UNIPROT:P04626 - FACTA Search

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Query: UNIPROT:P04626 (erbB-2)
5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of the c-erbB-2 gene-encoded p185 has been reported in approximately 30% of human breast cancers and has been correlated with lymph node metastasis and poor prognosis in breast cancer patients. To investigate whether overexpression of p185 can enhance the metastatic potential of human breast cancer cells, we have introduced the human c-erbB-2 gene into the very low p185-expressing MDA-MB-435 human breast cancer cells and established 435.eB transfectants that express higher levels of p185. In this study, we compared the metastatic phenotypes of the parental MDA-MB-435 cells and the 435.eB transfectants. In vivo experimental metastasis assays in which we injected MDA-MB-435 parental cells or 435.eB transfectants into the tail veins of ICR-SCID mice demonstrated that mice injected with p185-overexpressing 435.eB transfectants formed significantly more metastatic tumors than the mice injected with parental and control cells. The changes in experimental metastatic potential in vivo were accompanied by increased invasiveness in vitro. In addition, the secretion of basement membrane-degradative enzymes, which is an important step in the invasion and metastasis process, was also increased in the p185-overexpressing 435.eB transfectants. These results indicated that p185 overexpression can enhance the metastatic potential of MDA-MB-435 human breast cancer cells. To investigate whether enhanced metastatic potential in the p185-overexpressing 435.eB transfectants was the result of increased cancer cell growth and transformation potential, we compared the growth rate, anchorage-independent growth ability, and tumorigenicity of the 435.eB transfectants with that of the parental cells. The transfectants and the parental cells all had similar growth rates and anchorage-independent growth abilities and demonstrated similar tumorigenic potential. These findings suggest that c-erbB-2 is a metastasis-promoting gene for breast cancers that is distinct from other tumor-promoting genes in that the c-erbB-2 gene can enhance the intrinsic metastatic potentials of MDA-MB-435 cells without increasing their transformation abilities.
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PMID:Overexpression of the c-erbB-2 gene enhanced intrinsic metastasis potential in human breast cancer cells without increasing their transformation abilities. 906 93

We previously demonstrated that delivery of a gene encoding an anti-erbB-2 intracellular single-chain antibody (sFv) resulted in down-regulation of cell surface erbB-2 levels and induction of apoptosis in erbB-2 overexpressing ovarian cancer cells. Based upon these findings, we hypothesized that human breast carcinomas overexpressing erbB-2 would be similarly affected by this genetic intervention. We evaluated the phenotypic effects resulting from intracellular expression of the anti-erbB-2 sFv on the human breast cancer cell lines MDA-MB-361, SK-BR-3, BT-474, MCF-7 and MDA-MB-231. Recombinant adenoviruses encoding either a reporter gene (AdCMVLacZ) or the endoplasmic reticulum (ER) directed anti-erbB-2 sFv (Ad21) were delivered to various breast cancer cell lines. Cell viability was determined by a proliferation assay and fluorescent microscopy allowed visualization of apoptotic cells. An erbB-2 ELISA quantified the endogenous erbB-2 levels of each cell line. The anti-erbB-2 sFv-encoding-adenovirus, Ad21, but not the beta-galactosidase encoding adenovirus, AdCMVLacZ, was cytotoxic to > 95% of the tumor cells in the MDA-MB-361 and SK-BR-3 lines, and > 60% of the tumor cells in the BT-474 line. In marked contrast, the MCF-7 and MDA-MB-231 cell lines showed no change in the rate of cell proliferation following this treatment. The cytotoxic effects generated in the first three lines were a consequence of the induction of apoptosis by the anti-erbB-2 sFv. An ELISA specific for erbB-2 showed that the breast cancer cell lines most susceptible to the anti-erbB-2 sFv, MDA-MB-361, SK-BR-3 and BT-474, overexpressed the erbB-2 protein while the cell lines demonstrating no response to the anti-erbB-2 sFv, MCF-7 and MDA-MB-231, expressed the lowest levels of erbB-2. These results demonstrate that targeted killing of erbB-2 overexpressing cells via intracellular knockout can be accomplished in the context of breast carcinoma. Furthermore, erbB-2 levels in breast tumor cells may be predictive of their sensitivity to sFv-mediated killing. The ability to accomplish selective cytotoxicity of breast cancer cell lines overexpressing the erbB-2 tumor marker should allow for derivation of clinical gene therapy strategies for breast cancer utilizing this approach.
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PMID:An intracellular anti-erbB-2 single-chain antibody is specifically cytotoxic to human breast carcinoma cells overexpressing erbB-2. 917 17

