Li Jingping, Zhang Xiangmei, Liu Beichen, Shi Chao, Ma Xindi, Ren Shuguang, Zhao Xiaohan, Liu Yunjiang
Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Hebei Provincial Key Laboratory of Tumor Microenvironment and Drug Resistance, Shijiazhuang, China.
Ann Transl Med. 2022 Jul;10(14):801. doi: 10.21037/atm-22-3080.
Forkhead Box Protein 3 (FOXP3), as an essential marker of regulatory T cell (Treg) development, is reportedly overexpressed in invasive breast carcinoma (BRCA) and could be a potential prognostic factor for BRCA. However, the biological function of FOXP3 in BRCA is still unclear. In this study, we comprehensively explored the expression landscape of FOXP3 and its prognostic value in BRCA.
FOXP3 transcriptomic expression data were mainly obtained from The Cancer Genome Atlas (TCGA). The Kaplan-Meier plotter and receiver operating characteristic (ROC) curve were used to assess the prognostic and diagnostic value of FOXP3 in BRCA. UALCAN, cBio-Portal, and MethSurv were used to evaluate the genomic variation of FOXP3. Gene set enrichment analysis (GSEA) was performed to explore the FOXP3 pathways involved in BRCA. Morover, we detected the expression of FOXP3 in 123 BRCA specimens and 5 BRCA cell lines to verify the biological value of FOXP3 in BRCA. The Kaplan-Meier method was adopted for the overall survival (OS) analysis, and a Cox proportional hazards model was used to estimate the hazard ratio (HR) for OS.
FOXP3 was more highly expressed in BRCA than in normal tissues (2.808±1.020 1.409±0.656, P<0.001), and overexpressed FOXP3 was associated with a better prognosis. The ROC curve demonstrated a significant diagnostic value of FOXP3 in BRCA (area under the ROC curve, AUC: 0.877). Genomic analysis revealed that promoter hypomethylation of FOXP3 may be the underlying mechanism of FOXP3's upregulation in BRCA. GSEA found that FOXP3 coexpressed genes were mainly involved in the Toll-like receptor pathway, JAK/STAT pathway, cell cycle, and apoptosis. Moreover, high FOXP3 expression was an independent protective factor for OS in our 123 BRCA tissues (HR: 0.367; P=0.036). , we found that FOXP3 knockdown with siRNA promoted migration and invasion in MCF-7 cells.
This study demonstrated that FOXP3 shows prognostic and diagnostic value for BRCA. We provided evidence that promoter hypomethylation and a high expression of FOXP3 were both related to a favorable prognosis in BRCA, which maybe associated with the Toll-like receptor pathway, JAK/STAT pathway, cell cycle, and apoptosis.
叉头框蛋白3（FOXP3）作为调节性T细胞（Treg）发育的关键标志物，据报道在浸润性乳腺癌（BRCA）中过表达，可能是BRCA的一个潜在预后因素。然而，FOXP3在BRCA中的生物学功能仍不清楚。在本研究中，我们全面探讨了FOXP3在BRCA中的表达情况及其预后价值。
FOXP3转录组表达数据主要来自癌症基因组图谱（TCGA）。使用Kaplan-Meier绘图仪和受试者工作特征（ROC）曲线评估FOXP3在BRCA中的预后和诊断价值。使用UALCAN、cBio-Portal和MethSurv评估FOXP3的基因组变异。进行基因集富集分析（GSEA）以探索BRCA中涉及的FOXP3途径。此外，我们检测了123个BRCA标本和5个BRCA细胞系中FOXP3的表达，以验证FOXP3在BRCA中的生物学价值。采用Kaplan-Meier方法进行总生存（OS）分析，并使用Cox比例风险模型估计OS的风险比（HR）。
FOXP3在BRCA中的表达高于正常组织（2.808±1.020对1.409±0.656，P<0.001），且FOXP3过表达与较好的预后相关。ROC曲线显示FOXP3在BRCA中具有显著的诊断价值（ROC曲线下面积，AUC：0.877）。基因组分析表明，FOXP3启动子低甲基化可能是BRCA中FOXP3上调的潜在机制。GSEA发现FOXP3共表达基因主要参与Toll样受体途径、JAK/STAT途径、细胞周期和凋亡。此外，在我们的123个BRCA组织中，高FOXP3表达是OS的独立保护因素（HR：0.367；P=0.036）。此外，我们发现用siRNA敲低FOXP3可促进MCF-7细胞的迁移和侵袭。
本研究表明FOXP3对BRCA具有预后和诊断价值。我们提供的证据表明，启动子低甲基化和FOXP3高表达均与BRCA的良好预后相关，这可能与Toll样受体途径、JAK/STAT途径、细胞周期和凋亡有关。
