Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Aberrrant signaling by the epidermal growth factor receptor [EGFR (HER1, erbB1)] and/or HER2/neu tyrosine kinases is present in a cohort of breast carcinomas. Because HER2 is constitutively phosphorylated in some breast tumors, we speculated that, in these cancers, transmodulation of HER2 may occur via EGFR signaling. To test this possibility, we examined the effect of EGFR-specific kinase inhibitors against the HER2-overexpressing human breast tumor lines BT-474, SKBR-3, MDA-361, and MDA-453. ZD1839 (Iressa) is an ATP-mimetic that inhibits the purified EGFR and HER2 kinases in vitro with an IC(50) of 0.033 and >3.7 microM, respectively. The specificity of ZD1839 against EGFR was confirmed in Rat1 fibroblasts transfected with EGFR or HER2 chimeric receptors activated by synthetic ligands without the interference of endogenous receptors. Treatment of all breast cancer cell lines (except MDA-453) with 1 microM ZD1839 almost completely eliminated HER2 phosphorylation. In contrast, the incorporation of [gamma-(32)P]ATP in vitro onto HER2 receptors isolated from BT-474 cells was unaffected by 1 microM ZD1839. EGFR is expressed by BT-474, SKBR-3, and MDA-361 but not by MDA-453 cells, suggesting that ZD1839-mediated inhibition of the EGFR kinase explained the inhibition of HER2 phosphorylation in vivo. In SKBR-3 cells, ZD1839 exhibited a greater growth-inhibitory effect than Herceptin, a monoclonal antibody against the HER2 ectodomain. In both SKBR-3 and BT-474 cells, treatment with ZD1839 plus Herceptin induced a greater apoptotic effect than either inhibitor alone. Finally, ZD1839 completely prevented growth of BT-474 xenografts established in nude mice and enhanced the antitumor effect of Herceptin. These data imply that EGFR tyrosine kinase inhibitors will be effective against HER2-overexpressing breast tumor cells that also express EGFR and support their use in combination with HER2 antibodies, such as Herceptin, against mammary carcinomas with high levels of the HER2 proto-oncogene.
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PMID:Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. 1175 13

The capsid proteins of adenovirus serotype 5 (Ad5) are key to the virus' highly efficient cell binding and entry mechanism. In particular, the penton base plays a significant role in both viral internalization and endosome penetration. We have produced an adenovirus penton fusion protein (HerPBK10) containing moieties for DNA transport and targeted delivery to breast cancer cells. HerPBK10 binds DNA through a polylysine appendage, while the EGF-like domain of the heregulin-alpha(1) isoform is used as the targeting ligand. This ligand binds with high affinity to HER2/3 or HER2/4 heterodimers, which are overexpressed on certain aggressive breast cancers. In addition, this ligand is rapidly internalized after binding, thus adding to the utility of heregulin for targeting. HerPBK10 binds MDA-MB-453 breast cancer cells in a receptor-specific manner, and mediates the entry of a reporter plasmid in MDA-MB-453 cells in culture. Delivery can be competed by excess heregulin peptide, thus confirming receptor specificity. Importantly, the penton segment appears to contribute significantly to enhanced delivery. Complexes containing HerPBK10 and DNA have been optimized to provide targeted gene delivery to breast cancer cells in vitro. We demonstrate that delivery can be accomplished in the presence of serum, thus suggesting a potential use for in vivo delivery.
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PMID:Nonviral gene delivery to human breast cancer cells by targeted Ad5 penton proteins. 1180 94

Expression analysis of genes encoding components of the phosphotyrosine signaling system by cDNA array hybridization revealed elevated levels of FGFR4 transcripts in several mammary carcinoma cell lines. In the FGFR4 gene transcript from MDA-MB-453 mammary carcinoma cells, a G to A conversion was discovered that results in the substitution of glycine by arginine at position 388 in the transmembrane domain of the receptor. The Arg(388) allele was also found in cell lines derived from a variety of other tumor types as well as in the germ-line of cancer patients and healthy individuals. Analysis of three geographically separated groups indicated that it occurs in approximately 50% of the human population. Investigation of the clinical data of 84 breast cancer patients revealed that homo- or heterozygous carriers of the Arg(388) allele had a significantly reduced disease-free survival time (P = 0.01) within a median follow-up of 62 months. Moreover, the FGFR4 Arg(388) allele was associated with early lymph node metastasis and advanced tumor-node-metastasis (TNM) stage in 82 colon cancer patients. Consistent with this finding, MDA-MB-231 mammary tumor cells expressing FGFR4 Arg(388) exhibited increased motility relative to cells expressing the FGFR4 Gly(388) isotype. Our results support the conclusion that the FGFR4 Arg(388) allele represents a determinant that is innocuous in healthy individuals but predisposes cancer patients for significantly accelerated disease progression.
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PMID:Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele. 1183 May 41

