Significance of HER2-related factor in HER2-low breast cancer

Human epidermal growth factor receptor 2 (HER2)-targeted therapies are widely used to treat of HER2-positive breast cancer. HER2 expression is evaluated by the HER2 protein using immunohistochemistry (IHC), and ERBB2 gene amplification by fluorescence in situ hybridization (FISH) is performed in routine clinical practice for breast cancer. Some studies have suggested that increased ERBB2 mRNA expression is involved in the HER2-dependent progression of breast cancer. In addition, various binding proteins for HER2 and HER2-dependent signaling are promoted by their interactions. In this study, we aimed to investigate the relationship between HER2 expression in IHC, ERBB2 expression, and HER2-binding proteins and to clarify the characteristics of cases with different levels of HER2 expression. The subjects were 58 cases from Tohoku University Hospital. ERBB2 expression was determined by RNA-scope, and HER2-binding proteins, NRG1 (neuregulin 1), ERBIN (erbb2 interacting protein), Grb2 (growth factor receptor-binding protein 2), CEACAM6 (carcinoembryonic antigen-related cell adhesion molecule 6), and HER3, were detected by IHC. ERBB2 expression showed a positive correlation with HER2 expression. HER3 expression was significantly higher in HER2-low breast cancers than in HER2-negative breast cancers. Cluster analysis showed that HER2-negative breast cancers classified into the same cluster as HER2-low breast cancers exhibited high HER2 binding protein expression. Furthermore, clusters containing breast cancers with positive, low, and negative HER2 expression were characterized by high ERBB2 scores and high expression of HER2 binding protein, suggesting the possibility that breast cancer may be promoted in a HER2-dependent manner through interaction with HER2 binding protein. These results suggest that HER2-low and HER2-negative breast cancers contain cases with similar characteristics to HER2-positive breast cancers, particularly when focusing on HER2 binding proteins and treatment targeting HER3 and other HER2 binding proteins.