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

Lisa Andriani; Yun-Xiao Ling; Shao-Ying Yang; Qian Zhao; Xiao-Yan Ma; Min-Ying Huang; Yin-Ling Zhang; Fang-Lin Zhang; Da-Qiang Li; Zhi-Ming Shao

doi:10.1016/j.canlet.2024.217008

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

Cancer Lett. 2024 Aug 10:597:217008. doi: 10.1016/j.canlet.2024.217008. Epub 2024 Jun 5.

Authors

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: [email protected].
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: [email protected].
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: [email protected].

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.

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Autoantigens* / genetics
Autoantigens* / metabolism
Autophagy* / drug effects
Cation Transport Proteins* / genetics
Cation Transport Proteins* / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Disease Progression
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Lapatinib* / pharmacology
Membrane Proteins* / genetics
Membrane Proteins* / metabolism
Mice
Proteolysis / drug effects
Signal Transduction / drug effects
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / genetics
Triple Negative Breast Neoplasms* / metabolism
Triple Negative Breast Neoplasms* / pathology
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Autoantigens
CIP2A protein, human
Intracellular Signaling Peptides and Proteins
Lapatinib
Membrane Proteins
SFXN1 protein, human
Cation Transport Proteins