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<p>Therapeutic resistance to trastuzumab remains a critical limitation in the management of HER2-positive (HER2+) breast cancer. Emerging evidence implicates epigenetic regulators, including microRNAs and histone demethylases, in modulating HER2 signaling and drug responsiveness. This study aimed to investigate the mechanistic role of miR-770-5p and its interplay with KDM5B in the context of trastuzumab resistance. An integrative approach combining in silico analyses with in vitro functional assays was employed in trastuzumab-sensitive and -resistant HER2 + breast cancer cell lines. Molecular, subcellular, and phenotypic effects of miR-770-5p modulation were assessed using qRT-PCR, Western blotting, immunofluorescence, RNA-FISH, luciferase reporter assays, and live-cell imaging. KDM5B was significantly overexpressed in HER2 + tumors and inversely correlated with HER2 expression. miR-770-5p directly targeted KDM5B and was associated with coordinated regulation of HER2 signaling at both transcription-associated and post-transcriptional levels. Overexpression of miR-770-5p was associated with reduced expression of KDM5B, TCF12, and GRB7, supporting the involvement of a KDM5B–TCF12–GRB7 regulatory network in HER2 modulation. Functionally, miR-770-5p reversed EMT-associated phenotypic features and enhanced trastuzumab sensitivity. Clinically, reduced KDM5B expression was associated with improved distant metastasis-free survival in ER+/HER2-high breast cancer patients. Collectively, miR-770-5p functions as a nuclear-associated regulatory microRNA that modulates HER2 signaling through epigenetic regulation of KDM5B and associated downstream networks. These findings suggest a previously unrecognized regulatory mechanism contributing to trastuzumab response and provide potential therapeutic avenues for HER2-positive breast cancer.</p>

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miR-770-5p regulates KDM5B and links its nuclear localization to HER2 signaling in trastuzumab-resistant breast cancer

  • 期刊论文

  • 发表日期：

    2026年7月20日

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  • Senem Noyan,
  • Hakan Gurdal,
  • Alp Can,
  • Bala Gur Dedeoglu

摘要

Therapeutic resistance to trastuzumab remains a critical limitation in the management of HER2-positive (HER2+) breast cancer. Emerging evidence implicates epigenetic regulators, including microRNAs and histone demethylases, in modulating HER2 signaling and drug responsiveness. This study aimed to investigate the mechanistic role of miR-770-5p and its interplay with KDM5B in the context of trastuzumab resistance. An integrative approach combining in silico analyses with in vitro functional assays was employed in trastuzumab-sensitive and -resistant HER2 + breast cancer cell lines. Molecular, subcellular, and phenotypic effects of miR-770-5p modulation were assessed using qRT-PCR, Western blotting, immunofluorescence, RNA-FISH, luciferase reporter assays, and live-cell imaging. KDM5B was significantly overexpressed in HER2 + tumors and inversely correlated with HER2 expression. miR-770-5p directly targeted KDM5B and was associated with coordinated regulation of HER2 signaling at both transcription-associated and post-transcriptional levels. Overexpression of miR-770-5p was associated with reduced expression of KDM5B, TCF12, and GRB7, supporting the involvement of a KDM5B–TCF12–GRB7 regulatory network in HER2 modulation. Functionally, miR-770-5p reversed EMT-associated phenotypic features and enhanced trastuzumab sensitivity. Clinically, reduced KDM5B expression was associated with improved distant metastasis-free survival in ER+/HER2-high breast cancer patients. Collectively, miR-770-5p functions as a nuclear-associated regulatory microRNA that modulates HER2 signaling through epigenetic regulation of KDM5B and associated downstream networks. These findings suggest a previously unrecognized regulatory mechanism contributing to trastuzumab response and provide potential therapeutic avenues for HER2-positive breast cancer.