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PTEN neddylation aggravates CDK4/6 inhibitor resistance in breast cancer

Oncogene volume 44, pages 2997–3013 (2025)Cite this article

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Abstract

The gradual emergence of a novel therapeutic approach lies in the restoration of tumor suppressive machinery. PTEN is a crucial negative regulator of the PI3K/Akt signaling pathway. Protein neddylation modification contributes to PTEN inactivation and fuels breast cancer progression. Here, we highlight that an elevated level of PTEN neddylation is markedly associated with resistance to palbociclib, a CDK4/6 inhibitor used in luminal subtype breast cancer patients. Mechanistically, PTEN neddylation activates the PI3K/Akt signaling pathway, and more notably, upregulates the activity of the AP-1 transcription factor. Our data showed that PTEN neddylation stabilizes JUND, a transcription factor involved in the AP-1 complex, by disrupting its interaction with the E3 ubiquitin ligase ITCH. Consequently, activated JUND leads to the release of cytokines and chemokines, which in turn may drive an inflammatory tumor microenvironment, potentially contributing to drug resistance. Then, we identified Echinacoside as a potent inhibitor of PTEN neddylation both in vivo and in vitro by disrupting its interaction with XIAP, the E3 ligase responsible for PTEN neddylation. Combination of Echinacoside effectively overcome resistance to palbociclib in breast cancer treatment. These findings highlight targeting PTEN neddylation as a promising strategy for restoring tumor suppressor activity and overcoming resistance.

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Fig. 1: Palbociclib-resistant breast cancer cells express higher levels of PTEN neddylation modification.
Fig. 2: Upregulation of XIAP increases the PTEN neddylation in palbociclib-resistant breast cancer.
Fig. 3: PTEN neddylation enhances JUND protein stability.
Fig. 4: PTEN neddylation hinders the ITCH-mediated ubiquitination degradation of JUND.
Fig. 5: Echinacoside is identified as an inhibitor of PTEN neddylation.
Fig. 6: ECH is dependent on PTEN neddylation to suppress tumorigenesis.
Fig. 7: Combination ECH enhances the sensitivity of palbociclib in breast cancer.

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Data availability

RNA-seq data have been deposited at SRA (PRJNA1143082 and PRJNA1144658) and are publicly available as of the date of publication. All data are available in the main text or the supplementary materials.

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Acknowledgements

Thanks to Core Facility Center, Capital Medical University for providing platform support for this research.

Funding

This work was supported by the National Outstanding Youth Science Fund Project of National Natural Science Foundation of China (No. 82122052), National Natural Science Foundation of China (NSFC) (No. 32471305), Outstanding Young Talents Program in Chinese Institutes for Medical Research (No. CX23YQA03), Innovative Group Cultivation Project for Basic Medicine (No. CX25XT03).

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  1. These authors contributed equally: Fan Liu, Weixiao Liu, Yawen Tan.

Authors and Affiliations

  1. Department of Cell Biology, Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China

    Fan Liu, Weixiao Liu, Yaxin Shang, Sihui Ling & Ping Xie

  2. Beijing lnstitute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China

    Fan Liu, Weixiao Liu & Ping Xie

  3. Department of Breast and Thyroid Surgery, The Second People’s Hospital of Shenzhen, Shenzhen, Guangdong, 518035, China

    Yawen Tan & Shiyao Sun

  4. Department of Neurosurgery, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China

    Xiaokun Jiang & Zhen Zhang

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Contributions

Conceptualization: PX; Methodology: FL, WXL, YXS, SHL, XKJ; Formal Analysis: FL; Investigation: PX, FL; Resources: SYS, YWT, ZZ; Writing-Original Draft: PX; Funding Acquisition: PX.

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Correspondence to Ping Xie.

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The authors declare that there are no competing financial, commercial, or professional interest that could influence the performance, interpretation, or reporting of the research presented in this manuscript. All authors have read and approved this declaration of interests, confirming that it accurately reflects their current situation.

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All animals were handled in strict accordance to the “Guide for the Care and Use of Laboratory Animals” and the “Principles for the Utilization and Care of Vertebrate Animals”, and all animal work was approved by Capital Medical University Ethics Committee. The clinical samples were approved by the department of breast and thyroid surgery at the Second People’s Hospital of Shenzhen and Hunan Cancer Hospital. Informed consent was obtained from all subjects or their relatives. All methods were performed in accordance with the relevant guidelines and regulations.

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Liu, F., Liu, W., Tan, Y. et al. PTEN neddylation aggravates CDK4/6 inhibitor resistance in breast cancer. Oncogene 44, 2997–3013 (2025). https://doi.org/10.1038/s41388-025-03468-z

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