Loss of angulin-1/LSR promotes vasculogenic mimicry and epithelial-mesenchymal transition in breast cancer

Vasculogenic mimicry (VM) is a process by which tumor cells form vessel-like network to secure oxygen and nutrients essential for tumor growth. Intercellular junctions, including tight junctions, may play a critical role in this process, important for VM. Here, we investigated the role of angulin-1/LSR (Ang-1), a key component of tricellular tight junctions, in VM regulation. We performed VM assay using Ang-1 KO breast cancer cells. Compared with control cells, Ang-1/KO cells exhibited significantly enhanced VM formation, accompanied by increasing epithelial-mesenchymal transition features. In a xenograft model, tumors derived from Ang-1/KO cells showed increased mass and elevated VM ratios. Re-expression of Ang-1 isoforms 3, 4, or 6-2 in Ang-1/KO cells suppressed VM formation, whereas isoforms 1, 2, and 6 had no effect. RT-PCR analysis of breast cancer patient tissues confirmed the lower expression of Ang-1 isoform 6-2, which suppresses VM. These findings identify Ang-1 as a novel regulator of VM and suggest that specific isoforms, particularly isoform 6-2, may serve as isoform-specific diagnostic markers or therapeutic targets in breast cancer.