HER3 / ERBB3 plays an important role in cell proliferation and survival. HER3 / ERBB3 was identified based on its homology to EGFR and thereafter it was determined that HER3 / ERBB3 has an impaired kinase function. Neuregulin binding (NRG) to HER3 / ERBB3 induces heterodimerization of HER3 / ERBB3 with other EGFR family receptors, particularly HER2, resulting in the phosphorylation of tyrosine residues of the C-terminal tail of HER3 / ERBB3. Phosphotyrosines of HER3 / ERBB3 provide binding sites for PI3K, Shc and other HER3 / ERBB3 interacting proteins, which mediate activation of the PI3K/ AKT and Ras/Raf/MAPK pathways. Although HER3 / ERBB3 has been suggested to play a role in oncogenesis for many years, its absolute significance in cancer biology has begun to emerge in recent years. HER3 / ERBB3 was initially studied in HER2 - amplified breast cancers. HER3 / ERBB3 was also detected in various cancers under the conditions of acquired resistance to other HER family member therapeutic interventions. For example, a study established that resistance to the EGFR kinase inhibitor gefitinib in lung cancer leads to amplification of the MET proto-oncogene. This augmentation of the MET proto-oncogene was due to the activation of HER3 / ERBB3 phosphorylation and PI3K activation in an EGFR and HER2 independent manner. Overexpression of HER3 / ERBB3 has been reported in primary cancers and in cultured cells including the carcinomas of breast, ovarian, prostate, colon, pancreas, stomach, oral cavity and lung. Studies have shown that 50-70% of human breast cancers have detectable HER3 / ERBB3 levels as evaluated by IHC and activated HER3 / ERBB3 is usually co-overexpressed with HER2 in breast cancers. Oncogenic mutations in HER3 / ERBB3 gene were reported in human colon and gastric cancers and some of these mutations were shown to be gain of function mutations. The study further provided evidence of oncogenic activity with HER3 / ERBB3 for Q809R in gastric cancer. Furthermore, although HER3 / ERBB3 mutation at V714M was identified in non-small cell lung cancer(NSCLC) patients and S846I mutation was identified in colon cancer, oncogenic function of these mutants has not been tested.
Mujoo K, Choi B K, Huang Z, et al. Regulation of ERBB3/HER3 signaling in cancer[J]. Oncotarget, 2014, 5(21): 10222-36. Jiang N, Saba N F, Chen Z G. Advances in targeting HER3 as an anticancer therapy[J]. Chemotherapy research and practice, 2012, 2012.