Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ERBB2/HER2/NEU receptor tyrosine kinase gene is amplified in up to 30% of human breast cancers. The frequent and specific selection of this receptor kinase gene for amplification in breast cancer implies that it has important normal functions in the mammary gland. To investigate the functions of ErbB2 during normal mouse mammary gland development, we transplanted mammary buds from genetically rescued ErbB2(-/-) embryos that express ErbB2 in the cardiac muscle. ErbB2(-/-) mammary buds transplanted to a wild-type mammary fat pad support outgrowth of an epithelial tree that advances only slowly through the mammary fat pad at puberty. This penetration defect is associated with structural defects in terminal end buds, characterized by a decrease in body cell number, an increased presence of cap-like cells in the prelumenal compartment, and the presence of large luminal spaces. Lobuloalveolar development was not affected in glands that developed from ErbB2(-/-) transplanted tissue. The results may have implications for the aggressive phenotypes associated with ERBB2-overexpressing mammary carcinomas.
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PMID:ErbB2 is required for ductal morphogenesis of the mammary gland. 1556 31

V-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2; synonyms HER2, NEU) encodes a transmembrane glycoprotein with tyrosine kinase-specific activity that acts as a major switch in different signal-transduction processes. ERBB2 amplification and overexpression have been found in a number of human cancers, including breast, ovary and kidney carcinoma. Our aim was to detect ERBB2-regulated target genes that contribute to its tumorigenic effect on a genomewide scale. The differential gene expression profile of ERBB2-transfected and wild-type mouse fibroblasts was monitored employing DNA microarrays. Regulated expression of selected genes was verified by RT-PCR and validated by Western blot analysis. Genome wide gene expression profiling identified (i) known targets of ERBB2 signaling, (ii) genes implicated in tumorigenesis but so far not associated with ERBB2 signaling as well as (iii) genes not yet associated with oncogenic transformation, including novel genes without functional annotation. We also found that at least a fraction of coexpressed genes are closely linked on the genome. ERBB2 overexpression suppresses the transcription of antiangiogenic factors (e.g., Sparc, Timp3, Serpinf1) but induces expression of angiogenic factors (e.g., Klf5, Tnfaip2, Sema3c). Profiling of ERBB2-dependent gene regulation revealed a compendium of potential diagnostic markers and putative therapeutic targets. Identification of coexpressed genes that colocalize in the genome may indicate gene regulatory mechanisms that require further study to evaluate functional coregulation. (Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.)
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PMID:Identification and validation of novel ERBB2 (HER2, NEU) targets including genes involved in angiogenesis. 1560 25

Mutations in the epidermal growth factor receptor gene (EGFR) in lung cancers predict for sensitivity to EGFR kinase inhibitors. HER2 (also known as NEU, EGFR2, or ERBB2) is a member of the EGFR family of receptor tyrosine kinases and plays important roles in the pathogenesis of certain human cancers, and mutations have recently been reported in lung cancers. We sequenced the tyrosine kinase domain of HER2 in 671 primary non-small cell lung cancers (NSCLC), 80 NSCLC cell lines, and 55 SCLCs and other neuroendocrine lung tumors as well as 85 other epithelial cancers (breast, bladder, prostate, and colorectal cancers) and compared the mutational status with clinicopathologic features and the presence of EGFR or KRAS mutations. HER2 mutations were present in 1.6% (11 of 671) of NSCLC and were absent in other types of cancers. Only one adenocarcinoma cell line (NCI-H1781) had a mutation. All HER2 mutations were in-frame insertions in exon 20 and target the identical corresponding region as did EGFR insertions. HER2 mutations were significantly more frequent in never smokers (3.2%, 8 of 248; P=0.02) and adenocarcinoma histology (2.8%, 11 of 394; P=0.003). In 394 adenocarcinoma cases, HER2 mutations preferentially targeted Oriental ethnicity (3.9%) compared with other ethnicities (0.7%), female gender (3.6%) compared with male gender (1.9%) and never smokers (4.1%) compared with smokers (1.4%). Mutations in EGFR, HER2, and KRAS genes were never present together in individual tumors and cell lines. The remarkable similarities of mutations in EGFR and HER2 genes involving tumor type and subtype, mutation type, gene location, and specific patient subpopulations targeted are unprecedented and suggest similar etiologic factors. EGFR, HER2, and KRAS mutations are mutually exclusive, suggesting different pathways to lung cancer in smokers and never smokers.
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PMID:Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. 1575 57

