Disease relevance of ERBB3

• Expression profiling of t(12;22) positive clear cell sarcoma of soft tissue cell lines reveals characteristic up-regulation of potential new marker genes including ERBB3 [1].
• Expression of the ERBB3 gene product in breast cancer [2].
• High expression of ERBB3 is positively associated with the presence of lymph node metastases, but there was no demonstrable relationship with patient survival in this series [2].
• These results suggested that overexpression of ERBB2 and ERBB3 is related to tumor differentiation and invasion in adenoid cystic carcinomas [3].
• Prognostic significance of ERBB3 overexpression in oral squamous cell carcinoma [4].
• P45-sErbB3 may mediate the bidirectional interactions between prostate cancer cells and bone via osteonectin [5].
• Our results provide novel insights into the role of HER3 in melanoma and point out new possibilities for therapeutic intervention [6].
• HER3 overexpression is strongly associated with tumor progression and poor prognosis of patients with gastric cancer [7].

High impact information on ERBB3

• Here we show that treatment of the prostate cancer cell line LNCaP with IL-6 induces tyrosine phosphorylation of ErbB2 and ErbB3, but not ErbB1/EGFR [8].
• Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases [9].
• Recombinant neuregulin-2beta induces the tyrosine-phosphorylation of ErbB2, ErbB3 and ErbB4 in cell lines expressing all of these ErbB-family receptors [10].
• Through their interaction with the ErbB family of receptors (ErbB2, ErbB3 and ErbB4), neuregulins help to regulate cell growth and differentiation in many tissues [10].
• Ligand-induced down-regulation of two growth factor receptors, EGF receptor (ErbB-1) and ErbB-3, correlates with differential ability to recruit c-Cbl, whose invertebrate orthologs are negative regulators of ErbB [11].

Chemical compound and disease context of ERBB3

• ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines [12].
• A recombinant human NGC extracellular domain induced tyrosine phosphorylation of ErbB2 and ErbB3 as well as cell growth of the human breast tumor cell lines, T47D and MDA-MB-453 [13].
• Since ErbB receptor is important for growth, metastasis and drug resistance, inhibition of ErbB-2 and ErbB-3 by pharmacological doses of quercetin may provide a new approach for treatment of prostate cancers [14].
• Transfection of HER2 in MCF7 breast cancer cells that express HER3 caused a phosphoinoside-3 kinase (PI-3K)-dependent activation of Akt, and was associated with an increased resistance of the cells to multiple chemotherapeutic agents (paclitaxel, doxorubicin, 5-fluorouracil, etoposide, and camptothecin) [15].
• Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells [16].

Biological context of ERBB3

• We found the avian erythroblastic leukemia viral oncogene homologue 3 (ERBB3) to be one of the most dramatically up-regulated genes in CCSST [1].
• In conclusion, our data demonstrate new aspects of the phenotype and the biological behavior of CCSST and reveal ERBB3 to be a useful diagnostic marker [1].
• Application of nonparametric Wilcoxon statistical analyses (P < 1 x 10(-6)) and the criteria of 1.5-fold differential gene expression change resulted in the identification of 218 genes, including BMI-1, ERBB3, and those involved in the ubiquitin-proteasome pathway [17].
• This has been attributed to the disruption of ERBB3/ERBB2 heterodimers that maintain a crucial cell survival signal via phosphatidylinositol 3-kinase/AKT [18].
• Overexpression of ERBB3 appears to result from increased levels of gene transcription since in none of the cell lines or primary cancers analysed did we find evidence of gene amplification [2].

Anatomical context of ERBB3

• Markedly elevated ERBB3 mRNA levels were demonstrated in certain human mammary tumor cell lines [19].
• The protein product of the member of the epidermal growth factor receptor family ERBB3 could be shown to be highly present in all of the CCSST cell lines investigated, as well as in 18 of 20 primary tumor biopsies [1].
• Another gene, ERBB3, is involved in oligodendrocyte differentiation [20].
• NRG activated ErbB3 in normal endothelial cells and inhibited growth of these cells [21].
• ErbB2 and ErbB3 receptors mediate inhibition of calcium-dependent chloride secretion in colonic epithelial cells [22].

