2. Academic Validation
  3. ATM promotes bone metastatic propensity of breast cancer by inducing osteoclastogenesis via the NFκB-CCL2 pathway

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

  • Acta Pharmacol Sin. 2025 Dec 1. doi: 10.1038/s41401-025-01699-0.
Ming-Yang Qin # 1 2,  Yuan-Hui Liu # 3,  Ze-Liang Wu # 4,  Yi Huang 5,  Jiang Wang 6,  Tian Xia 7,  Lin Zhu 8,  Hui Liu 1 9,  Rong Xu 10 11
Affiliations

Affiliations

  • 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.
  • 10 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. [email protected].
  • 11 The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 430030, China. [email protected].
  • # Contributed equally.
PMID: 41326811 DOI: 10.1038/s41401-025-01699-0
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

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

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