摘要：SummaryDysregulation of inositol-requiring enzyme 1 (IRE1), the primary transducer of Unfolded Protein Response (UPR), has been observed in tumor initiation and progression, but the underlying mechanism remains to be further elucidated. In this study, we identified that theIRE1gene is frequently amplified and over-expressed in aggressive luminal B breast cancer cells and that IRE1 upregulation is significantly associated with worse overall survival of patients with breast cancer. IRE1 processes and mediates degradation of a subset of tumor suppressor microRNAs (miRNAs), including miR-3607, miR-374a, and miR-96, via a mechanism called Regulated IRE1-Dependent Decay (RIDD). IRE1-dependent degradation of tumor suppressor miR-3607 leads to elevation of RAS oncogene GTPase RAB3B in breast cancer cells. Inhibition of IRE1 endoribonuclease activity with the pharmacological compound 4μ8C or genetic approaches effectively suppresses luminal breast cancer cell proliferation and aggressive cancer phenotypes. Our work revealed the IRE1-RIDD-miRNAs pathway that promotes malignancy of luminal breast cancer.Graphical AbstractDisplay OmittedHighlights•IRE1gene is amplified and over-expressed in Luminal B breast cancer cells•IRE1 processes and mediates degradation of tumor suppressor miRNAs•IRE1-dependent degradation of tumor suppressor miRNAs elevates expression of RAB3B•Inhibition of IRE1 suppresses Luminal breast cancer cell proliferationBioinformatics; Cancer; Molecular Mechanism of Gene Regulation
