RNF146 enhances olaparib sensitivity in triple-negative breast cancer via XRCC5 downregulation.

To investigate RNF146 expression in triple-negative breast cancer (TNBC) and its role in modulating sensitivity to the PARP inhibitor olaparib, we analyzed RNF146 expression and its association with patient survival using The Cancer Genome Atlas (TCGA) database. Functional studies were performed in 4T1 cells with stable RNF146 overexpression generated via lentiviral transduction. Cell viability and clonogenic capacity were assessed by CCK-8 and colony formation assays, respectively. An orthotopic nude mouse model was used to evaluate tumor growth and therapeutic response in vivo. Potential substrates of RNF146 were screened using the BioGRID database and validated by Western blot analysis. RNF146 expression was significantly reduced in breast cancer tissues, including TNBC, compared with normal tissues, and low RNF146 expression was associated with poor overall survival. RNF146 overexpression markedly enhanced olaparib sensitivity in vitro and significantly inhibited tumor growth while promoting apoptosis in vivo. XRCC5 was identified as a potential substrate of RNF146 and was confirmed to be downregulated by RNF146 both in vitro and in tumor tissues. These findings indicate that RNF146 enhances olaparib sensitivity in TNBC, at least in part, through downregulation of XRCC5, and suggest that RNF146 may serve as a prognostic biomarker and a potential therapeutic target for improving PARP inhibitor efficacy in TNBC.