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Cellular and Molecular Biology

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

British Journal of Cancer (2025)Cite this article

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Abstract

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.

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Fig. 1: AR expression is positively correlated with TNBC osteolytic bone metastasis.
Fig. 2: c-Myc is closely associated with AR-mediated bone metastasis.
Fig. 3: AR interacts with c-Myc to facilitate TNBC bone metastasis.
Fig. 4: Activation of AR promotes macrophage M2 polarization and exhibits osteoclast differentiation characteristics.
Fig. 5: AR interacts with c-Myc to promote macrophage to osteoclast differentiation as well as osteoclast activation.
Fig. 6: AR/c-Myc interaction promotes osteoclast differentiation and activation through MMP13.
Fig. 7: In vivo validation of dual-target inhibition of AR and c-Myc versus single-agent inhibition in suppressing TNBC bone metastasis.

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Data availability

The accession number for the scRNA-seq data of Ctrl and DHT bone metastatic tumors and CUT&TAG-seq data generated in this article is GEO(GSE236558) and SRA(PRJNA1268216). Other data analyzed in this study were obtained from GEO with accession numbers GSE2603, GSE2034, GSE12276, GSE125989, and GSE110590. All other raw data are available upon request from the corresponding author. Full, uncut gel images are available in the supplemental materials.

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Acknowledgements

This work was supported by a Key National Natural Science Foundation of China (No.82430093).

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Author notes

  1. These authors contributed equally: Yiqiu Liu, Lingling Fan, Fan Ye

Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China

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

  2. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China

    Xiaoxiang Guan

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Contributions

Y. Liu: Conceptualization, data curation, software, formal analysis, investigation, visualization, methodology, writing–original draft. L. Fan: Data curation, software, formal analysis, investigation, visualization, methodology. F. Ye: Investigation, visualization, methodology. Y. Zhao: Investigation, visualization, methodology. Y. Zhu: Data curation, software, formal analysis, investigation. Y. Yang: Data curation, software, formal analysis, supervision. F. Xu: Data curation, supervision. Y. Gu: Data curation, supervision. X. Guan: Conceptualization, resources, data curation, supervision, project administration, writing–review and editing. Y. Liu, L. Fan and F. Ye contributed equally to this work as first authors. All authors read and approved the final paper.

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Correspondence to Xiaoxiang Guan.

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All animal studies were conducted according to the NIH Guide for the Care and Use of Laboratory Animals (National Academies Press, 2011) and were approved by the Institutional Animal Care and Use Committee of Nanjing Medical University (IACUC-2205019).

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Liu, Y., Fan, L., Ye, F. et al. Androgen receptor interacts with c-Myc to regulate macrophage-osteoclast axis and drive bone metastasis in triple negative breast cancer. Br J Cancer (2025). https://doi.org/10.1038/s41416-025-03202-2

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