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FSIP1 enhances the therapeutic sensitivity to CDK4/6 inhibitors in triple-negative breast cancer patients by activating the Nanog pathway

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Abstract

CDK4/6 inhibitors are routinely recommended agents for the treatment of advanced HR+HER2− breast cancer. However, their therapeutic effectiveness in triple-negative breast cancer (TNBC) remains controversial. Here, we observed that the expression level of fibrous sheath interacting protein 1 (FSIP1) could predict the treatment response of TNBC to CDK4/6 inhibitors. High FSIP1 expression level was related to a poor prognosis in TNBC, which was associated with the ability of FSIP1 to promote tumor cell proliferation. FSIP1 downregulation led to slowed tumor growth and reduced lung metastasis in TNBC. FSIP1 knockout caused cell cycle arrest at the G0/G1 phase and reduced treatment sensitivity to CDK4/6 inhibitors by inactivating the Nanog/CCND1/CDK4/6 pathway. FSIP1 could form a complex with Nanog, protecting it from ubiquitination and degradation, which may facilitate the rapid cell cycle transition from G0/G1 to S phase and exhibit enhanced sensitivity to CDK4/6 inhibitors. Our findings suggest that TNBC patients with high FSIP1 expression levels may be suitable candidates for CDK4/6 inhibitor treatment.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82203804, 81872159), and 345 Talent Project of Shengjing Hospital of China Medical University.

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Authors and Affiliations

  1. Department of Oncology, Cancer Stem Cell and Translation Medicine Lab, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, Shenyang, 110004, China

    Guanglei Chen, Lisha Sun, Xi Gu, Liping Ai, Jie Yang, Zhan Zhang, Pengjie Hou, Yining Wang, Xunyan Ou, Xiaofan Jiang, Xinbo Qiao, Qingtian Ma, Nan Niu, Jinqi Xue, Hao Zhang & Caigang Liu

  2. School of Bioengineering, Dalian University of Technology, Dalian, 116024, China

    Yongliang Yang

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Correspondence to Caigang Liu.

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Compliance and ethics The authors declare that they have no competing interests. The National Institutes of Health Guide for the Care and Use of Laboratory Animals was followed in this study (2020PS395K). Written informed consent was obtained from all patients. This study was approved by the institutional research ethics committee of Shengjing Hospital of China Medical University. Information about the individual’s illness and tissue samples used in this study were obtained with the individual’s consent for publication.

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Chen, G., Sun, L., Gu, X. et al. FSIP1 enhances the therapeutic sensitivity to CDK4/6 inhibitors in triple-negative breast cancer patients by activating the Nanog pathway. Sci. China Life Sci. 66, 2805–2817 (2023). https://doi.org/10.1007/s11427-023-2343-y

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