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)

Promoter elements accounting for HER2 (c-erbB-2/neu) overexpression were searched for in several human breast cancer cell lines (MDA-453, BT-474, ZR-75-1, MCF-7) known to express constitutively a 30-fold range in HER2 transcripts per gene copy. HER2 overexpressing cells showed a single prominent DNase I hypersensitive site near a conserved and hitherto unrecognized ets response element (GAGGAA), located 38 bases down-stream from the CAAT box and directly 5' of the TATA box in the human HER2 promoter. Transient transfection of HER2 promoter constructs (0.125, 0.5, and 2.0 kilobase pairs (kb)) demonstrated that the most proximal promoter region (0.125 kb) was capable of conferring up to 30-fold enhanced activity in HER2-overexpressing cell lines relative to low HER2-expressing control lines. Site-directed mutagenesis of the ets response element (GAGGAA-->GAGAGA) caused a > or = 60% reduction in promoter activity affecting at least 0.5 kb of upstream HER2 regulatory sequence. Gel-shift assays with nuclear extracts and oligonucleotide sequences spanning the 0.125-kb promoter region detected an ETS-immunoreactive complex, present most abundantly in cells overexpressing HER2, whose high-affinity binding depended on the GAGGAA response element. Methylation interference confirmed the ETS-specific pattern of protein binding by this complex to guanine bases in the ets response element. UV cross-linking and immunoprecipitation implicate a approximately 60-kDa ETS protein, and candidate ETS genes expressed in these breast cancer cells include GABP alpha, elk-1, elf-1, and PEA3.
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PMID:Binding of an ETS-related protein within the DNase I hypersensitive site of the HER2/neu promoter in human breast cancer cells. 791 92

Spatially regulated activation of the Drosophila epidermal growth factor (EGF) receptor by its ligand, Gurken, is required for establishment of the dorsal/ventral axis of the oocyte and embryo. During mid-oogenesis, Gurken is concentrated at the dorsal-anterior of the oocyte and is thought to activate the EGF receptor pathway in adjacent follicle cells. In response to this signal, dorsal follicle cell fate is determined. These cells further differentiate into either appendage-producing or midline cells, resulting in patterning in the dorsal follicle cell layer. We show here that Pointed, an ETS transcription factor, is required in dorsal follicle cells for this patterning. Loss of pointed results in the loss of midline cells and an excess of appendage-forming cells, a phenotype associated with overactivation of the EGF receptor pathway in the dorsal region. Overexpression of pointed leads to a phenotype similar to that generated by loss of the EGF receptor pathway. This suggests that Pointed normally down-regulates EGF receptor signaling in the midline to generate patterning in the dorsal region. Interestingly, pointed expression is induced by the EGF receptor pathway. These data indicate a novel antagonistic function for Pointed in oogenesis; in response to activation of the EGF receptor, pointed is expressed and negatively regulates the EGF receptor pathway, possibly by integrating information from a second pathway.
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PMID:Pointed, an ETS domain transcription factor, negatively regulates the EGF receptor pathway in Drosophila oogenesis. 901 96

