Disease relevance of Erbb2

• These results may have implications for the design of ErbB2 RTK-based therapies for both leprosy nerve damage and other demyelinating neurodegenerative diseases [1].
• Among these agents, Herceptin (trastuzumab), a humanized anti-human epidermal growth factor receptor 2 (HER2/c-erbB2) monoclonal antibody, has been used successfully in patients with breast cancer [2].
• In fact, approximately 30-fold amplification of c-erbB-2 was observed in a human adenocarcinoma of the salivary gland [3].
• ErbB2 provides the target for a novel and effective antibody-based therapy (Trastuzumab/Herceptin) used for the treatment of mammary carcinomas [4].
• In addition, these studies provide a rationale for the application of the Neu ectodomain in gene therapy approaches to human malignant glioma and, potentially, to other systemic epithelial malignancies expressing erbB family receptors [5].

Psychiatry related information on Erbb2

• Female transgenic mice coexpressing activated Akt-1 and ErbB-2 develop multifocal mammary tumors with a significantly shorter latency period than mice expressing activated ErbB-2 alone [6].
• There was no statistically significant correlation between over-expression of the p53 and c-erbB-2 proteins and the age of the patients, tumor site, tumor grade, clinical stage, histopathological grading of the tumor, alcohol consumption, and clinical outcome [7].

High impact information on Erbb2

• Amplification of the ErbB2 locus, which encodes a receptor tyrosine kinase, is common in aggressive breast tumors and correlates with poor prognosis [8].
• Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis [8].
• Finally, deletion of the beta 4 signaling domain enhances the efficacy of ErbB2-targeted therapy [8].
• Together these results suggest that the expression of the activated c-neu oncogene was necessary but not sufficient to induce malignant transformation of the mammary epithelial cells [9].
• Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene [10].

Chemical compound and disease context of Erbb2

• CONCLUSIONS: These results suggest that overexpression and increased activity of HER2/neu might be responsible for the development of raloxifene-resistant breast cancer [11].
• Iressa induces cytostasis and augments Fas-mediated apoptosis in acinic cell adenocarcinoma overexpressing HER2/neu [12].
• Role for HER2/neu and HER3 in fulvestrant-resistant breast cancer [13].
• One exception may be the HER-2/neu oncogene product, which is down-regulated by estrogen in responsive breast carcinoma cells but not in two ovarian carcinoma cell lines [14].
• Notably, LFM-A13-delayed tumor progression in the MMTV/neu transgenic mouse model of HER2 positive breast cancer at least as effectively as paclitaxel and gemcitabine [15].

Biological context of Erbb2

• Chromosome 11 amplicons distal to Erbb2 arise in a model (DB) overexpressing a mutant variant of PyMT (Y315/322F) unable to activate phosphatidylinositol 3-kinase [16].
• Here, we identified and characterized mouse Erbb2 gene by using bioinformatics [17].
• Because AK031099 cDNA showed 806 C-->A nucleotide substitution compared with mouse genome draft sequences and mouse Erbb2 ESTs, the nucleotide sequence of mouse Erbb2 cDNA was determined in silico by correcting 806 A of AK031099 cDNA to C [17].
• In addition, constitutive tyrosine phosphorylation of both ErbB2 and ErbB4 was significantly reduced in HB(del/del) hearts [18].
• The cardiac valve and the ventricular chamber phenotypes resembled those displayed by mice lacking EGFR, a receptor for HB-EGF, and by mice conditionally lacking ErbB2, respectively [18].

Anatomical context of Erbb2

• Erbb2 regulates neuromuscular synapse formation and is essential for muscle spindle development [19].
• Sensory Ia afferent neurons establish initial contact with Erbb2-deficient myotubes [19].
• The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1, are essential for development of the sympathetic nervous system [20].
• Neuregulin-1 provides an important axonally derived signal for the survival and growth of developing Schwann cells, which is transmitted by the ErbB2/ErbB3 receptor tyrosine kinases [21].
• HB-EGF induced tyrosine phosphorylation of ErbB2 and ErbB4, and to a lesser degree, of EGFR in cardiac myocytes [18].

