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

The effect of linoleic acid (LNA, n-6) and eicosopentanoic acid (EPA, n-3) was investigated on the parental MCF-7 cells and those transfected with v-H-ras. Transfection of v-H-ras oncogene renders the normally estrogen dependent MCF-7 cells estrogen independent. The effects of LNA and EPA in both the cell lines were measured by their ability to enhance the steady state cytoplasmic mRNA levels of 1-8 and 2-5 A, two genes whose transcription is enhanced in various cells in response to interferons (IFNs). The modulatory effect of these fatty acids on the level of an oncogene HER-2/neu was also investigated. Our results indicate that both the fatty acids induce mRNA 1-8 in parental MCF-7 cells but not in the ras transfected cell line, although the gene is induced in both cell lines in response to IFNs. mRNA 2-5A was not induced by LNA or EPA in either of the cell lines. HER-2/neu levels were enhanced by EPA in MCF-7-ras cells. Our data provide evidence to support the concept that selected, nutritionally relevant, fatty acids can regulate gene expression in vitro. These fatty acids can also induce second messenger signals similar to the ones generated by IFNs.
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PMID:Modulation of gene expression by selected fatty acids in human breast cancer cells. 168 95

A wide repertoire of transmembrane proteins are proteolytically released from the cell surface by a process known as 'ectodomain shedding', under both normal and pathophysiological conditions. Little is known about the physiological mechanisms that regulate this process. As a model system, we have investigated the metalloproteinase-mediated cleavage of the hepatocyte growth factor receptor, Met. We show that epidermal growth factor (EGF) receptor activation, either directly by EGF or indirectly via the G-protein coupled receptor (GPCR) agonist lysophosphatidic acid (LPA), induces cleavage of Met through activation of the Erk MAP kinase signalling cascade. The tyrosine kinase activity of the EGFR was a prerequisite for this stimulation, since treatment of cells with a synthetic inhibitor of this receptor, AG1478, completely abrogated shedding. The metalloproteinase mediating Met cleavage was specifically inhibited by the tissue inhibitor of metalloproteinases (TIMP)-3, but not by TIMP-1 or TIMP-2. Furthermore, the level of Met shedding could be modulated by different cell-matrix interactions. Our results indicate that ectodomain shedding is a highly regulated process that can be stimulated by EGFR signalling pathways and integrin ligation.
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PMID:Shedding of c-Met is regulated by crosstalk between a G-protein coupled receptor and the EGF receptor and is mediated by a TIMP-3 sensitive metalloproteinase. 1122 64

Vascular endothelial growth factor (VEGF) and its receptor Flk-1/KDR play an important role in vascular permeability and tumor angiogenesis. Prompted by the hypothesis that VEGF/Flk-1 system may have regulatory roles in breast carcinogenesis, we investigated the expression of Flk-1 in 141 invasive breast carcinomas in correlation with clinical and immunohistochemical prognostic parameters, including proliferation indices like Ki-67 and Topoisomerase IIalpha (Topo-IIalpha). The immunohistochemical avidin-biotin-peroxidase method was performed on paraffin sections for the detection of Flk-1, p53, Bcl-2, c-erbB-2, Ki-67, Topo-IIalpha, ER, and PR. Flk-1 was detected in 91 of 141 (64.5%) of invasive breast carcinomas showing a widespread cytoplasmic expression in most of the neoplastic cells. Flk-1 expression was correlated with the menopausal status (P = 0.051) of the patient and the nuclear grade of the invasive breast carcinoma (P = 0.003), but demonstrated no correlation with histologic grade, stage, and patient survival. It is interesting that Flk-1 expression demonstrated a significant correlation with 2 well-established proliferation indices, Ki-67 (P = 0.037) and topo-IIalpha (P = 0.009), whereas there was no correlation with the expression of ER, PR, p53, Bcl-2, and c-erbB-2. Moreover, Flk-1 expression showed an inverse correlation with TIMP-1 mRNA localization in intratumoral stromal cells (P = 0.013). In conclusion, the significant correlation of Flk-1 expression in invasive breast carcinomas with proliferation indices like Ki-67 and topo-IIalpha suggests that VEGF may exert a growth factor activity on mammary cancer cells through its receptor Flk-1. On the other hand, the inverse correlation of Flk-1 with TIMP-1 mRNA in intratumoral stromal cells supports the notion that TIMP-1 may have an inhibitory role on angiogenesis.
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PMID:Expression of the vascular endothelial growth factor receptor-2/Flk-1 in breast carcinomas: correlation with proliferation. 1245 8