Associations of ERBB3 with chemical compounds

• We conclude that ErbB2 and ErbB3 are expressed in T(84) cells and are functionally coupled to inhibition of calcium-dependent chloride secretion [22].
• We tested this hypothesis using bleomycin lung injury of transgenic mice incapable of signaling through HER2/HER3 due to lung-specific dominant-negative HER3 (DNHER3) expression [23].
• In fact, abundant ErbB-3 expression is detected only in gefitinib-sensitive NSCLC cell lines [12].
• While EGF, transforming growth factor (TGF)-alpha, and amphiregulin only had a moderate effect, NDF dramatically increased the ErbB-3 phosphotyrosine content [24].
• Binding interaction of the heregulinbeta egf domain with ErbB3 and ErbB4 receptors assessed by alanine scanning mutagenesis [25].

Physical interactions of ERBB3

• These data show that the linear N-terminal region of EGF-like growth factors is directly involved in binding to ErbB-3 [26].
• Previous biophysical studies suggest that the ErbB3 extracellular region remains monomeric when bound to NRG [27].
• Using the yeast two-hybrid system, we have isolated an ErbB-3 binding protein (Ebp1) that interacts with the juxtamembrane domain of ErbB-3 [28].
• We also show that the binding of neuregulin-1beta to ErbB4 and ErbB3 and the binding of betacellulin to both ErbB4 and ErbB1 does not decrease at low pH, unlike the binding of epidermal growth factor and transforming growth factor-alpha to ErbB1 [29].
• We conclude that ErbB-3 is used to couple EGFR to the PI3K/Akt pathway in gefitinib-sensitive NSCLC cell lines harboring WT and mutant EGFRs [12].

Regulatory relationships of ERBB3

• RESULTS: Our results demonstrate that NRG activates ErbB-2/ErbB-3 heterodimers and induces cell death of LNCaP cells [30].
• Furthermore, EGF- and BTC-induced activation of ErbB-3 is impaired in the absence of ErbB-2, suggesting that ErbB-2 has a role in the lateral transmission of signals between other ErbB receptors [31].
• By reverse transcription polymerase chain reaction and Western blotting, we found that the breast cells also express HER3 and that the ovarian line co-expresses the HER4 message [32].
• Our results suggest that the final outcome of patients with high HER1- and HER2-expressing tumours depends on the expression of HER3 and HER4 [33].
• Neither EGF nor heregulin (HRG) induced c-erbB2/c-erbB3 receptor complexes in BT474 [34].

Other interactions of ERBB3

• These findings suggest that increased ERBB3 expression, as in the case of epidermal growth factor receptor and ERBB2, may play a role in some human malignancies [19].
• All primary tumors examined expressed readily detectable levels of HER1 and HER3 and lower levels of HER2 and HER4 [35].
• This sequence-independent effect of the N-terminal domain correlates with an enhanced ability of full-size neuregulin 1 to disrupt higher order oligomers of the ERBB3 extracellular domains in vitro [36].
• However, compared with epidermal growth factor (EGF) receptor, the ERBB2/ERBB3 signaling pair is considered to be attenuation-deficient [36].
• Immunoprecipitation experiments revealed that gp130 was constitutively associated with ErbB-2 and ErbB-3 [37].

Analytical, diagnostic and therapeutic context of ERBB3

• In this report we demonstrate by nucleic acid analysis and immunohistochemistry that the recently recognised third member of this gene family, ERBB3, shows a wide range of expression in breast cancer, and shows stronger immunoreactivity than that observed in normal tissue in 43 out of 195 cases (22%) of primary breast cancer [2].
• We have examined the expression of the two ERBB3 transcripts by Northern blotting in cancer cell lines and normal human fetal and adult tissues [38].
• In a former microarray expression study, we identified ERBB3, a member of the epidermal growth factor receptor (EGFR) family, as a promising new diagnostic marker in the differential diagnosis of CCSST [39].
• Schizophrenia is not associated with the functional candidate gene ERBB3: Results from a case-control study [40].
• We used in situ hybridization to show that normal epidermal cells produce heregulin-alpha messenger RNA and that heregulin receptors, HER3 and/or HER4, as well as their coreceptor HER2/NEU, are expressed by Paget cells [41].

References