The HER2/neu oncogene is overexpressed in up to 70% of human pancreatic cancer specimens when compared to normal pancreatic tissue. This cell surface receptor can be targeted specifically by the neutralizing antibody Herceptin. Herceptin has been successfully used in combination with other chemotherapeutic agents in breast cancer, a cancer in which only 30% of patients harbor elevated HER2/neu levels. In the present study, we investigated the therapeutic efficacy of Herceptin in combination with gemcitabine and docetaxel. Gemcitabine is currently the standard chemotherapeutic agent used to treat pancreatic cancer. In contrast, docetaxel, a taxane, is only just being investigated in pancreatic cancer. Tumor cell resistance to taxanes is at least in part mediated by the HER2/NEU oncogene. We have previously characterized HER2/NEU expression in human pancreatic cancer cell lines and studied the anti-tumor activity of Herceptin monotherapy in vitro and in vivo. In the present study, combination therapy resulted in a dramatic improvement of animals bearing human pancreatic cancer xenografts. Furthermore, metastasis and production of ascites was lower when a combination of these three agents was used. We conclude that, as with breast cancer, the anti-tumor activity of Herceptin may be improved by combination with taxanes or gemcitabine.
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PMID:Combination therapy for advanced pancreatic cancer using Herceptin plus chemotherapy. 1614 31

NEU (ERBB2) and other members of the epidermal growth factor receptor (EGFR) family have been implicated in human prostate cancer (CAP) development and progression to an androgen-independent state, but the extent of involvement and precise role of this signaling pathway remain unclear. To begin addressing such open questions in an animal model, we have developed a transgenic line in which an oncogenic Neu cDNA (Neu*) driven by the probasin gene promoter is overexpressed in the mouse prostate and causes development of prostatic intraepithelial neoplasia (PIN) that progresses to invasive carcinoma. Expression profiling using microarrays, which was selectively validated and extended by immunophenotyping of Neu*-induced PIN and CAP, led to the identification of some novel biomarkers and also revealed increased expression of Egfr, Erbb3 and phosphorylated androgen receptor. In view of this information from our mouse model, which can be used to analyze further the role of Erbb signaling in prostatic tumorigenesis, we examined human prostate cancer tissue arrays by immunohistochemistry. Based on statistical analyses of the results, we propose the testable hypothesis that ERBB3, shown to be expressed in 86% of the human CAP cases that we examined, is the pivotal element of the Erbb pathway promoting tumorigenesis by heterodimerization with NEU or EGFR, while a NEU/EGFR dimer does not appear to play a significant role in CAP.
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PMID:Prostatic intraepithelial neoplasia and adenocarcinoma in mice expressing a probasin-Neu oncogenic transgene. 1640 39

This retrospective and descriptive study was carried out in the University of Malaya Medical Center (UMMC) from January to September, 2004. This study aimed to evaluate the diagnostic utility of the Cell-Dyn 4000 hematology analyzer's depolarization analysis and to determine the sensitivity and specificity of this technique in the context of malaria diagnosis. A total of 889 cases presenting with pyrexia of unknown origin or clinically suspected of malaria were examined. Sixteen of these blood samples were found to be positive; 12 for P. vivax, 3 for P. malariae, and 1 for P. falciparum by peripheral blood smear as the standard technique for parasite detection and species identification. Demographic characteristics showed that the majority of patients were in the age range of 20-57 with a mean of 35.9 (+/- SD) 11.4 years, and male foreign workers. Of these, 16 positive blood samples were also processed by Cell-Dyne 4000 analyzer in the normal complete blood count (CBC) operational mode. Malaria parasites produce hemozoin, which depolarizes light and this allows the automated detection of malaria during routine complete blood count analysis with the Abbot Cell-Dyn CD4000 instrument. The white blood cell (WBC) differential plots of all malaria positive samples showed abnormal depolarization events in the NEU-EOS and EOS I plots. This was not seen in the negative samples. In 12 patients with P. vivax infection, a cluster pattern in the Neu-EOS and EOS I plots was observed, and appeared color-coded green or black. In 3 patients with P. malariae infection, few random depolarization events in the NEU-EOS and EOS I plots were seen, and appeared color-coded green, black or blue. While in the patient with P. falciparum infection, the sample was color-coded green with a few random purple depolarizing events in the NEU-EOS and EOS I plots. This study confirms that automated depolarization analysis is a highly sensitive and specific method to diagnose whether or not a patient has malaria. This automated approach may prove to be particularly useful in situations where there is little or no clinical suspicion of malaria.
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PMID:Malaria: the value of the automated depolarization analysis. 1643 83

We evaluated the relationship of amplification and polysomy of both the CCND1 and the ERBB2 (alias HER-2/NEU) genes to the overexpression of their proteins in esophageal and gastric cancers and also their association with clinicopathological features. CCND1 gene amplification (45%) was more prevalent than polysomy (25%) in esophageal carcinoma, but the pattern observed was similar in gastric adenocarcinoma (10% amplification, 15% polysomy). For ERBB2, polysomy was a more frequent mechanism than amplification in both esophageal (32.5 vs. 7.5%) and gastric (15 vs. 5%) cancers. Overexpression of cyclin D1 protein was identified in 37.5% of the specimens of esophageal tumors and 35% of gastric tumors, and overexpression of Her-2/neu protein in 12.5 and 7.5%, respectively. The kappa-statistics revealed a fair agreement in both types of tumors only in overexpression and amplification of the CCND1 gene; the ERBB2 gene showed a fair agreement in amplification and polysomy and the level of protein expression in gastric adenocarcinoma. Thus, polysomy 17 could contribute to a high Her-2/neu protein level, at least in gastric cancer. Our data indicated an association with alcohol consumption and the CCND1 gene or protein levels, in both esophageal and gastric cancers.
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PMID:Alterations of the CCND1 and HER-2/neu (ERBB2) proteins in esophageal and gastric cancers. 1649 May 96

