Dual regulation of FZD1/7 by IGF2BP3 enhances stem-like properties and carboplatin resistance in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) progression is driven by cancer stem cells (CSCs), contributing to chemoresistance and tumor recurrence. N6-methyladenosine (m6A) modification plays a critical role in regulating CSC plasticity; however, the key m6A regulators in TNBC-CSCs remain poorly defined. Here, we identified IGF2BP3 as a dominant m6A reader enriched in TNBC-CSCs through transcriptomic analysis of the TCGA-BRCA dataset and validation by fluorescence-activated cell sorting (FACS). Functional assays demonstrated that IGF2BP3 knockdown markedly impaired stem-like properties and sensitized CSCs to carboplatin. Mechanistically, IGF2BP3 directly bound to the 3'-untranslated regions of frizzled class receptor 1 and 7 (FZD1/7) mRNAs in an m6A-dependent manner, stabilizing their transcripts and promoting heterodimerization. This interaction activated the β-catenin pathway by facilitating nuclear translocation of non-phosphorylated β-catenin (Ser37/Thr41). RBM15 contributed to the m6A methylation of FZD1/7, enhancing IGF2BP3 recognition. Notably, Fz7-21, a small-molecule inhibitor of FZD1/7, phenocopied the effects of IGF2BP3 knockdown, disrupting CSC maintenance and homologous recombination repair (HRR). Moreover, Fz7-21 synergized with carboplatin to enhance its therapeutic efficacy in TNBC-CSCs. These findings establish IGF2BP3 as a central m6A reader that promotes stemness and carboplatin resistance via FZD1/7 stabilization and β-catenin signaling activation. Targeting IGF2BP3 and FZD1/7 have therapeutic potential to eliminate cancer stem cells and reduce carboplatin dosage in TNBC treatment.