Breast cancer produces a variety of growth factors to promote its behavior at primary and secondary sites in autocrine/paracrine manners. However, the role of these growth factors in the colonization of cancer cells in bone, which is one of the most common metastatic sites, is poorly understood. To study this, we established an in vivo model in which the MCF-7 human breast cancer cells caused predominant osteosclerotic bone metastases 20-25 weeks after inoculation into the left cardiac ventricle in female nude mice. To make this model more time efficient, we overexpressed the oncogene Neu, which is associated with aggressive behavior in human breast cancers, in MCF-7 cells (MCF-7/Neu). MCF-7/Neu cells grew without estrogen and developed osteosclerotic bone metastases in 10-12 weeks in animals. Of note, MCF-7/Neu-bearing mice showed substantial plasma levels of human platelet-derived growth factor-BB (hPDGF-BB; 855 +/- 347 pg/ml; mean +/- SE, n = 5), indicating hPDGF-BB production by inoculated MCF-7/Neu cells. MCF-7/Neu cells in culture also produced large amounts of hPDGF-BB. Conditioned medium harvested from MCF-7/Neu cells stimulated osteoblastic bone formation in organ cultures of neonatal mouse calvariae, and a neutralizing antibody to hPDGF-BB blocked the osteoblastic bone formation. Stable transfection of the hPDGF-B AS in MCF-7/Neu cells reduced hPDGF-BB production in culture. Mice bearing these MCF-7/Neu cells with antisense showed reduced bone metastases with decreased plasma hPDGF-BB levels (54 +/- 20 and 35 +/- 21 in two different antisense and 696 +/- 312 pg/ml in empty vector; mean +/- SE; n = 5). Introduction of hPDGF-B cDNA in the MDA-MB-231 human breast cancer cells, which consistently formed osteolytic bone metastases, induced osteosclerotic lesions in the osteolytic bone metastases. In conclusion, we show that MCF-7 cells cause osteosclerotic bone metastases and that Neu enhances this capacity of MCF-7 cells. Our data suggest that MCF-7/Neu-derived hPDGF-BB plays a causative role in the development of osteosclerotic bone metastases in this model.
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PMID:Tumor-derived platelet-derived growth factor-BB plays a critical role in osteosclerotic bone metastasis in an animal model of human breast cancer. 1183 May 52

Overexpession of EGFR has been reported in a variety of human cancers and serves as a target for diagnosis and therapy. In the case of breast cancer, about 48% EGFR and have poor clinical prognosis. Besides the prognostic factors like tumor size, nodal status, histological grade etc., which are significant in the management of breast cancer, EGFR level might also serve as an additional parameter. Immunocytochemical assay has been extensively used to study the expression of EGFR in various cancers. We have generated a panel of monoclonal antibodies against human EGFR with a view to evaluate their application for the diagnosis and therapy of these cancers. In the present study, an EIA has been developed using 2 monoclonal antibodies against hEGFR designated as CIBCNSH3 as the capture antibody and CIBCRGC1 as the detector antibody. EGFR isolated from MDA MB 468, a human breast carcinoma cell line, with high expression of EGFR and purified by conA affinity chromatography and HPLC has been used to develop the EIA procedure. Sera samples of 150 healthy women donors, of 300 breast cancer patients with different histological types of malignancies and of various other types of cancers have been analyzed. The control women had a range for serum EGFR level of 7-162 fmol/ml, whereas the 300 breast cancer patients studied had a range of 126-1587 fmol/ml with a cut off value of 180 fmol/ml. It is interesting to note that 67.5% of breast cancer patients had elevated levels of circulating EGFR. These results might suggest that serum EGFR level can be used as prognostic marker for breast cancer. The serum EGFR level will be compared with disease free interval and patient survival.
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PMID:Enzyme immunoassay of human epidermal growth factor receptor (hEGFR). 1184 25

