CAND1 mediates CUL7-dependent HER2 protein stability to drive breast cancer progression

HER2-positive breast cancer is a prevalent pathological subtype of breast cancer. Resistance to anti-HER2 targeted therapies remains a significant challenge in treatment. Understanding the role of HER2 in breast cancer progression is essential.

The proteomics analysis was used to explore the regulated proteins in patients with HER2-positive breast cancer. MTS, EdU staininig, flow cytometry and colony formation assays were used to cell proliferation and apoptosis. Protein expressions and interaction of CAND1 and HER2 were clarified by western blot, immunofluorescence and co-immunoprecipitation experiments. In vivo studies using nude mice demonstrated the role of CAND1 in HER2-positive breast cancer cell growth.

An increase in CAND1 expression, which is associated with poor prognosis in patients with HER2-positive breast cancer. Functionally, CAND1-KD suppresses the growth of HER2-positive breast cancer cells by inducing cell cycle arrest and apoptosis. In vivo, CAND1-KD inhibits tumor growth in xenograft models. Mechanistically, CAND1 expression is positively correlated with HER2 protein levels in breast cancer tissues. CAND1 directly interacts with HER2, stabilizing its protein expression. The E3 ligase CUL7 promotes HER2 ubiquitination and is essential for the interaction between CAND1 and HER2. CAND1-KD enhances CUL7 neddylation, which activates its ligase activity and leads to HER2 ubiquitination. Importantly, HER2 overexpression reverses the proliferation inhibition caused by CAND1 loss both in vitro and in vivo.

In summary, this study highlights the critical role of CAND1 in regulating HER2 ubiquitination and suggests a potential therapeutic strategy for patients with HER2-positive breast cancer.