Abstract

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.

Original languageEnglish
Pages (from-to)1255-1267
Number of pages13
JournalJournal of Molecular Medicine
Volume98
Issue number9
DOIs
Publication statusPublished - Sep 1 2020

Keywords

  • Autophagy
  • Chemotherapy
  • Paclitaxel
  • TNFSF13
  • Triple-negative breast cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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