Intracellular sclerostin promotes tumor progression and metastasis as a potential therapeutic target in triple-negative breast cancer

  • Cell Rep Med. 2026 May 19;7(5):102763. doi: 10.1016/j.xcrm.2026.102763.
Meiheng Sun  1 ,  Hang Luo  2 ,  Shuangying Qiao  3 ,  Zefeng Chen  4 ,  Hewen Jiang  2 ,  Xin Yang  5 ,  Shijian Ding  5 ,  Yuan Tian  4 ,  Yingchao Wu  6 ,  Peng Wu  6 ,  Yihao Zhang  2 ,  Xiaohui Tao  4 ,  Yuanyuan Yu  4 ,  Luyao Wang  4 ,  Jianhui Tian  7 ,  Wei Kang  8 ,  Daqing Ma  9 ,  Yixin He  10 ,  Aiping Lu  11 ,  Feng-Lai Yuan  12 ,  Yuan Ma  13 ,  Fangfei Li  14 ,  Bao-Ting Zhang  15 ,  Qianjun Chen  16 ,  Ge Zhang  17
Affiliations
  • 1. Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, Hong Kong Baptist University, Hong Kong 000000, China; School of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong 000000, China.
  • 2. School of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong 000000, China.
  • 3. Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, Hong Kong Baptist University, Hong Kong 000000, China.
  • 4. Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, Hong Kong Baptist University, Hong Kong 000000, China.
  • 5. Institute of Integrated Bioinformedicine and Translational Science, Hong Kong Baptist University, Hong Kong, China.
  • 6. Department of Breast, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China.
  • 7. Department of Oncology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 8. Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 000000, China.
  • 9. Perioperative and Systems Medicine Laboratory and Department of Anesthesiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescent's Health and Diseases, Hangzhou 310051, China; Division of Anaesthetics, Pain Medicine & Intensive Care, Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London SW10 9NH, UK.
  • 10. Aptacure Therapeutics Limited, Hong Kong 000000, China.
  • 11. Institute of Integrated Bioinformedicine and Translational Science, Hong Kong Baptist University, Hong Kong, China. Electronic address: [email protected].
  • 12. Institute of Integrated Chinese and Western Medicine, Affiliated Hospital of Jiangnan University, Wuxi 214122, China. Electronic address: [email protected].
  • 13. Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong 000000, China. Electronic address: [email protected].
  • 14. Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, Hong Kong Baptist University, Hong Kong 000000, China. Electronic address: [email protected].
  • 15. School of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong 000000, China. Electronic address: [email protected].
  • 16. Department of Breast, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China; State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China; Chinese Medicine Guangdong Laboratory, Guangzhou 510120, China. Electronic address: [email protected].
  • 17. Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, Hong Kong Baptist University, Hong Kong 000000, China. Electronic address: [email protected].
PMID: 42030934 DOI: 10.1016/j.xcrm.2026.102763
Abstract

Triple-negative breast Cancer (TNBC) urgently requires promising therapeutic targets. This study identifies sclerostin, an osteocyte-derived secretory protein traditionally linked to bone homeostasis, as an unexpected intracellular oncogenic driver in TNBC. Although genetic ablation of sclerostin markedly suppresses tumor progression and lung metastasis, neither its antibody nor recombinant protein exerts any effects, excluding the role of extracellular sclerostin in TNBC. Genetic and pharmacological approaches (sclerostin aptamer-based proteolysis-targeting chimera with potent intracellular sclerostin-degrading activity, Apc101) show the emerging role of intracellular sclerostin in promoting TNBC progression and metastasis. Notably, in both TNBC cell-derived and patient-derived xenograft models, Apc101 significantly suppresses tumor progression. Mechanistically, intracellular sclerostin interacts with caprin1 to stabilize CDK1 and Cyclin B1 mRNAs. Collectively, this study reveals an oncogenic function of intracellular sclerostin in TNBC and proposes that targeting it represents a promising therapeutic strategy.

Keywords
aptamer-based proteolysis-targeting chimeras; intracellular sclerostin; sclerostin-caprin1 interaction; triple-negative breast cancer; tumor progression and metastasis.
Products