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<p>Patients with advanced breast cancer (BC) often experience bone metastasis, leading to severe skeletal complications and a significant decline in prognosis. However, the molecular mechanisms underlying BC bone metastasis remain largely unexplored. This study identified the long non-coding RNA LCAL4 as specifically upregulated in bone-metastatic BC, where it serves as an independent predictor of poor survival. Gain- and loss-of-function experiments in intracardiac and intratibial mouse models demonstrate that ectopic LCAL4 expression markedly enhances BC cell-mediated osteolytic bone metastasis. Mechanistically, LCAL4 acts as a molecular scaffold, directly binding the RNA/DNA-binding protein FUS, promoting its nuclear accumulation, and recruiting it to the MMP13 promoter. The LCAL4–FUS ribonucleoprotein complex then recruits RNA polymerase II and induces H3K4me3 deposition, thereby activating MMP13 transcription. Secreted MMP13 stimulates osteoclast differentiation and enhances bone-resorptive activity. The release of TGF-β from resorbed bone further accelerates tumor proliferation, establishing a self-reinforcing cycle that drives osteolytic metastasis. Notably, genetic disruption of the LCAL4–FUS–MMP13 pathway significantly suppresses BC bone metastasis. These findings highlight the pivotal role of the LCAL4–FUS–MMP13 axis in BC skeletal colonization and osteolytic progression, highlighting its potential as a therapeutic target for managing BC bone metastasis.</p><p></p>

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LCAL4–FUS cooperation switches on MMP13 and drives osteolytic bone metastasis in breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月18日

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  • Qiji Li,
  • Mingjian Fan,
  • Xiaoting Sun,
  • Xiaoying Yang,
  • Yuhao Zhang,
  • Zihan Zheng,
  • Xuan Zhang,
  • Xian Zhang,
  • Qingqing Zhu,
  • Zhenchong Xiong,
  • Kefeng Lei,
  • Chengming Zhu,
  • Qin Tian,
  • Yun Wang,
  • Meng Wang,
  • Liping Ye

摘要

Patients with advanced breast cancer (BC) often experience bone metastasis, leading to severe skeletal complications and a significant decline in prognosis. However, the molecular mechanisms underlying BC bone metastasis remain largely unexplored. This study identified the long non-coding RNA LCAL4 as specifically upregulated in bone-metastatic BC, where it serves as an independent predictor of poor survival. Gain- and loss-of-function experiments in intracardiac and intratibial mouse models demonstrate that ectopic LCAL4 expression markedly enhances BC cell-mediated osteolytic bone metastasis. Mechanistically, LCAL4 acts as a molecular scaffold, directly binding the RNA/DNA-binding protein FUS, promoting its nuclear accumulation, and recruiting it to the MMP13 promoter. The LCAL4–FUS ribonucleoprotein complex then recruits RNA polymerase II and induces H3K4me3 deposition, thereby activating MMP13 transcription. Secreted MMP13 stimulates osteoclast differentiation and enhances bone-resorptive activity. The release of TGF-β from resorbed bone further accelerates tumor proliferation, establishing a self-reinforcing cycle that drives osteolytic metastasis. Notably, genetic disruption of the LCAL4–FUS–MMP13 pathway significantly suppresses BC bone metastasis. These findings highlight the pivotal role of the LCAL4–FUS–MMP13 axis in BC skeletal colonization and osteolytic progression, highlighting its potential as a therapeutic target for managing BC bone metastasis.