Cai Meng-Yuan, Yin Peng, Wang Zi-Wen, Huang Yu-Zhou, Wang Yu-Xin, Wu Kei-Fei, Zhang Xu, Shi Liang, Wei Ji-Fu, Ding Qiang
Jiangsu Breast Disease Center & Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China.
Department of Pharmacy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 211166, China.
Cancer Lett. 2025 Jul 22;632:217944. doi: 10.1016/j.canlet.2025.217944.
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.
三阴性乳腺癌（TNBC）的进展由癌症干细胞（CSC）驱动，导致化疗耐药和肿瘤复发。N6-甲基腺苷（m6A）修饰在调节CSC可塑性中起关键作用；然而，TNBC-CSC中的关键m6A调节因子仍不清楚。在这里，我们通过对TCGA-BRCA数据集进行转录组分析并通过荧光激活细胞分选（FACS）验证，确定IGF2BP3是一种在TNBC-CSC中富集的主要m6A阅读器。功能分析表明，敲低IGF2BP3显著损害干细胞样特性，并使CSC对卡铂敏感。机制上，IGF2BP3以m6A依赖的方式直接结合卷曲蛋白家族受体1和7（FZD1/7）mRNA的3'非翻译区，稳定其转录本并促进异二聚化。这种相互作用通过促进非磷酸化β-连环蛋白（Ser37/Thr41）的核转位激活β-连环蛋白信号通路。RBM15促进FZD1/7的m6A甲基化，增强IGF2BP3的识别。值得注意的是，Fz7-21是FZD1/7的小分子抑制剂，模拟了敲低IGF2BP3的效果，破坏了CSC的维持和同源重组修复（HRR）。此外，Fz7-21与卡铂协同增强其对TNBC-CSC的治疗效果。这些发现确立了IGF2BP3作为一个核心m6A阅读器，通过稳定FZD1/7和激活β-连环蛋白信号通路促进干性和卡铂耐药性。靶向IGF2BP3和FZD1/7在TNBC治疗中具有消除癌症干细胞和减少卡铂剂量的治疗潜力。
