The novel β-TrCP protein isoform hidden in circular RNA confers trastuzumab resistance in HER2-positive breast cancer.

ABSTRACT: Trastuzumab notably improves the outcome of human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, however, resistance to trastuzumab remains a major hurdle to clinical treatment. In the present study, we identify a circular RNA intimately linked to trastuzumab resistance. circ-β-TrCP, derived from the back-splicing of β-TrCP exon 7 and 13, confers trastuzumab resistance by regulating NRF2-mediated antioxidant pathway in a KEAP1-independent manner. Concretely, circ-β-TrCP encodes a novel truncated 343-amino acid peptide located in the nucleus, referred as β-TrCP-343aa, which competitively binds to NRF2, blocks SCF^β-TrCP-mediated NRF2 proteasomal degradation, and this protective effect of β-TrCP-343aa on NRF2 protein requires GSK3 activity. Subsequently,

SUBMITTER: Wang S 

PROVIDER: S-EPMC10551893 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature