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<p>FOXQ1 overexpression and Wnt/β-catenin pathway hyperactivation are implicated in TNBC, but their functional interconnection is poorly defined. The expression pattern, clinical significance, and oncogenic role of FOXQ1 were systematically assessed using data from The Cancer Genome Atlas (TCGA) combined with RT-PCR, western blotting, and Transwell assays. To explore the transcriptional regulation of FOXQ1 on WNT2, we integrated bioinformatic predictions with analyses of the CCLE dataset, RT-qPCR, western blotting, and luciferase reporter assays. The functional interplay within the FOXQ1-WNT2-β-catenin signaling axis was evaluated through immunofluorescence staining, TOP/FOP flash reporter assays, and pharmacological inhibition using the Wnt pathway inhibitor IWP-2. miR-96-5p was identified through multi-database screening and experimentally validated by 3’UTR reporter assays, functional experiments, and in vivo xenograft models. FOXQ1 is upregulated in TNBC and correlates with poor patient survival (HR = 1.34, <i>p</i> = 0.041). It promotes epithelial-mesenchymal transition (EMT), cell migration, and invasion in TNBC. Mechanistically, FOXQ1 directly transactivates WNT2, leading to enhanced nuclear translocation and transcriptional activation of β-catenin. Although IWP-2 inhibits β-catenin activation, it does not prevent FOXQ1-induced upregulation of WNT2, indicating that FOXQ1 acts both upstream of and independently within the Wnt signaling pathway. Furthermore, miR-96-5p directly targets the 3’UTR of FOXQ1, is associated with an improved prognosis (HR = 0.82, <i>p</i> = 0.048), and suppresses TNBC tumor growth and aggressiveness in vitro and in vivo. In conclusion, we have identified a FOXQ1-WNT2-β-catenin positive feedback loop as a critical driver of TNBC pathogenesis and propose miR-96-5p as a promising therapeutic strategy to suppress this signaling pathway.</p>

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miR-96-5p antagonizes FOXQ1-driven WNT/β-catenin signaling to inhibit triple-negative breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月4日

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  • Zhuoran Zhang,
  • Chenshan Zhang,
  • Yuxuan Meng,
  • Xianyu Zhu,
  • Jianying Yang,
  • Bing Ran,
  • Zhonglin Gan,
  • Kejiang Wang,
  • Mao Yang,
  • Pinjun Lu,
  • Sakorn Pornprasert,
  • Tao He,
  • Yan Lin

摘要

FOXQ1 overexpression and Wnt/β-catenin pathway hyperactivation are implicated in TNBC, but their functional interconnection is poorly defined. The expression pattern, clinical significance, and oncogenic role of FOXQ1 were systematically assessed using data from The Cancer Genome Atlas (TCGA) combined with RT-PCR, western blotting, and Transwell assays. To explore the transcriptional regulation of FOXQ1 on WNT2, we integrated bioinformatic predictions with analyses of the CCLE dataset, RT-qPCR, western blotting, and luciferase reporter assays. The functional interplay within the FOXQ1-WNT2-β-catenin signaling axis was evaluated through immunofluorescence staining, TOP/FOP flash reporter assays, and pharmacological inhibition using the Wnt pathway inhibitor IWP-2. miR-96-5p was identified through multi-database screening and experimentally validated by 3’UTR reporter assays, functional experiments, and in vivo xenograft models. FOXQ1 is upregulated in TNBC and correlates with poor patient survival (HR = 1.34, p = 0.041). It promotes epithelial-mesenchymal transition (EMT), cell migration, and invasion in TNBC. Mechanistically, FOXQ1 directly transactivates WNT2, leading to enhanced nuclear translocation and transcriptional activation of β-catenin. Although IWP-2 inhibits β-catenin activation, it does not prevent FOXQ1-induced upregulation of WNT2, indicating that FOXQ1 acts both upstream of and independently within the Wnt signaling pathway. Furthermore, miR-96-5p directly targets the 3’UTR of FOXQ1, is associated with an improved prognosis (HR = 0.82, p = 0.048), and suppresses TNBC tumor growth and aggressiveness in vitro and in vivo. In conclusion, we have identified a FOXQ1-WNT2-β-catenin positive feedback loop as a critical driver of TNBC pathogenesis and propose miR-96-5p as a promising therapeutic strategy to suppress this signaling pathway.