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.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Cancer Lett. 2024 Aug 10;597:217008. doi: 10.1016/j.canlet.2024.217008. Epub 2024 Jun 5.
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.
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，缺乏特定的治疗靶点和有效的治疗方案。通过分析蛋白质组学 TNBC 数据集，我们发现肿瘤组织中 sideroflexin 1（SFXN1）显著上调。然而，SFXN1 在 TNBC 中的确切功能仍不清楚。通过免疫印迹法测定 SFXN1 表达水平。使用无标记定量蛋白质组学和液相色谱-串联质谱法鉴定 SFXN1 的下游靶标。使用免疫印迹法、免疫荧光染色和逆转录-定量聚合酶链反应（RT-qPCR）进行 SFXN1 和细胞蛋白磷酸酶 2A 抑制剂 C（CIP2A）的机制研究。功能实验用于研究 SFXN1 在 TNBC 细胞中的作用。SFXN1 在 TNBC 肿瘤组织中明显过表达，并与 TNBC 患者的不良预后相关。功能实验表明，SFXN1 促进了 TNBC 的体外和体内生长和转移。机制研究表明，SFXN1 通过抑制自噬受体 TOLLIP（toll 相互作用蛋白）介导的 CIP2A 自噬降解来促进 TNBC 的进展。Lapatinib 介导的 CIP2A/PP2A/p-AKT 通路抑制部分阻止了 SFXN1 过表达的促肿瘤作用。这些发现可能为 TNBC 患者提供新的靶向治疗方法。
