Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p53 and c-erbB-2 protein expression was immunohistochemically examined in a consecutive series of 49 primary breast cancer patients with a 10-year follow-up. The study was performed on paraffin sections using the monoclonal antibodies DO7 and CBE1; the former recognizes both the wild-type and the mutant p53 forms, the latter recognizes the external domain of the transmembrane c-erbB-2 protein. Positive staining was expressed in 12.2% and 16.3% of cases for p53 and c-erbB-2 proteins, respectively. The results were related to clinicopathological parameters by the chi 2 test. A significant correlation was found between positive c-erbB-2 immunostaining and poor survival (P = 0.04) and between p53 and c-erbB-2 overexpression (P = 0.003); this co-overexpression correlated well with a poor clinical outcome (P = 0.040). From our results, we may speculate that simultaneous expression of p53 and c-erbB-2 oncoproteins could be a critical event in breast tumor progression, and therefore, of prognostic value to identify patients at high risk.
 ...
PMID:Value of c-erbB-2 and p53 oncoprotein co-overexpression in human breast cancer. 906 84

Overexpression of p185erbB2/neu has been detected in many adenocarcinomas, including prostatic cancer. In this study, a nontumorigenic cell line isolated from the rat prostatic epithelium (NbE) transfected with the activated oncogene p185neu-T was used to investigate the role of this oncogene in tumor progression. When clones overexpressing p185neu-T were injected orthotopically (1.5 to 2 x 10(6) cells) into the dorsal-lateral prostates of nude mice, prostatic tumors were detected in all mice injected and metastasis to the skeletal muscle in the rib area in 60-80% of the mice injected. Tumor and metastasis origin was confirmed by reselection with G418 and reverse transcriptase-polymerase chain reaction. Control cell lines produced no prostatic tumors or metastases. Incubation at low density (12500 cells/2 cm2) in serum-free medium revealed that clones overexpressing p185neu-T had a higher rate of [3H]thymidine incorporation than did control clones on 3, 5, and 7 d after plating (P < or = 0.0001) and constitutively overexpressed the 2.6-kb ornithine decarboxylase transcript. Additionally, clones overexpressing p185neu-T demonstrated an increased expression of epidermal growth factor receptor and p180erbB4, as judged by RNA blot analysis. Together these data support the hypothesis that overexpression of p185neu-T fosters tumor progression by several pathways, including induction of the metastatic cascade, increased proliferative capabilities, and increased expression of other members of the erbB2 gene family.
 ...
PMID:Metastasis induced by overexpression of p185neu-T after orthotopic injection into a prostatic epithelial cell line (NbE). 925 83

In different types of human cancer there is an overexpression of the c-erbB-2 (HER2/neu) oncogene, which is thought to be involved in tumor progression. Therefore the c-erbB-2 oncogene is an attractive target for tumor-specific gene therapy. In this report we have characterized a hammerhead ribozyme against the c-erbB-2 mRNA with high cleavage activity. To select the optimum sequence, the activity of five hammerhead ribozymes was tested in a cell-free assay. The hammerhead ribozyme recognizing the GUC sequence at position +631 to +633 of the c-erbB-2 mRNA (RZ631) efficiently cleaves in vitro transcribed fragments of the c-erbB-2 mRNA [169 to 1450 nucleotides (nt)] under multiple-turnover conditions. The ribozyme coding sequence was subsequently cloned between the A and the B box promoter sequences of the fowl adenovirus type 1 virus-associated RNA (CELO VA) gene. The in vitro activity of RZ631 was shown to be unaffected by the polymerase III promoter flanking sequences. The ability of RZ631 to inhibit the synthesis of the c-erbB-2 gene product in tumor cells was assayed by cotransfection of the ribozyme with a fusion gene of c-erbB-2 and the gene for the enhanced green fluorescent protein as a reporter. The synthesis of the fluorescent fusion protein in NIH:OVCAR-3 ovarian cancer cells was potently inhibited by RZ631, as assayed by flow cytometry. An antisense control vector, where the catalytic core was replaced by a single base, showed a weaker inhibition of expression of the c-erbB-2 derivative. The results suggest that the inhibitory effect of this c-erbB-2 ribozyme is caused by an antisense effect as well as by an additional ribozyme-mediated increase in inhibition. We conclude that this c-erbB-2 ribozyme in conjunction with a polymerase III-based expression system should be useful for the efficient downregulation of the c-erbB-2 oncogene in ovarian cancer cells.
 ...
PMID:Selection of a high activity c-erbB-2 ribozyme using a fusion gene of c-erbB-2 and the enhanced green fluorescent protein. 947 66

