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FBXL2 promotes E47 protein instability to inhibit breast cancer stemness and paclitaxel resistance

Oncogene volume 42, pages 339–350 (2023)Cite this article

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Abstract

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high risk of metastasis and recurrence. Although chemotherapy has greatly improved the clinical outcome of TNBC patients, acquired drug resistance remains a huge challenge for TNBC treatment. Breast cancer stem cells (BCSCs) play a critical role in breast cancer development, metastasis, recurrence, and chemotherapy resistance. Thus, it is of great importance to decipher the underlying molecular mechanism of BCSCs regulation for TNBC drug resistance. In this study, we demonstrate that the F-box protein FBXL2 is a critical negative regulator of BCSCs stemness and that downregulation of FBXL2 plays a causal role in TNBC drug resistance. We show that expression levels of FBXL2 significantly influence CD44high/CD24low subpopulation and the mammosphere formation ability of TNBC cells. Ectopic expression of FBXL2 inhibits initiation of TNBC and overcomes paclitaxel resistance in vivo. In addition, activation of FBXL2 by nebivolol, a clinically used small-molecule inhibitor of the beta-1 receptor, markedly overcomes BCSCs-induced paclitaxel resistance. Mechanistically, we show that FBXL2 targets transcriptional factor E47 for polyubiquitin- and proteasome-mediated degradation, resulting in inhibition of BCSC stemness. Clinical analyses indicate that low expression of FBXL2 correlates with high expression of E47 as well as with high stemness features, and is associated with poor clinical outcomes of breast cancer patients. Taken together, these results highlight that the FBXL2-E47 axis plays a critical role in the regulation of BCSC stemness and paclitaxel resistance. Thus, targeting FBXL2 might be a potential therapeutic strategy for drug-resistant TNBC.

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Fig. 1: Reduced FBXL2 expression correlates with BCSCs marker CD44/CD24 expression and is associated with poor clinical outcomes of breast cancer patients.
Fig. 2: FBXL2 inhibits stemness and tumor initiation ability of BCSCs.
Fig. 3: FBXL2 binds to and targets E47 protein for proteasomal degradation to inhibit stemness of breast cancer cells.
Fig. 4: Inhibition of FBXL2 expression critically contributes to paclitaxel (PTX) resistance of TNBC in vivo.
Fig. 5: Activation of FBXL2 by nebivolol inhibits paclitaxel resistance of TNBC.

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Data availability

All data supporting the findings of this study are available from the corresponding authors upon reasonable request. The public datasets used to bioinformatic analyses are available in supplementary tables (Supplementary Tables S1–S3).

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Acknowledgements

We thank members of Z-XX laboratory for stimulating discussions during the study.

Funding

This work was supported by National Natural Science Foundation of China (81830108, 81861148031, and 31701242) to Z-XX or MN; National Key R&D Program of China (2018YFC2000100) to Z-XX; Department of Science and technology of Sichuan Province (23NSFSC3804) to MN; and the Fundamental Research Funds for the Central Universities (2021SCU12099) to MN.

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  1. These authors contributed equally: Fengtian Li, Mengmeng Niu.

Authors and Affiliations

  1. Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, P.R. China

    Fengtian Li, Mengmeng Niu, Kewei Qin, Rongtian Guo, Yong Yi, Jing Xu, Luping Li, Siyi Xie, Mengyuan Fu, Nasi Wen & Zhi-Xiong Jim Xiao

  2. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P.R. China

    Fengtian Li & Wenting Liao

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Contributions

Z-XX and MN conceived the project and performed the project planning; FL, KQ, RG, YY, JX, LL, SX, MF, NW, WL, and MN performed research; FL, MN, and Z-XX contributed to data analyses; Z-XX, MN, and FL analyzed data and wrote the manuscript.

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Li, F., Niu, M., Qin, K. et al. FBXL2 promotes E47 protein instability to inhibit breast cancer stemness and paclitaxel resistance. Oncogene 42, 339–350 (2023). https://doi.org/10.1038/s41388-022-02559-5

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