The PEA3 group of transcription factors belongs to the ets family and is composed of 3 known members, PEA3, ERM and ER81, which are more than 95% identical within the DNA-binding ETS domain and exhibit 50% aa identity overall. Recently, transgenic mice bearing the c-erbB-2/neu oncogene have been shown to over-express PEA3 mRNA in mammary adenocarcinomas, suggesting a role for this gene family in mammary tumorigenesis. In the present work we characterized the mRNA expression levels of PEA3-group genes in a series of human epithelial breast cell lines. Each of the 3 genes was highly expressed in normal human HMEC 1001-7 and HMEC 219-4 cells. In breast-cancer cell lines, the 3 genes were highly expressed in the ER- MDA-MB-436, MDA-MB-330, MDA-MB-231 and BT-20 cell lines, but not in the ER+ MDA-MB-134-VI and ZR-75-1 cells. In an attempt to characterize the PEA3-group proteins in breast-cancer cells, we first produced and characterized specific antibodies against each of these 3 proteins. The anti-ERM and anti-ER81 antibodies recognized specific strong bands at approximately 72 kDa and 62 kDa, corresponding to ERM and ER81, respectively, in MDA-MB-231 and Hs-578T cells expressing significant levels of the 3 mRNAs. No protein was detected in MCF-7 cells expressing low levels of mRNA for PEA3-group-family genes, or in ZR-75-1 cells, where mRNA was undetectable by Northern blot. Although in vitro-translated PEA3 is specifically immunoprecipitated by anti-PEA3 anti-serum, we were unable to immunoprecipitate PEA3 protein from MDA-MB-231 and Hs-578T cells. In order to study the transcription factor activity of ERM, PEA3 and ER81 proteins in mammary-cancer cells, we tested their ability to transactivate a reporter plasmid containing 3 Ets-binding sites, and were able to show that, in all the breast-cancer cells tested, transfected ERM, PEA3 and ER81 are able to transactivate. Although the target genes of the PEA3 group of transcription factors in breast-cancer cells have yet to be determined, these genes have a potential role in the regulation of growth and the progression of human breast cancer.
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PMID:Expression of the PEA3 group of ETS-related transcription factors in human breast-cancer cells. 905 61

The ETS protein PEA3 functions as a transcription factor to regulate gene expression. Although members of the ETS family have been reported to be involved in tumor progression, ectopic expression of PEA3 has been shown to suppress tumor formation. Despite several studies demonstrated frequent expression of PEA3 and its high association with HER-2/neu and have suggested a potential role of PEA3 in breast cancer, contradictory result has shown that the PEA3 was associated with better survival rate in breast cancer. In the current study, we address this discrepancy by examining the expression of PEA3 and HER-2/neu on 289 archived breast cancer tumor tissues and their correlation with clinicopathologic factors and prognosis. The staining of PEA3 was further validated by in situ hybridization for PEA3 mRNA. We found PEA3 was positive in 22.2% (64/289) of all cases and only 25.6% (21/82) of HER-2/neu-overexpressing cases showed co-expression of PEA3. In contrast to HER-2/neu, PEA3 expression was not correlated with prognosis or major clinicopathologic factors, except for a negative correlation with lymphovascular permeation ( p=0.007). This study demonstrates that PEA3 expression is not correlated with HER-2/neu expression in breast cancer tumor tissues, nor is it associated with adverse clinicopathologic factors or prognosis.
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PMID:Expression of PEA3 and lack of correlation between PEA3 and HER-2/neu expression in breast cancer. 1675 78

Elevated expression of the epidermal growth factor (EGF) receptor (EGFR) is detected in human ovarian tumors and is associated with decreased recurrence-free and overall survival. EGFR activation affects tumor progression in part by promoting tumor invasion through the induction of prometastatic matrix metalloproteinases (MMP). PEA3, an ETS family transcription factor, is elevated in advanced and metastatic ovarian cancer and regulates MMPs in various cell types, therefore, we investigated whether PEA3 is required for the EGFR-dependent induction of MMP mRNA. MMP-9 and MMP-14 mRNA levels were selectively increased in response to EGFR activity in ovarian tumor cells. EGFR activation resulted in nuclear accumulation of PEA3 and direct binding of PEA3, but not the related protein ETS-1, to the endogenous MMP-9 and MMP-14 promoters. Furthermore, PEA3 overexpression was sufficient to induce MMP-9 and MMP-14 mRNA, tumor cell migration, and invasion, suggesting that PEA3 is an important contributor to the metastatic phenotype. Additionally, inhibition of PEA3 expression via short interfering RNA reduced the EGF induction of MMP-9 and MMP-14 gene expression by 92% and 50%, respectively, and impaired EGF-stimulated tumor cell invasion. These results suggest that PEA3 is regulated by EGFR and that the elevated PEA3 expression detected in human ovarian cancer may divert cells to a more invasive phenotype by regulating MMP-9 and MMP-14.
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PMID:PEA3 is necessary for optimal epidermal growth factor receptor-stimulated matrix metalloproteinase expression and invasion of ovarian tumor cells. 1747 71