An immunoglobulin phage display library constructed from a tumour-associated pericolic lymph node was panned against the extracellular domain of the oncoprotein c-erbB-2. Sixteen independent clones were confirmed as positive binders based on ELISA analysis of soluble Fabs. Nucleotide sequencing demonstrated that the V(H) region of 12 clones belonged to four different V gene families, and the clones demonstrated varying degrees of somatic mutation compared with germ-line sequences. Fab fragments were examined for cross-reactivity by ELISA and shown to be negative against a panel of irrelevant self and non-self antigens, including bovine serum albumin (BSA), mouse immunoglobulin, tetanus toxoid, heregulin-PE40-FLAG and insulin. Reactivity of Fabs in vitro was verified by immunocytochemistry, which showed binding to the c-erbB-2 over-expressing breast cancer cell line SKBR3 but not to the low-expressing cell line MDA-MB-231. We conclude that a single lymph node library of moderate diversity (2 x 10(7) kappa light chain and gamma heavy chain clones), when derived from an individual whose colorectal tumour over-expressed c-erbB-2, can be successfully panned to isolate a number of unique Fabs specific for this antigen. The nature of the anti-c-erbB-2 Fabs recovered from this library suggests that they may have resulted from a humoral immune response in the individual, and that in vivo antibody responses to tumour-associated antigens may be exploited in vitro for the production of tumour-specific recombinant antibodies.
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PMID:Isolation of human anti-c-erbB-2 Fabs from a lymph node-derived phage display library. 921 40

Breast cancer cells that overexpress HER-2/neu are more resistant to chemotherapeutic agents such as paclitaxel (Taxol) and docetaxel (Taxotere) than those that do not overexpress HER-2/neu. In previous work, we showed that the adenovirus type 5 E1A can repress HER-2/neu expression at the transcriptional level. Here we first demonstrated that paclitaxel sensitivity correlates with HER-2/neu expression level in a panel of mouse fibroblasts expressing different levels of HER-2/ neu, and that downregulation of HER-2/neu expression by E1A sensitizes the cells to paclitaxel. To further test whether E1A can sensitize HER-2/neu-overexpressing human breast cancer cells to paclitaxel through E1A-mediated HER-2/neu repression, an adenoviral vector was used to transfer the E1A gene into two human breast cancer cell lines, MDA-MB-453 and MDA-MB-361, that overexpress HER-2/neu. After E1A delivery, we observed that HER-2/neu expression level was reduced, and cells were treated with paclitaxel. Cell proliferation assays showed a synergistic growth inhibition effect of E1A and paclitaxel. The synergistic effect was also confirmed by soft agar colony-formation assay. Breast cancer cell lines that express low levels of HER-2/neu, MDA-MB-435 and MDA-MB-231 cells showed no synergistic growth inhibition effect when treated on the same protocols. Thus, we concluded that the adenovirus type 5 E1A gene can sensitize paclitaxel-resistant HER-2/neu-overexpressing breast cancer cells to the drug by repressing HER-2/neu expression. This in turn may have important implications for the development of a novel therapy that combines chemotherapy and gene therapy.
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PMID:Chemosensitization of HER-2/neu-overexpressing human breast cancer cells to paclitaxel (Taxol) by adenovirus type 5 E1A. 928 90

