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Background <p>Breast cancer distant metastasis is known to exhibit organotropism, with triple negative breast cancer (TNBC) subtypes also displaying organ-specific metastasis. The precise regulatory mechanisms governing this specificity remain unclear.</p> Methods <p>Retrospective analysis of metastatic data from public databases was utilized to explore the organotropism of TNBC subtypes. Mouse models combined with single-cell sequencing and immunoprecipitation (CoIP) experiments were utilized to investigate the role and mechanism of androgen receptor (AR)&#xa0;on&#xa0;TNBC bone metastasis. Further analysis of the bone microenvironment combined with CUT&amp;TAG sequencing and osteoclast differentiation experiments was performed to validate the effect of AR and c-Myc interaction on macrophage-osteoclast axis differentiation.</p> Results <p>Analysis revealed the luminal androgen receptor (LAR) TNBC subtype had significant bone metastasis propensity. Mouse models showed&#xa0;AR&#xa0;activation promoted LAR TNBC bone metastasis. Using single-cell sequencing, we discovered that c-Myc played a critical role in AR-mediated bone metastasis. Further investigation of the bone microenvironment showed that AR-c-Myc interaction promoted macrophage-osteoclast axis differentiation and macrophage activation via MMP13, ultimately increasing bone resorption.</p> Conclusions <p>AR and c-Myc interaction induces macrophage differentiation into osteoclasts and promotes TNBC bone metastasis. These findings elucidate the mechanisms underlying bone metastasis in TNBC subtypes and inform potential interventions for TNBC bone metastasis.</p>

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Androgen receptor interacts with c-Myc to regulate macrophage-osteoclast axis and drive bone metastasis in triple negative breast cancer

  • 期刊论文

  • 发表日期：

    2025年10月2日

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  • Yiqiu Liu,
  • Lingling Fan,
  • Fan Ye,
  • Yuhan Zhao,
  • Ye Zhu,
  • Yixing Yang,
  • Feng Xu,
  • Yunru Gu,
  • Xiaoxiang Guan

摘要

Background

Breast cancer distant metastasis is known to exhibit organotropism, with triple negative breast cancer (TNBC) subtypes also displaying organ-specific metastasis. The precise regulatory mechanisms governing this specificity remain unclear.

Methods

Retrospective analysis of metastatic data from public databases was utilized to explore the organotropism of TNBC subtypes. Mouse models combined with single-cell sequencing and immunoprecipitation (CoIP) experiments were utilized to investigate the role and mechanism of androgen receptor (AR) on TNBC bone metastasis. Further analysis of the bone microenvironment combined with CUT&TAG sequencing and osteoclast differentiation experiments was performed to validate the effect of AR and c-Myc interaction on macrophage-osteoclast axis differentiation.

Results

Analysis revealed the luminal androgen receptor (LAR) TNBC subtype had significant bone metastasis propensity. Mouse models showed AR activation promoted LAR TNBC bone metastasis. Using single-cell sequencing, we discovered that c-Myc played a critical role in AR-mediated bone metastasis. Further investigation of the bone microenvironment showed that AR-c-Myc interaction promoted macrophage-osteoclast axis differentiation and macrophage activation via MMP13, ultimately increasing bone resorption.

Conclusions

AR and c-Myc interaction induces macrophage differentiation into osteoclasts and promotes TNBC bone metastasis. These findings elucidate the mechanisms underlying bone metastasis in TNBC subtypes and inform potential interventions for TNBC bone metastasis.