Beta-catenin has a crucial role in cell-cell adhesion as well as a signaling role as a member of the Wnt pathway. The aim of this study was to examine the clinicopathological and prognostic value of phosphorylated beta-catenin, as well as its relation to the tumors' phenotype, in breast cancer. Immunohistochemistry was applied on 141 paraffin-embedded breast tissue specimens for the detection of phospho-beta-catenin, ER, PR, c-erbB-2, p53, Ki-67, bcl-2, uPAR and TIMP-1. For each case, a phospho-beta-catenin index was determined by image analysis. Phospho-beta-catenin staining was detected in the cytoplasm and the nucleus of the malignant cells. Cytoplasmic phospho-beta-catenin was statistically higher in carcinomas of smaller tumor size (P = 0.030), lower stage (P = 0.026), decreased Ki-67 and high c-erbB-2 immunoreactivity (P = 0.052 and P = 0.037, respectively). Nuclear phospho-beta-catenin showed a parallel correlation with ER and ERbeta (P = 0.022 and P = 0.043, respectively), bcl-2 (P = 0.042), uPAR in cancer cells (P = 0.041) and TIMP-1, although the correlation was borderline (P = 0.066). Cytoplasmic phospho-beta-catenin was found to be independently correlated with prolonged disease-free and overall survival (P = 0.046 and P = 0.002, respectively), whereas nuclear localization was correlated with a shortened overall survival (P = 0.046). In conclusion, phospho-beta-catenin may have a different involvement in invasive breast carcinomas, according to its subcellular distribution. Nuclear localization seems to be related to an aggressive tumor phenotype, negatively affecting patients' overall survival, whereas cytoplasmic localization is associated with a favorable tumor phenotype and a longer disease-free and overall survival.
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PMID:Study of phospho-beta-catenin subcellular distribution in invasive breast carcinomas in relation to their phenotype and the clinical outcome. 1647 76

Preeclampsia is a complication of pregnancy manifested as hypertension-in-pregnancy (HTN-Preg) and often intrauterine growth restriction (IUGR). Placental ischemia could be an initiating event, but the molecular mechanisms are unclear. To test the hypothesis that dimerization of matrix metalloproteinases (MMPs) plays a role in HTN-Preg and IUGR, the levels/activity of MMP-9, tissue inhibitor of metalloproteinase (TIMP-1), and their dimerization forms were measured in the placenta, uterus, and uterine artery of normal pregnant (Preg) rats and a rat model of reduced uteroplacental perfusion pressure (RUPP). Consistent with our previous report, blood pressure (BP) was higher, pup weight was lower, and gelatin zymography showed different gelatinolytic activity for pro-MMP-9, MMP-9, pro-MMP-2 and MMP-2 in RUPP vs Preg rats. Careful examination of the zymograms showed additional bands at 200 and 135kDa. Western blots with MMP-9 antibody suggested that the 200kDa band was a MMP-9 homodimer. Western blots with TIMP-1 antibody as well as reverse zymography suggested that the 135kDa band was a MMP-9/TIMP-1 complex. The protein levels and gelatinase activity of MMP-9 homodimer were decreased while MMP-9/TIMP-1 complex was increased in placenta, uterus and uterine artery of RUPP vs Preg rats. The epidermal growth factor (EGF) receptor blocker erlotinib and protein kinase C (PKC) inhibitor bisindolylmaleimide decreased MMP-9 homodimer and increased MMP-9/TIMP-1 complex in placenta, uterus and uterine artery of Preg rats. EGF and the PKC activator phorbol-12,13-dibutyrate (PDBu) reversed the decreases in MMP-9 homodimer and the increases in MMP-9/TIMP-1 complex in tissues of RUPP rats. Thus, the increased BP and decreased pup weight in placental ischemia model of HTN-Preg are associated with a decrease in MMP-9 homodimer and an increase in MMP-9/TIMP-1 complex in placenta, uterus, and uterine artery, which together would cause a net decrease in MMP-9 activity and reduce uteroplacental and vascular remodeling in the setting of HTN-Preg and IUGR. Enhancing EGFR/PKC signaling may reverse the MMP-9 unfavorable dimerization patterns and thereby promote uteroplacental and vascular remodeling in preeclampsia.
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PMID:Decreased homodimerization and increased TIMP-1 complexation of uteroplacental and uterine arterial matrix metalloproteinase-9 during hypertension-in-pregnancy. 2850 58