2. Academic Validation
  3. Sideroflexin-1 promotes progression and sensitivity to lapatinib in triple-negative breast cancer by inhibiting TOLLIP-mediated autophagic degradation of CIP2A

Sideroflexin-1 promotes progression and sensitivity to lapatinib in triple-negative breast cancer by inhibiting TOLLIP-mediated autophagic degradation of CIP2A

  • Cancer Lett. 2024 Jun 5:597:217008. doi: 10.1016/j.canlet.2024.217008.
Lisa Andriani 1,  Yun-Xiao Ling 1,  Shao-Ying Yang 2,  Qian Zhao 1,  Xiao-Yan Ma 1,  Min-Ying Huang 3,  Yin-Ling Zhang 4,  Fang-Lin Zhang 5,  Da-Qiang Li 6,  Zhi-Ming Shao 7
Affiliations

Affiliations

  • 1 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 3 Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
  • 4 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 5 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Electronic address: zhangfanglin555@sina.com.
  • 6 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Electronic address: daqiangli1974@fudan.edu.cn.
  • 7 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. Electronic address: zhimingshao@fudan.edu.cn.
PMID: 38849012 DOI: 10.1016/j.canlet.2024.217008
Abstract

Triple-negative breast Cancer (TNBC) is the most aggressive subtype of breast Cancer and it lacks specific therapeutic targets and effective treatment protocols. By analyzing a proteomic TNBC dataset, we found significant upregulation of sideroflexin 1 (SFXN1) in tumor tissues. However, the precise function of SFXN1 in TNBC remains unclear. Immunoblotting was performed to determine SFXN1 expression levels. Label-free quantitative proteomics and liquid chromatography-tandem mass spectrometry were used to identify the downstream targets of SFXN1. Mechanistic studies of SFXN1 and cellular inhibitor of PP2A (CIP2A) were performed using immunoblotting, immunofluorescence staining, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Functional experiments were used to investigate the role of SFXN1 in TNBC cells. SFXN1 was significantly overexpressed in TNBC tumor tissues and was associated with unfavorable outcomes in patients with TNBC. Functional experiments demonstrated that SFXN1 promoted TNBC growth and metastasis in vitro and in vivo. Mechanistic studies revealed that SFXN1 promoted TNBC progression by inhibiting the Autophagy receptor TOLLIP (toll interacting protein)-mediated autophagic degradation of CIP2A. The pro-tumorigenic effect of SFXN1 overexpression was partially prevented by lapatinib-mediated inhibition of the CIP2A/PP2A/p-AKT pathway. These findings may provide a new targeted therapy for patients with TNBC.

Keywords

Autophagy; CIP2A; Lapatinib; SFXN1; TNBC.

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