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<p>Triple-negative breast cancer (TNBC), particularly in metastatic cases, lacks effective therapeutic vulnerabilities. We previously identified <i>TNS3-S</i> as a variant of <i>TNS3</i> that is selectively expressed in TNBC. Here, we show that <i>TNS3-S</i> expression is regulated by TGFβ signaling and CpG methylation at its regulatory region. Notably, <i>TNS3-S</i> expression is markedly elevated in lung-metastasized TNBC tumors compared to primary tumors. Knockout of <i>TNS3-S</i> suppressed lung metastasis and rendered the cells sensitive to anoikis, both of which were reversed by rescued expression of <i>TNS3-S</i>. Mechanistically, TNS3-S stabilizes focal adhesion kinase, thereby facilitating adhesion-mediated proliferative signaling. Exploratory analyses of TCGA cohorts suggested that reduced promoter CpG methylation correlates with increased <i>TNS3-S</i> expression and could be associated with poorer outcomes across several cancer types. Collectively, these findings identify <i>TNS3-S</i> as a metastasis-associated regulator that promotes tumor outgrowth in distant organs and raise the possibility that epigenetic de-repression contributes to its activation during disease progression.</p><p></p>

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A truncated TNS3 isoform expressed in metastatic triple negative breast cancer stabilizes FAK and promotes lung metastasis

  • 期刊论文

  • 发表日期：

    2026年7月10日

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  • Takao Morinaga,
  • Shouko Hayama,
  • Yuki Nakamura,
  • Katsushige Kawase,
  • Hideki Ikeda,
  • Suguru Miyata,
  • Megumi Mogi,
  • Eri Katayama,
  • Rikiya Nakamura,
  • Masahito Kawazu

摘要

Triple-negative breast cancer (TNBC), particularly in metastatic cases, lacks effective therapeutic vulnerabilities. We previously identified TNS3-S as a variant of TNS3 that is selectively expressed in TNBC. Here, we show that TNS3-S expression is regulated by TGFβ signaling and CpG methylation at its regulatory region. Notably, TNS3-S expression is markedly elevated in lung-metastasized TNBC tumors compared to primary tumors. Knockout of TNS3-S suppressed lung metastasis and rendered the cells sensitive to anoikis, both of which were reversed by rescued expression of TNS3-S. Mechanistically, TNS3-S stabilizes focal adhesion kinase, thereby facilitating adhesion-mediated proliferative signaling. Exploratory analyses of TCGA cohorts suggested that reduced promoter CpG methylation correlates with increased TNS3-S expression and could be associated with poorer outcomes across several cancer types. Collectively, these findings identify TNS3-S as a metastasis-associated regulator that promotes tumor outgrowth in distant organs and raise the possibility that epigenetic de-repression contributes to its activation during disease progression.