Saturday 11 February 2006
The oncogene originally called HER/NEU was derived from rat neuro/glioblastoma cell lines. It encodes a tumor antigen, p185, which is serologically related to EGFR, the epidermal growth factor receptor (MIM.131550).
ERBB2 has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase.
Allelic variations at amino acid positions 654 and 655 of isoform a (positions 624 and 625 of isoform b) have been reported, with the most common allele, Ile654/Ile655, shown here.
Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized.
The NEU/ERBB2 protooncogene encodes a molecule that is closely related to epidermal growth factor receptor (EGFR) (MIM.131550) but binds none of the ligands of this receptor.
The existence of a NEU-specific ligand of endogenous nature activating NEU at a specific developmental stage was suggested. This ligand, known as NRG1 (or heregulin-1 or neuregulin-1) or NEU differentiation factor-1 (NDF1), is a 44-kD glycoprotein that interacts with the NEU/ERBB2 receptor tyrosine kinase to increase its phosphorylation on tyrosine residues. Splice variants of NRG1, referred to as neuregulin-1 betas have been described.
ERBB2 amplification and overexpression in
One-third of patients with breast cancer overexpress the ERBB2 receptor tyrosine kinase, which is associated not only with a more aggressive phenotype but also reduced responsiveness to hormonal therapies.
ERBB2 somatic mutations in
- pulmonary adenocarcinoma (MIM.211980)
- glioblastoma (MIM.137800)
- gastric adenocarcinoma (MIM.137215)
- ovarian carcinomas
Originally, NEU/ERBB2 was identified as a dominant transforming gene in tumors of the peripheral nervous system that were induced by transplacental treatment of rat embryos with N-ethylnitrosourea.
The period of susceptibility of NEU to carcinogenesis, i.e., midgestation, correlated with the timing of its expression in the nervous system.
Over the past two decades, many ERBB2 mouse models for breast cancer have conclusively shown that this receptor has a causal role in breast cancer development.
These mouse models have also enabled the mechanisms controlling tumour growth, angiogenesis, metastasis, dormancy and recurrence in ERBB2-positive breast cancer to be elucidated. In addition, a mouse model has recently been described that accurately recapitulates many of the hallmarks associated with the early stages of the human disease.
ErbB signaling pathway
Morrison LE, Jewell SS, Usha L, Blondin BA, Rao RD, Tabesh B, Kemper M, Batus M, Coon JS. Effects of ERBB2 amplicon size and genomic alterations of chromosomes 1, 3, and 10 on patient response to trastuzumab in metastatic breast cancer. Genes Chromosomes Cancer. 2007 Apr;46(4):397-405. PMID: 17243161
Benz CC, Fedele V, Xu F, Ylstra B, Ginzinger D, Yu M, Moore D, Hall RK, Wolff DJ, Disis ML, Eppenberger-Castori S, Eppenberger U, Schittulli F, Tommasi S, Paradiso A, Scott GK, Albertson DG. Altered promoter usage characterizes monoallelic transcription arising with ERBB2 amplification in human breast cancers. Genes Chromosomes Cancer. 2006 Nov;45(11):983-94. PMID: 16883574