PCBP2 Mediates Olaparib Resistance in Breast Cancer by Inhibiting m6A Methylation to Stabilize PARP1 mRNA

Abstract Base excision repair (BER), a critical pathway for repairing DNA single-strand breaks, is mediated by PARP, which plays a pivotal role in maintaining genomic stability. Targeting PARP with PARP inhibitors (PARPi) has emerged as an effective strategy for treating BRCA-mutated breast cancers characterized by homologous recombination deficiency. However, PARPi resistance remains a major challenge in the treatment of BRCA-mutated breast cancer. Using bioinformatics analysis and cellular-level experiments, we discovered that the RNA-binding protein PCBP2 contributes to resistance to the PARPi olaparib in BRCA-mutated breast cancer by increasing PARP1 expression via interference with the m6A methylation machinery. PCBP2 was upregulated in olaparib-resistant cells, and PCBP2 overexpression in BRCA-mutated breast cancer cells increased resistance to olaparib and enhanced cell proliferation under treatment. Mechanistically, PCBP2 directly interacted with PARP1 mRNA, inhibiting m6A methylation and stabilizing the mRNA. PCBP2-mediated upregulation of PARP1 enhanced DNA repair activity, contributing to olaparib resistance. Together, these findings unveil a mechanism by which PCBP2 upregulates PARP1 to promote olaparib resistance in BRCA-mutated breast cancer, indicating that targeting this pathway could represent a therapeutic strategy to overcome PARPi resistance in breast cancer. Significance: PCBP2-induced suppression of m6A methylation increases PARP1 to promote DNA damage repair and confer resistance to olaparib in BRCA-mutated breast cancer, making PCBP2 a potential therapeutic target to enhance PARP inhibitor sensitivity.