Unveiling isoleucyl-tRNA synthetase 2 as a novel driver of breast cancer via β-catenin pathway activation.

Breast cancer represents the most common malignant tumor in women globally. Isoleucyl-tRNA synthetase 2 (IARS2), a member of the aminoacyl-tRNA synthetase family, promotes tumorigenesis across various cancers. Herein, the effects and mechanisms of IARS2 in breast cancer were investigated. IARS2 is upregulated in breast cancer tissues compared to normal tissues, correlating with the poor prognosis of patients with breast cancer. In order to knock down and overexpress IARS2, plasmids carrying short hairpin RNA targeting IARS2 and IARS2-overexpression plasmids were transfected into breast cancer cells, respectively. Our results demonstrated that silencing IARS2 repressed breast cancer cell progression. IARS2 deficiency attenuated tumor growth in MDA-MB-231 cell xenograft mouse models. Conversely, overexpression of IARS2 aggravated malignant cell behaviors in vitro and accelerated tumor growth in vivo. Mechanistically, IARS2 depletion stimulated ubiquitination-mediated degradation of β-catenin in breast cancer cells. Notably, the β-catenin inhibitor XAV-939 reversed IARS2-driven breast cancer malignant progression. Furthermore, differentially expressed genes were identified in IARS2-overexpressed breast cancer cells with or without XAV-939 in the light of mRNA-seq results. Overall, our findings uncovered that silencing IARS2 blocked the β-catenin signaling axis, thereby impeding breast cancer progression. IARS2 might become a promising novel therapeutic target for breast cancer intervention.