Associations of Erbb2 with chemical compounds

• These genes-Rara, Thra, and Erbb2- encode receptors for retinoic acid, thyroxine, and neuregulin, respectively [22].
• ErbB2 receptor tyrosine kinase signaling mediates early demyelination induced by leprosy bacilli [1].
• HER2 (or c-erbB-2), the human homolog of the rat neu proto-oncogene, encodes a transmembrane glycoprotein of the tyrosine kinase family that appears to play an important role in human breast carcinoma [23].
• In contrast, serum-starved, EGF-treated neu proto-oncogene- and oncogene-expressing cells showed constitutively low and high glucose transporter and ODC activities, respectively [24].
• Azoxymethane significantly induced pro-transforming growth factor-alpha (6.4+/-1.3-fold) and increased phospho-(active) EGFR (5.9+/-1.1-fold), phospho-(active) ErbB2 (2.3+/-0.2-fold), and phospho-(active) extracellular signal-regulated kinase (3.3+/-0.4-fold) in premalignant colonocytes [25].

Physical interactions of Erbb2

• We found that SHP2 interacted with ErbB2 and ErbB3 after neuregulin stimulation of muscle cells [26].
• When crossed with mice expressing activated forms of the Neu receptor tyrosine kinase that selectively couple to the Grb2 or Shc signaling pathways the activated type I receptor increased the latency of mammary tumor formation but also enhanced the frequency of extravascular lung metastasis [27].
• Furthermore, this tyrosine phosphorylated protein was not detected in c-Src complexes derived from fibroblasts transformed by either Neu or PyV middle T [28].
• Unlike other ErbB proteins, ErbB-2 binds no known EGF-like ligand [29].
• Heregulin receptors are unable to mediate the rapid internalization of bound ligand as demonstrated in cells transfected with chimeric or wild-type ErbB-2, -3, or -4 receptors (Baulida et al., 1996, J. Biol. Chem. 271, 5251-5257; Pinkas-Kramanski et al., 1996, EMBO J. 15, 2452-2467) [30].

Co-localisations of Erbb2

• Confocal images of double labeling showed that ErbB2 was colocalized with caveolin-3 in cardiac muscle and with dihydropyridine receptor in skeletal muscle, suggesting that ErbB2 was localized at the T-tubule [31].

Regulatory relationships of Erbb2

• Infection of mice transgenic for both MMTV-Wnt-1 and MMTV-tva with RCAS virus carrying an activated Neu oncogene dramatically enhanced tumor formation over what is observed in uninfected bitransgenic animals [32].
• Formation of Neu/ErbB2-induced mammary tumors is unaffected by loss of ErbB4 [33].
• Secondary events also appear to be required for mammary tumorigenesis in MMTV-Neu transgenic mice because the transgene in the tumors usually contains an acquired mutation that activates the Neu protein-tyrosine kinase [34].
• ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors [35].
• Recently, we have shown that these Neu-induced mammary tumors possess elevated c-Src tyrosine kinase activity [36].

Other interactions of Erbb2

• Heterodimerization of epidermal growth factor receptor and wild-type or kinase-deficient Neu: a mechanism of interreceptor kinase activation and transphosphorylation [37].
• ErbB2 expression increases the spectrum and potency of ligand-mediated signal transduction through ErbB4 [38].
• This suggests that, although the c-erbB-2 and epidermal growth factor receptors are structurally quite similar, their activation has different effects upon mammary epithelial cell differentiation [39].
• Synergistic interaction of the Neu proto-oncogene product and transforming growth factor alpha in the mammary epithelium of transgenic mice [40].
• The development of these mammary tumors was correlated with the tyrosine phosphorylation of Neu and the recruitment of c-Src to the Neu complex [40].

Analytical, diagnostic and therapeutic context of Erbb2

• Southern blot analysis showed close similarity of the restriction patterns of the rat c-erbB-2 gene and the rat neu oncogene, suggesting possible involvement of c-erbB-2 in human cancer [3].
• Immunoprecipitation and immunoblot analyses with EGFR- and Neu-specific antisera, however, failed to detect physical complexes of these two receptors [40].
• Indeed, certain monoclonal antibodies (mAbs) to ErbB-2 effectively inhibit tumor growth in animal models and in clinical trials, but the underlying mechanism is incompletely understood [41].
• To begin addressing such open questions in an animal model, we have developed a transgenic line in which an oncogenic Neu cDNA (Neu*) driven by the probasin gene promoter is overexpressed in the mouse prostate and causes development of prostatic intraepithelial neoplasia (PIN) that progresses to invasive carcinoma [42].
• In order to determine whether the functional interaction of HER2/neu with HER3 is critical for growth of fulvestrant-stimulated MCF-7TAMLT tumors, pertuzumab (an antibody that blocks HER2/neu-HER3 interaction) was used in an in vivo xenograft growth assay [13].

References