2/neu over-expression in breast cancer lines and that multiple mechanisms may function simultaneously within a single cell line.
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PMID:Mechanisms of deregulated her2/neu expression in breast-cancer cell-lines. 2156 65