The tyrosine kinase inhibitors PD 69896, 153717, and 158780, which belong to the chemical class 4-[ar(alk)ylamino]pyridopyrimidines, have been characterized with respect to enzymology, target specificity, and antiproliferative effects in tumor cells. These compounds were competitive inhibitors with respect to ATP against purified epidermal growth factor (EGF) receptor tyrosine kinase and inhibited EGF receptor autophosphorylation in A431 human epidermoid carcinoma with IC50 values of 2085, 110, and 13 nM, respectively. Onset of inhibition was immediate once cells were exposed to these compounds, whereas recovery of receptor autophosphorylation activity after the cells were washed free of the compound was dependent on inhibitory potency. Thus, full activity returned immediately after removal of PD 69896 but required 8 hr after exposure to PD 158780. PD 158780 was highly specific for the EGF receptor in Swiss 3T3 fibroblasts, inhibiting EGF-dependent receptor autophosphorylation and thymidine incorporation at low nanomolar concentrations while requiring micromolar levels for platelet-derived growth factor- and basic fibroblast growth factor-dependent processes. PD 158780 inhibited heregulin-stimulated phosphorylation in the SK-BR-3 and MDA-MB-453 breast carcinomas with IC50 values of 49 and 52 nM, respectively, suggesting that the compound was active against other members of the EGF receptor family. The antiproliferative effects of this series of compounds against A431 cells correlated precisely with the inhibitory potency against EGF receptor autophosphorylation. PD 158780 reduced clone formation in soft agar of fibroblasts transformed by EGF, EGF receptor, or the neu oncogene but not ras or raf, further demonstrating its high degree of specificity. Finally, this compound was active against clone formation in several breast tumors having different expression patterns of the erbB family, indicating an anticancer utility in tumors expressing these receptors.
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PMID:Biochemical and antiproliferative properties of 4-[ar(alk)ylamino]pyridopyrimidines, a new chemical class of potent and specific epidermal growth factor receptor tyrosine kinase inhibitor. 935 88

We adapted competitive reverse transcription-polymerase chain reaction (RT-PCR) for quantitative evaluation of c-erbB-2 expression in breast cancer. A fixed amount of cDNA target was coamplified with dilutions of a nonhomologous DNA sequence used as an internal standard (IS). The IS and the target shared the same primer sequences but yielded PCR products of different sizes (348 and 340 bp, respectively). A fluorescent sense primer was used so that the PCR products separated on denaturing polyacrylamide gels could be quantified with an automated DNA sequencer. In human breast cancer cell lines, c-erbB-2 expression was found to range from 0.151 to 652 zmol/microgram total RNA (i.e., 91 to 391,200 molecules/microgram total RNA; 1 zmol = 10(-3) amol), with the two highest values corresponding to the c-erbB-2 overexpressing cell lines MDA-MB-453 and SK-BR-3. In a series of 39 breast cancer biopsies, the concentrations ranged from 0.117 zmol/micrograms to 1.15 amol/microgram total RNA (i.e., 70 to 690,000 molecules/microgram total RNA). The c-erbB-2 oncoprotein (p185) was determined in 30 samples by an enzyme immunoassay. A close correlation was found between c-erbB-2 gene and oncoprotein expression (P = 0.0067). Thus, this competitive RT-PCR method appears to be a reliable way to evaluate the expression of c-erbB-2 in small tumor samples.
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PMID:Quantification of c-erbB-2 gene expression in breast cancer by competitive RT-PCR. 936 96

