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Significance Resistance to endocrine therapy is a major obstacle to managing breast cancer. Here, we introduce that tripartite motif protein TRIM47 enhances endocrine therapy resistance and facilitates breast cancer tumorigenesis. We showed that TRIM47 immunoreactivity scores in breast cancer specimens were positively associated with shorter disease-free survival of the patients with postoperative endocrine therapy. Overexpression of TRIM47 in breast cancer cells activated NF-κB signaling, which is partly due to the stabilization of PKC-ε and PKD3 by interacting with TRIM47. As an underlying mechanism, we demonstrated TRIM47-dependent modification of PKC-ε by atypical lysine 27–linked polyubiquitination. Our study implies that TRIM47 and its associated kinases can be potential diagnostic and therapeutic targets for patients with breast cancer refractory to endocrine therapy.

TRIM47 activates NF-κB signaling via PKC-ε/PKD3 stabilization and contributes to endocrine therapy resistance in breast cancer