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ATM promotes bone metastatic propensity of breast cancer by inducing osteoclastogenesis via the NFκB-CCL2 pathway

Acta Pharmacologica Sinica volume 47, pages 1029–1041 (2026)Cite this article

Abstract

Metastasis in breast cancer frequently spreads to the bones, significantly impacting patient outcomes and escalating mortality rates. The ataxia-telangiectasia mutated (ATM) kinase plays a pivotal role in regulating the DNA damage response (DDR) and has been linked to the invasion and spread of breast cancer. In this study we investigated the regulatory mechanisms of ATM in bone metastasis of breast cancer. The bone metastases models were constructed in female nude mice: The MDA-MB-231 tumor model was generated by implanting luciferase-tagged MDA-MB-231 cells into the left hind tibia and intra-caudal artery. For the SK-BR-3 tumor model, luciferase-tagged SK-BR-3 cells were injected through the intra-caudal artery. By conducting bioinformatics analyses and in vitro and in vivo experiments, we found that ATM expression was markedly elevated in bone metastasis samples compared to liver, lung or skin metastases. We demonstrated that ATM boosted the migrative and invasive abilities and pre-osteoclast differentiation of MDA-MB-231 and SK-BR-3 cell lines via expression of CCL2, an osteoclast-related cytokine. The regulation of ATM on CCL2 was found to be NFκB dependent. In vivo experiments confirmed that ATM knockout (ATM KO) or treatment with small-molecule ATM inhibitor KU55933 markedly inhibited osteoclastogenesis of SK-BR-3 cells and the progression of breast cancer bone metastasis. Our results underscore the pivotal role of ATM in regulating NFκB-CCL2 expression and promoting the progression of breast cancer bone metastasis.

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Fig. 1: ATM promotes breast carcinoma bone metastasis.
Fig. 2: ATM boosts migrative and invasive abilities and pre-osteoclast differentiation.
Fig. 3: ATM regulates the expression and secretion of osteoclast-related cytokines in breast cancer cells.
Fig. 4: The breast cancer bone metastasis promoted by ATM is CCL2-dependent.
Fig. 5: ATM depletion in breast tumor cells inhibits bone metastases.
Fig. 6: ATM inhibitor KU55933 ameliorates murine bone metastasis.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (NSFC) (81974450 and 82303830), 2023 Open Project of Guangxi Key Laboratory of Bio-Targeting Theranostics (GXSWBX202301), the Fundamental Research Funds for the Central Universities, HUST (2023JYCXJJ055), and the Natural Science Foundation of Hubei Province (2021CFB521). Thanks for the technical support from the Huazhong University of Science & Technology Analytical & Testing Center, Medical sub-center.

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Author notes

  1. These authors contributed equally: Ming-yang Qin, Yuan-hui Liu, Ze-liang Wu

Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Ming-yang Qin, Hui Liu & Rong Xu

  2. Henan Eye Institute, Henan Eye Hospital, Henan Provincial People’s Hospital, Zhengzhou, 450003, China

    Ming-yang Qin

  3. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Yuan-hui Liu

  4. Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Ze-liang Wu

  5. Biomedical Analysis Center, Army Medical University, Chongqing, 400038, China

    Yi Huang

  6. Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Jiang Wang

  7. Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Tian Xia

  8. Wuhan Wuchang Hospital, Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, 430064, China

    Lin Zhu

  9. The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, China

    Hui Liu & Rong Xu

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Contributions

RX conceived of the study, participated in its design, and edited the manuscript. MYQ, YHL, and ZLW performed the study and drafted the manuscript. YH and LZ performed the cell experiments. JW and TX are responsible for the collection of clinical samples. YHL, MYQ, ZLW, and HL revised the manuscript.

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Correspondence to Rong Xu.

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Qin, My., Liu, Yh., Wu, Zl. et al. ATM promotes bone metastatic propensity of breast cancer by inducing osteoclastogenesis via the NFκB-CCL2 pathway. Acta Pharmacol Sin 47, 1029–1041 (2026). https://doi.org/10.1038/s41401-025-01699-0

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