Background: Aggressive forms of breast cancer, such as triple-negative breast cancer (TNBC), are associated with an increase in cancer cells that exhibit stem cell properties. The activation of the epithelial–mesenchymal transition (EMT) program, mediated by the transcription factor FOXC2, generates these stem-like cells. FOXC2 is linked to poor prognoses across various cancer types and is notably upregulated in TNBC, where it establishes and sustains these stem-like cells within the tumor population.Methods: Here, we decode the pathways regulating FOXC2 activation using EMT-enriched cell line models. Stemness was assessed using mammosphere assays and mesenchymal markers by western blot. Expression correlations with clinical data was examined using the EMTome.Results: We demonstrate that β-catenin serves as a critical mediator of mesenchymal and stemness characteristics through FOXC2 upregulation. By disrupting β-catenin, we find that FOXC2 expression, mesenchymal properties, and stemness are reduced; however, the introduction of exogenous FOXC2 expression in β-catenin deficient cells is enough to restore the mesenchymal and stemness phenotype. These findings support the idea that FOXC2 acts as the downstream regulator of β-catenin and influences both mesenchymal and stemness properties. Moreover, there is a positive correlation between the expression of β-catenin and FOXC2 in various cancer subtypes observed in clinical patient samples.Conclusions: Our study clarifies the role of the β-catenin/FOXC2 signaling axis in maintaining stemness properties, suggesting potential targets for TNBC and other cancers driven by EMT-related mesenchymal and stemness characteristics.
背景：侵袭性乳腺癌，如三阴性乳腺癌（TNBC），与表现出干细胞特性的癌细胞增多相关。由转录因子FOXC2介导的上皮-间质转化（EMT）程序激活可产生此类干细胞样细胞。FOXC2与多种癌症类型的不良预后相关，在TNBC中显著上调，并在肿瘤群体中建立并维持这些干细胞样细胞。 方法：本研究利用EMT富集的细胞系模型解析调控FOXC2激活的通路。通过乳腺球形成实验评估干细胞特性，并通过蛋白质印迹法检测间质标志物。使用EMTome数据库分析表达水平与临床数据的相关性。 结果：我们证明β-连环蛋白通过上调FOXC2成为间质特性和干细胞特性的关键介质。通过干扰β-连环蛋白，发现FOXC2表达、间质特性和干细胞特性均降低；但在β-连环蛋白缺陷细胞中引入外源性FOXC2表达足以恢复间质和干细胞表型。这些发现支持FOXC2作为β-连环蛋白下游调节因子，同时影响间质和干细胞特性的观点。此外，临床患者样本中观察到多种癌症亚型的β-连环蛋白与FOXC2表达呈正相关。 结论：本研究阐明了β-连环蛋白/FOXC2信号轴在维持干细胞特性中的作用，为TNBC及其他由EMT相关间质和干细胞特性驱动的癌症提供了潜在治疗靶点。
肿瘤(癌症)患者之家