Article

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

Ming-yang Qin1,2, Yuan-hui Liu3, Ze-liang Wu4, Yi Huang5, Jiang Wang6, Tian Xia7, Lin Zhu8, Hui Liu1,9, Rong Xu1,9
1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
2 Henan Eye Institute, Henan Eye Hospital, Henan Provincial People’s Hospital, Zhengzhou 450003, China
3 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
4 Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
5 Biomedical Analysis Center, Army Medical University, Chongqing 400038, China
6 Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
7 Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
8 Wuhan Wuchang Hospital, Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan 430064, China
9 The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China
Correspondence to: Rong Xu: rongxu@hust.edu.cn,
DOI: 10.1038/s41401-025-01699-0
Received: 14 May 2025
Accepted: 20 October 2025
Advance online: 1 December 2025

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.
Keywords: breast cancer; bone metastasis; ATM; CCL2; osteoclastogenesis; KU55933

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