The erbB family of tyrosine kinase receptors is involved in the regulation of a variety of vital functions including cell proliferation, cell differentiation, and stress response. Alteration in the expression of erbB receptors occurs in numerous tumor types and plays an important role in cancer development, cancer progression, and susceptibility to cell killing by anticancer agents. Of particular interest is the intrinsic drug resistance associated with overexpression of the erbB-2 receptor. In general, tumor cells overexpressing erbB-2 are intrinsically resistant to DNA-damaging agents such as cisplatin. While the molecular mechanisms by which erbB-2 induces drug resistance are not yet established, there is evidence that this may be a consequence of altered cell cycle checkpoint and DNA repair mechanisms and dysregulation of apoptotic pathway(s). The apoptotic signal induced by many anticancer drugs originates at a receptor on the cell membrane and is transduced through a signaling cascade to the nucleus. Drug-induced apoptosis is dependent on the balance between cell cycle checkpoints and DNA repair mechanisms. Blockade of erbB-2 signaling using erbB-2 antagonists, dominant negative mutants, or chemical inhibitors of erbB-2 tyrosine kinase activity induces cell cycle arrest, inhibits DNA repair, and (or) promotes apoptosis. Less understood are downstream signal transduction cascades by which erbB-2 affects these regulatory mechanisms. The diversity of erbB receptors results in an interconnected network of cell signaling pathways that determine tumor cell fate in response to chemotherapy stress. Further investigations on the role of erbB-coupled signaling in the regulation of stress responsive genes are critical to understand the mechanisms by which tumor cells escape cell death, and will contribute to the development of alternative therapeutic targets to overcome intrinsic drug resistance in clinical settings.
 ...
PMID:The role of ErbB-2 tyrosine kinase receptor in cellular intrinsic chemoresistance: mechanisms and implications. 949 54

In C3H/10T1/2 murine fibroblasts, overexpression of both c-Src and the human epidermal growth factor (EGF) receptor 1 (HER1) is required for detection of stable complexes between the two molecules and results in hyperactivation of the receptor and synergistic increases in tumor formation in nude mice, as compared with cells that overexpress only one of the pair. Elevated levels or activities of c-Src and HER1 also occur in a subset of later-stage breast cancers, suggesting that interactions between these two molecules could contribute to a more aggressive clinical course. To determine whether stable complexes between c-Src and HER1 occur in human breast cancers under the same conditions as in murine fibroblasts and whether the appearance of such complexes correlates with enhanced signaling through the EGF receptor and increased tumor growth, human breast tumor cell lines and tumor tissues were analyzed for a number of c-Src/HER1-mediated signaling events and tumorigenicity. In a panel of 14 cell lines, 10 overexpressed c-Src, and of these, five contained elevated levels of HER1 and exhibited an EGF-dependent association between HER1 and c-Src. This association was also present in a HER1/c-Src-overexpressing tumor sample from a breast cancer patient. Further analysis of signaling events revealed that phosphorylation of the HER1 substrate, Shc, and its downstream effector, mitogen-activated protein kinase, was increased in EGF-stimulated MDA-MB-468, MDA-MB-231, and BT-549 cells (which overexpress both c-Src and HER1) as compared with MCF7 and ZR-75-1 cells (which only overexpress c-Src). Furthermore, MDA-MB-468 and MDA-MB-231 cells displayed increased tumorigenicity in nude mice. These results support the hypothesis that c-Src/HER1 interactions contribute to tumor progression in certain late-stage breast tumor cells.
 ...
PMID:Characterization of human epidermal growth factor receptor and c-Src interactions in human breast tumor cells. 958 56

Molecular changes associated with breast cancer progression were characterized using the MCF-10F cell series. MCF-10F was established from fibrous mastectomy tissue of a patient without detectable cancer. In vitro treatment of MCF-10F cells with benzo(a)pyrene resulted in a transformed subclone MCF-10F-BP1 (BP1). Transfection of clone BP1 with T24-Hras resulted in the tumorigenic line MCF-10F-BP1-Tras (BP1-Tras). Using flow cytometry, the expression of HLA I, ERBB-2 and MUC-1 was found to be comparable in 'normal' MCF-10F, transformed BP1 and tumorigenic BP1-Tras cells. Glycosylated mucin is elevated in BP1 but reduced in BP1-Tras cells. Using mRNA differential display analysis, cDNA profiles of the 'normal', transformed and tumorigenic cell lines were strikingly similar, yet distinct and elevated expression of several common cDNA fragments was detected in BP1 and BP1-Tras when compared with MCF-10F cells. These fragments were cloned and sequenced. The sequences of clones T1-360 and C4-310 are homologous to two reported EST cDNA clones from human fetal tissue and were further characterized. Elevated expression of the genes corresponding to clones T1-360 and C4-310 was verified using Northern blotting. High-level expression of these genes was also detected in the breast cancer cell line MCF-7 that was derived from the pleural effusion of a patient with advanced breast cancer. Therefore, specific molecular changes associated with breast cancer development were identified and may be indicators of neoplastic progression.
 ...
PMID:Neoplastic progression of breast epithelial cells--a molecular analysis. 968 93