ERBB4/HER4 (referred to here as ERBB4) is a unique member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. In contrast to the other three members of the EGFR family (i.e., EGFR, ERBB2/HER2/NEU, and ERBB3), which are associated with aggressive forms of human cancers, ERBB4 expression seems to be selectively lost in tumors with aggressive phenotypes. Consistent with this observation, we show that ERBB4 induces apoptosis when reintroduced into breast cancer cell lines or when endogenous ERBB4 is activated by a ligand. We further show that ligand activation and subsequent proteolytic processing of endogenous ERBB4 results in mitochondrial accumulation of the ERBB4 intracellular domain (4ICD) and cytochrome c efflux, the essential and committed step of mitochondrial regulated apoptosis. Our results indicate that 4ICD is functionally similar to BH3-only proteins, proapoptotic members of the BCL-2 family required for initiation of mitochondrial dysfunction through activation of the proapoptotic multi-BH domain proteins BAX/BAK. Similar to other BH3-only proteins, 4ICD cell-killing activity requires an intact BH3 domain and 4ICD interaction with the antiapoptotic protein BCL-2, suppressed 4ICD-induced apoptosis. Unique among BH3-only proteins, however, is the essential requirement of BAK but not BAX to transmit the 4ICD apoptotic signal. Clinically, cytosolic but not membrane ERBB4/4ICD expression in primary human breast tumors was associated with tumor apoptosis, providing a mechanistic explanation for the loss of ERBB4 expression during tumor progression. Thus, we propose that ligand-induced mitochondrial accumulation of 4ICD represents a unique mechanism of action for transmembrane receptors, directly coupling a cell surface signal to the tumor cell mitochondrial apoptotic pathway.
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PMID:The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells. 1677 20

Overexpression of the HER2/NEU gene is associated with aggressive behavior and poor prognosis in breast cancer, making the Her2/neu protein a directed-therapy target. Tumors of two Puerto Rican (PR) patients overexpressed Her2/neu and resulting partial clinical responses motivated us to compare Her2/neu expression in PR (n = 101) and Caucasian non-Hispanic (n = 95) patients. Immunohistochemistry of tumors showed overexpression of p-Stat3, Cyclin D1, and Her2/neu, compared to non-neoplastic mucosa. Her2/neu and EGF-R protein levels were statistically significantly different with higher levels of both proteins in the PR group. Importantly, Her2/neu expression was strong and diffuse in tumors with signet-ring morphology, while other histo-pathological subtypes showed higher intra-tumoral Her2/neu heterogeneity than typically observed in breast cancer. Targeted therapies in gastric cancer directed at EGF-R and Hers-2/neu pathways warrant further investigation. These therapies may be especially effective in PR patients and in patients with signet-ring cell morphologies with a dismal prognosis.
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PMID:Signal transduction proteins in tumors from Puerto Rican and Caucasian gastric adenocarcinoma patients: expression differences with potential for specific targeted therapies. 1822 43

Toker cells are epithelial cells with clear cytoplasm usually free of cytologic atypia localized within the nipple epidermis. Rarely, they can be so numerous and atypical as to require a careful distinction from malignant cells of Paget's disease. The purpose of this paper was to better define the prevalence of these atypical Toker cells and to investigate phenotypic markers that can be helpful in the differential diagnosis with Paget's disease. Forty cases containing Toker cells were identified in the nipples of 390 patients (10.2%) who underwent complete breast mastectomy. In 24 cases (60%), Toker cells were cytologically bland and benign, disappearing after a few consecutive sections ("normal Toker cells"). In 11 cases (27.5%), Toker cells were more numerous and persistent on serial sections, still retaining bland cytologic features ("hyperplastic Toker cells"). In 5 cases (12.5%), hyperplastic Toker cells also became cytologically atypical ("hyperplastic and atypical Toker cells"). On immunohistochemistry, Toker cells were positive for estrogen (25/25) and progesterone (20/23) receptors, and negative for CD138 (18/19) and p53 (14/14); some hyperplastic and atypical Toker cells (4 cases) and hyperplastic Toker cells (1 case) showed faint immunoreactivity for HER2/NEU. For comparison, Paget's disease were negative for estrogen (6/10) and progesterone (7/10) receptors, and positive for CD138 (7/10), p53 (6/10), and HER2/NEU (9/10). Both Toker cells and Paget's disease stained positive for cytokeratin 7 and epithelial membrane antigen, and negative for p63. In conclusion, Toker cells are detectable in 10% of the nipples and are usually cytologically bland, but in 10% of the cases they can be morphologically atypical. The combined use of CD138/p53 is very helpful in distinguishing these atypical Toker cells from those of Paget's disease.
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PMID:Toker cells of the breast. Morphological and immunohistochemical characterization of 40 cases. 1861 97


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