Cyclooxygenase-2 (COX-2) is an inducible enzyme that converts arachidonic acid to prostaglandins. Overexpression of the COX-2 gene in mammary glands of transgenic mice was sufficient to induce tumorigenesis. We analyzed COX-2 expression in human breast cancers (and breast cancer cell lines) and adjacent ductal carcinoma in situ (DCIS) as well as its association with HER2/neu and clinicopathological variables. Archival primary breast carcinomas (n = 57), adjacent DCIS (n = 14) and DCIS alone (n = 2) were analyzed for COX-2 and HER2 expression by immunohistochemistry using specific monoclonal antibodies. An immunohistochemical scoring system was used. HER2 gene amplification had been analyzed previously by fluorescence in situ hybridization (n = 20). Histology of carcinomas included infiltrating ductal (n = 44), lobular (n = 2), and other (n = 7). Frozen breast cancers and adjacent normal tissue pairs (n = 9) were analyzed for COX-2 mRNA by reverse transcription-PCR. COX-2 and HER2 expression were also analyzed in human breast cancer cell lines (MCF-7, MCF-7/HER2, SK-BR-3, and MDA-MB-231) by immunoblotting. Cytoplasmic COX-2 expression was detected at an intermediate or high level in epithelial cells in 18 of 42 (43%) invasive breast cancers and in 10 of 16 (63%) cases of DCIS. Normal-appearing breast epithelia adjacent to cancer expressed COX-2 in 81% of cases and was generally focal and of similar or decreased intensity relative to adjacent neoplastic epithelia. COX-2 mRNA was detected in all samples analyzed by reverse transcription-PCR and was increased in eight of nine breast cancers relative to paired normal tissue. In archival tumors, no significant correlation was found between COX-2 and HER2 expression/amplification and clinicopathological variables. COX-2 expression was induced in MCF-7 cells stably transfected with HER2, in contrast to parental MCF-7 cells, and was detected in MDA-MB-231, but not SK-BR-3 cells. COX-2 is frequently overexpressed in invasive breast cancers and in adjacent DCIS and, thus, may be an early event in mammary tumorigenesis. Forced HER2 expression in MCF-7 cells was shown to up-regulate COX-2, although no association was found in human tumors. Our results suggest that nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors may be useful in the chemoprevention and therapy of human breast cancer.
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PMID:Cyclooxygenase-2 expression in human breast cancers and adjacent ductal carcinoma in situ. 1191 39

In this study we have investigated the effects of low dose ionizing radiation (2 Gy) on p70 S6 kinase and Akt signaling with respect to Erb-B receptors in both the A431 squamous and the MDA-MB-231 mammary carcinoma cell lines. Ionizing radiation caused a 2-3-fold increase in p70 S6 kinase activity that was blocked pharmacologically using an EGFR inhibitor (AG1478) alone, or in combination with an Erb-B2 inhibitor (AG825). These results suggested that both EGFR and Erb-B2 receptors could initiate radiation-induced activation of p70 S6K. EGFR dependent Erb-B3 signaling also contributed to p70 S6 kinase activity through recruitment and activation of PI3K, which has been shown to regulate p70 S6 kinase activity. Furthermore, inhibition of the EGFR blocked IR stimulated increases in protein translation, a biologic consequence of p70 S6 kinase activation. We also report that ionizing radiation stimulated Akt activity that was partially independent of PI3K activity, but dependent on Erb-B2 function. Erb-B2 inhibition also correlated with enhanced apoptosis following IR exposure, suggesting an important role for Erb-B2 in cell survival. Together this work demonstrates that the Erb-B receptor tyrosine kinase network stimulates cytoprotective p70 S6 kinase and Akt activity in response to clinically relevant doses of ionizing radiation.
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PMID:Ionizing radiation activates Erb-B receptor dependent Akt and p70 S6 kinase signaling in carcinoma cells. 1203 85

Osteolytic bone metastasis is a frequent problem in the treatment of cancer. Ipriflavone, a synthetic isoflavone that inhibits osteoclastic bone resorption, has been used for the treatment of osteoporosis in some countries. Some other isoflavones also exhibit an antitumor effect in vitro and in vivo. Here, we studied the effects of ipriflavone on osteolytic bone metastasis of MDA-231 human breast cancer cells injected intracardially into athymic nude mice (ICR-nu/nu). Daily oral administration of ipriflavone at 12 mg/mouse significantly inhibited the development of new osteolytic bone metastases (p < 0.05) and the progression of established osteolytic lesions (p = 0.01), prolonging the life of tumor-bearing mice (p = 0.01 vs. control). In addition, ipriflavone reduced the number of osteoclasts at the bone-cancer interface with no severe adverse effects on the host. In vitro, ipriflavone inhibited the proliferation and DNA synthesis of MDA-231 cells and blocked the ligand-induced phosphorylation of Tyr(845) of the EGFR. Ipriflavone did not promote apoptosis of MDA-231 cells. Our results show that ipriflavone not only directly inhibits the growth of cancer cells but also reduces osteoclasts to prevent the soft tissue tumor burden and osteolytic bone metastases. These findings raise the possibility that ipriflavone may be of use as a therapeutic agent against osteolytic bone metastasis.
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PMID:Ipriflavone inhibits osteolytic bone metastasis of human breast cancer cells in a nude mouse model. 1211 17