MDA-MB-468 is a human mammary adenocarcinoma cell line that overexpresses the epidermal growth factor (EGF) receptor and undergoes programmed cell death (apoptosis) in response to EGF treatment. Programmed cell death was shown to be greatly enhanced when cells were growth-arrested prior to EGF treatment. Apoptosis was characterized by an initial rounding up and detachment of the cells from their substrate starting about 12 h after EGF treatment, followed by chromatin condensation, nuclear fragmentation and oligonucleosomal fragmentation of the DNA at about 24 to 48 h. Cell death was dependent on de novo protein synthesis. We found a rapid induction of c-fos, c-jun and junB at the mRNA level after about 30 min of EGF treatment and a more delayed upregulation of fosB and fra-1. The junD gene was expressed in the absence of EGF, and it was moderately induced within 30 min of growth factor addition. The increase of the different fos and jun mRNAs were paralleled by an increase of activator protein-1 (AP-1) DNA binding activity. A characterization of the AP-1 complex revealed similar levels of several Fos and Jun proteins. Based on the kinetics of AP-1 accumulation and cell death, it seems likely that AP-1 contributes to the apoptotic cell death of EGF receptor-overexpressing MDA-MB-486 cells.
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PMID:EGF-induced programmed cell death of human mammary carcinoma MDA-MB-468 cells is preceded by activation AP-1. 953 53

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.
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PMID:Characterization of human epidermal growth factor receptor and c-Src interactions in human breast tumor cells. 958 56

Overexpression of the crbB-2 gene-encoded p185(c-erbB-2) is correlated with early onset of metastasis in breast cancer patients. Furthermore, the detection of blood-borne epithelium-derived clustered cells expressing p185(c-erbB-2) was related to advanced stages in breast cancer. To further elucidate the receptor's function in the metastatic process of human breast cancers, we analyzed disaggregated cells and cell clusters from freshly dissected breast cancer tissues. We studied whether their capability of extravasation is correlated with their expression of c-erbB-2. A model for the venular wall was constructed by growing human umbilical vein endothelial cells (HUVECs) on porous membranes coated with basement membrane extracellular matrix. In four control breast cancer cell lines (SK-BR-3, MCF-7, MDA-MB-468, and MDA-MB-468, the latter transfected with a full-length c-erbB-2 cDNA vector) producing different levels of the c-erbB-2 receptor, the expression level correlated positively with the invasiveness of the cells. The invasive, predominantly clustered cells from 14 of 23 tumors were positively stained for p185(c-erbB-2) by immunocytochemistry. Furthermore, we show that the invasive cell populations express the metastasis-associated proteins matrix metalloproteinase MMP-2, CD44, and integrins alpha(v)beta3 and alpha6. In this first study on the behavior of cells and cell clusters from disaggregated operated cancers in an extravasation model, we could demonstrate the presence of c-erbB-2-expressing cell subpopulations within the individual breast cancers that are presumably of high metastatic potential.
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PMID:Selection of potentially metastatic subpopulations expressing c-erbB-2 from breast cancer tissue by use of an extravasation model. 984 70

Ionizing radiation activates the epidermal growth factor receptor (EGFR) and downstream signaling involving the cytoprotective mitogen-activated protein kinase (MAPK) pathway. In our effort to investigate the role of EGFR in cellular responses to radiation, we generated mammary carcinoma cell clones, MCF-TR5-EGFR-CD533 and MDA-TR15-EGFR-CD533, that inducibly express EGFR-CD533, a truncated EGFR mutant lacking mitogenic and transformation activity. EGFR-CD533 expression inhibits radiation- and EGF-induced EGFR autophosphorylation and MAPK activation and, therefore, functions as a dominant-negative mutant without blocking the expression of EGFR or erbB-2, another member of the erbB receptor Tyr kinase family. Expression of EGFR-CD533 only minimally inhibited cell growth and did not alter radiosensitivity to single radiation exposures. However, repeated 2 Gy radiation exposures of cells, under conditions of EGFR-CD533 expression, essentially abolished their ability for subsequent cell growth. These results identify the inhibition of EGFR function through genetic manipulation as a potential therapeutic maneuver. The concept of such an intervention would be the radiosensitization of cells by counteracting a radiation-induced cytoprotective proliferation response.
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PMID:The inducible expression of dominant-negative epidermal growth factor receptor-CD533 results in radiosensitization of human mammary carcinoma cells. 1003 90

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