The deubiquitinase USP7 stabilizes HER2 expression and promotes breast cancer progression

The overexpression and amplification of HER2 occurs in breast cancer. However, the mechanism of HER2 action in tumor has not yet been elucidated. HER2 can be degraded by the UPS system, and several HER2-associated E3s have been identified, but the DUB for HER2 has not yet been uncovered. Targeted therapy against HER2 has achieved impressive efficacy in patients with HER2-positive breast cancer. Herein, using MTS, Western blot, Co-IP, colony formation, RT‒qPCR, EdU, flow cytometry, immunofluorescence assays and xenograft model, we elucidated that USP7 deletion inhibited the growth of HER2-positive breast cancer cell by decreasing HER2 protein abundance. We found that USP7 was highly expressed in HER2-positive breast cancer and the expression of USP7 and HER2 was positively correlated. USP7 overexpression accelerated cell cycle progression. Mechanistically, USP7 interacted with HER2 and decreased HER2 ubiquitination to stabilize its expression. Moreover, USP7 knockdown inhibited tumor growth in vivo and in vitro. In addition, HER2 overexpression partially reversed cell growth inhibition induced by USP7 inhibition. Analyses of clinical samples revealed that USP7 overexpression was associated with poor prognosis in patients with HER2+ breast cancer. Thus, this study revealed that USP7, as a DUB of HER2, may be a potential therapeutic target for patient with HER2+ breast cancer.