Cell membrane gp96 facilitates HER2 dimerization and serves as a novel target in breast cancer

HER2 receptor dimerization is a critical step in the HER2 activation process. Here, we demonstrated that heat shock protein gp96 on cell membrane interacts with HER2, facilitates HER2 dimerization and promotes cell proliferation. Cell membrane gp96 levels were observed to correlate with HER2 phosphorylation in primary breast tumors. Finally, we provide evidence that targeting gp96 with a specific monoclonal antibody led to decreased cell growth and increased apoptosis in vitro, and suppression of tumor growth in vivo. Our work represents a new therapeutic strategy for inhibiting HER2 signaling in cancer. What's new The chaperone protein gp96 normally resides in the endoplasmic reticulum, but in certain tumor cells, it may translocate to the cell membrane. In breast cancer, gp96 cell membrane expression is correlated with malignancy. In this study, cell membrane gp96 was found to promote HER2 dimerization and phosphorylation, and HER2 phosphorylation was correlated with cell membrane gp96 levels in breast cancer patients. Inhibition of gp96 suppressed HER2-driven cell growth. The findings provide insight into a possible therapeutic approach for managing HER2 overexpression in breast cancer, which is a recognized factor behind poor prognosis for patients with HER2-positive tumors.