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TNFSF13 upregulation confers chemotherapeutic resistance via triggering autophagy initiation in triple-negative breast cancer

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Abstract

Since chemotherapy is a main strategy to treat triple-negative breast cancer (TNBC) patients currently, identifying a biomarker to predict chemotherapeutic responses is urgently needed for patients to avoid suffering through unnecessary chemotherapeutic treatments. Here, we found that the endogenous expression of TNFSF13 in a panel of TNBC cell lines highly correlates with paclitaxel (PTX) and doxorubicin IC50 concentrations. Whereas knocking down TNFSF13 enhances PTX effectiveness in PTX-insensitive MDA-MB231 cells, recombinant TNFSF13 (recTNFSF13) desensitizes PTX-sensitive HCC1806 cells to PTX treatment. Moreover, Kaplan-Meier analysis revealed that higher TNFSF13 mRNA expression significantly predicts an increased risk for cancer recurrence in estrogen receptor (ER)-negative breast cancer patients receiving an anthracycline-based treatment. Accordingly, immunohistochemistry experiments indicated that higher levels of TNFSF13 protein are detected in TNBC patients who do not respond to an anthracycline-based treatment. The in silico analysis and Western blotting demonstrated that TNFSF13 expression inversely associates with the activity of the Akt-mTOR pathway, which acts as a negative regulator of autophagy activity. Significantly, the pharmaceutical inhibition of autophagy activity restores the therapeutic effectiveness of PTX in TNFSF13-treated HCC1806 cells. These findings suggest that TNFSF13 can serve as a predictive biomarker for TNBC patients, who can use it to decide whether to receive chemotherapy.

Key messages

  • TNFSF13 upregulation correlates with a poor response to chemotherapy in TNBCs.

  • TNFSF13 promotes autophagy initiation in chemotherapeutic resistant TNBCs.

  • Therapeutic targeting of autophagy initiation overcomes the TNFSF13-related chemoresistance.

  • TNFSF13 could be a predictive biomarker for TNBC patients receiving chemotherapy.

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Acknowledgment

The authors would like to thank Dr. Michael Hsiao from Academia Sinica in Taiwan for kindly providing TNBC cell lines.

Funding

This study was supported by the Ministry of Science and Technology, Taiwan to Yuan-Feng Lin (MOST 108-2320-B-038-017-MY3) and Hui-Yu Lin (MOST 108-2314-B-567-002), and Cardinal Tien Hospital, Xindian District, New Taipei City, Taiwan (CTH108A-2A02) to Hui-Yu Lin.

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Authors and Affiliations

  1. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, 110, Taipei, Taiwan

    Hui-Yu Lin, Chia-Hao Kuei, Hsun-Hua Lee, Chi-Long Chen & Yuan-Feng Lin

  2. Division of Breast Surgery and General Surgery, Department of Surgery, Cardinal Tien Hospital, Fu-Jen Catholic University, New Taipei City, Taiwan

    Hui-Yu Lin

  3. Division of Urology, Department of Surgery, Cardinal Tien Hospital, Fu-Jen Catholic University, New Taipei City, Taiwan

    Chia-Hao Kuei

  4. Department of Neurology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan

    Hsun-Hua Lee

  5. Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Hsun-Hua Lee

  6. Department of Neurology, Vertigo and Balance Impairment Center, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan

    Hsun-Hua Lee

  7. Department of Otolaryngology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Che-Hsuan Lin

  8. Department of Otolaryngology, TMU Hospital, TMU, Taipei, Taiwan

    Che-Hsuan Lin

  9. Department of Pathology, Cardinal Tien Hospital, School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan

    Yen-Lin Chen

  10. Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Chi-Long Chen

  11. Department of Pathology, Taipei Medical University Hospital, Taipei, Taiwan

    Chi-Long Chen

  12. Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Yuan-Feng Lin

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  1. Hui-Yu Lin
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Contributions

HYL, HHL, CHK, CHL, CLC, and YFL participated in data collection and analysis. HYL, YLC, CLC, and YFL participated in the design of the study. HYL, CLC, and YFL participated in the writing the manuscript and the data interpretation. All authors read and approved the final manuscript.

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Correspondence to Yuan-Feng Lin.

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The authors declare that they have no conflict of interest.

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This study was conducted with the approval of the local ethics committee (Cardinal Tien Hospital, New Taipei City, Taiwan, CTH-101-3-5-054).

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Lin, HY., Kuei, CH., Lee, HH. et al. TNFSF13 upregulation confers chemotherapeutic resistance via triggering autophagy initiation in triple-negative breast cancer. J Mol Med 98, 1255–1267 (2020). https://doi.org/10.1007/s00109-020-01952-5

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