Aberrant expression or activity of the epidermal growth factor (EGF) receptor family of tyrosine kinases has been associated with tumor progression and an invasive phenotype. In this study, we utilized 4 ovarian cancer cell lines, OVCA 432, DOV 13, OVEA6 and OVCA 429, to determine the effects of EGF on the regulation of proteolytic enzymes and their inhibitors, cellular migration and in vitro invasion. Induction of urinary-type plasminogen activator (u-PA) activity and tissue inhibitor of matrix metalloproteinase (TIMP)-1 was observed in all 4 cell lines. OVCA 432 cells showed strong PAI-1 induction; however, the other 3 lines displayed substantial baseline PAI-1 expression that was not induced by EGF. EGF-dependent stimulation of migration and induction of matrix metalloproteinase (MMP)-9 (gelatinase B) was observed in OVEA6 and OVCA 429 cells only. Upon EGF receptor activation, DOV 13, OVEA6 and OVCA 429 cells were induced to invade through an artificial basement membrane (Matrigel); however, no invasion was detected in OVCA 432 cells. Cell lines displaying induction of migration and MMP-9 (OVEA6 and OVCA 429) demonstrated robust EGF-induced invasion (5- to 20-fold), and cell invasion was substantially reduced in the presence of anti-catalytic MMP-9 antibody. Addition of anti-catalytic u-PA antibody inhibited the modest (<2-fold) EGF-induced invasion in a cell line that did not express MMP-9 (DOV 13) and in OVEA6 cells that displayed the highest baseline u-PA activity. Together, our findings indicate that multiple proteinases are important in ovarian cell invasion and implicate EGF induction of MMP-9 and migration as key components of more aggressive ligand-induced invasion.
 ...
PMID:Proteinase requirements of epidermal growth factor-induced ovarian cancer cell invasion. 976 68

Transgenic mice engineered to overexpress the HER-2/neu/erbB-2 protooncogene under the control of a mammary-specific promoter develop mammary tumors and are a model for human breast cancer. Signal transduction by Neu was examined in situ in the tumors of these transgenic mice. This was accomplished using the PN2A monoclonal antibody, which recognizes Neu only in the phosphorylated, and therefore actively signaling, state. Immunohistochemistry using PN2A demonstrated that Neu actively signals in the tumors of Neu transgenic mice. Expression of Neu was always accompanied by co-overexpression of the endogenous epidermal growth factor receptor. Qualitatively similar results were found in mammary tumors from mice bitransgenic for the neu and transforming growth factor-alpha genes (both driven by the mouse mammary tumor virus promoter). Early mammary lesions demonstrated distinctive patterns of Neu activation relative to expression levels. Overexpression and activation were separable both temporally and spatially. These results refine the multi-step model for the role of Neu in mammary neoplasia and establish phosphorylation-state specific antibodies as a powerful tool for investigating tumor progression.
 ...
PMID:Active signaling by Neu in transgenic mice. 977 54

The epidermal growth factor (EGF) receptor plays a central role in numerous aspects of keratinocyte biology. In normal epidermis, the EGF receptor is important for autocrine growth of this renewing tissue, suppression of terminal differentiation, promotion of cell survival, and regulation of cell migration during epidermal morphogenesis and wound healing. In wounded skin, the EGF receptor is transiently up-regulated and is an important contributor to the proliferative and migratory aspects of wound reepithelialization. In keratinocytic carcinomas, aberrant expression or activation of the EGF receptor is common and has been proposed to play a role in tumor progression. Many cellular processes such as altered cell adhesion, expression of matrix degrading proteinases, and cell migration are common to keratinocytes during wound healing and in metastatic tumors. The EGF receptor is able to regulate each of these cellular functions and we propose that transient and dynamic elevation of EGF receptor during wound healing, or constitutive overexpression in tumors, provides an important contribution to the migratory and invasive potential of keratinocytes.
 ...
PMID:Contributions of the epidermal growth factor receptor to keratinocyte motility. 985 41

To assess the importance of Neu activation during mammary tumorigenesis, altered receptors harboring in-frame deletions within the extracellular domain were expressed in transgenic mice. Females from several independent lines develop multiple mammary tumors that frequently metastasize to the lung. Tumor progression in these strains was associated with elevated levels of tyrosine-phosphorylated Neu and ErbB-3. Consistent with these observations, a survey of primary human breast tumors revealed frequent co-expression of both erbB-2 and erbB-3 transcripts. The ability of altered Neu receptors to induce mammary tumorigenesis in transgenic mice prompted us to examine whether similar mutations occurred in ErbB-2 during human breast cancer progression. Interestingly, an alternatively spliced form of erbB-2, closely resembling spontaneous activated forms of neu, was detected in human breast tumors. The ErbB-2 receptor encoded by this novel transcript harbors an in-frame deletion of 16 amino acids in the extracellular domain and can transform Rat-1 fibroblasts. Together, these observations argue that co-expression of ErbB-2 and ErbB-3 may play a critical role in the induction of human breast tumors, and raise the possibility that activating mutations in the ErbB-2 receptor may also contribute to this process.
 ...
PMID:Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer. 1020 69


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>