Geldanamycin (GA) was modified with N-tert-butyloxycarbonyl-1,3-diaminopropane to introduce a latent primary amine. After deprotection, this primary amine provided a site for introduction of a maleimide group that enabled linkage to proteins. This maleimido derivative of geldanamycin (GMB-APA-GA) was linked to the monoclonal antibody Herceptin after the antibody had been modified with Traut's reagent to introduce thiol groups. By this sequence, a new immunoconjugate (H:APA-GA) was generated that showed greater antiproliferative activity than the previously reported analogous immunoconjugate created with a 1,4-diaminobutane spacer derivative of geldanamycin to form an immunoconjugate, H:ABA-GA. Both immunoconjugates inhibited in vitro the growth of MDA-361/DYT2 cells, a cell line overexpressing the HER2 antigen, while Herceptin alone was ineffective. However, H:APA-GA showed better efficacy than H:ABA-GA (IC(50) = 0.2 vs 0.58 mg/mL and cell doubling time >12 vs 6 days, respectively). Results of the in vivo therapy experiments in a xenograft model were consistent with the in vitro findings. Treatment with Herceptin prolonged the survival of the tumor-bearing mice when compared with the control group, but H:ABA-GA and H:APA-GA were each more efficacious than unmodified Herceptin. However, unlike H:ABA-GA, the immunoconjugate H:APA-GA caused stable tumor regression (in 25% of the recipients), showing a qualitative improvement with potential clinical relevance.
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PMID:Modifications in synthesis strategy improve the yield and efficacy of geldanamycin-herceptin immunoconjugates. 1212 Nov 34

We have examined whether inhibition of phosphatidylinositol-3 kinase (PI3K) and its target, the serine/threonine kinase Akt, play a role in the antitumor effect of the HER2 antibody Herceptin. Herceptin inhibited colony formation, down-regulated cyclin D1, and increased p27 protein levels in the HER2 gene-amplified BT-474 and SKBR-3 human breast cancer cells. These effects were temporally associated with the inhibition of PI3K activity in vitro as well as Akt function as measured by steady-state levels of phospho-Ser473 Akt and kinase activity against glycogen synthase kinase (GSK)-3beta. These responses were not observed in MDA-361 and MDA-453 cells, which do not exhibit HER2 gene amplification and are relatively resistant to Herceptin. Treatment of BT-474 cells with Herceptin inhibited the constitutive tyrosine phosphorylation of HER3 and disrupted the basal association of HER3 with HER2 and of HER3 with p85alpha potentially explaining the inhibition of PI3K. Treatment with either Herceptin or the PI3K inhibitor LY294002 increased the levels of p27 in the nucleus>cytosol, thus increasing the ratio of p27:Cdk2 in the nucleus and inhibiting Cdk2 activity and cell proliferation. Antisense p27 oligonucleotides abrogated the increase in p27 induced by Herceptin and prevented the antibody-mediated reduction in S phase. Transduction of BT-474 cells with an adenovirus-encoding active (myristoylated) Akt (Myr-Akt), but not with a beta-galactosidase control adenovirus, prevented the Herceptin- or LY294002-induced down-regulation of cyclin D1 and of phosphorylated GSK-3beta and prevented the accumulation of p27 in the nucleus and cytosol. In addition, Myr-Akt prevented Herceptin-induced inhibition of the cell proliferation of BT-474 cells and Herceptin-induced apoptosis of SKBR-3 cells. These data suggest that (a) changes in cell cycle- and apoptosis-regulatory molecules after HER2 blockade with Herceptin result, at least in part, from the inhibition of Akt; and (b) disabling PI3K and Akt is required for the antitumor effect of HER2 inhibitors.
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PMID:Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. 1212 52


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