Claudin-low breast cancer has been identified as an aggressive breast cancer subtype by gene expression profiling, which is characterised by increased cellular plasticity and high expression of mesenchymal markers. Tumour-associated vasculature contributes to tumour growth and metastasis and can be established through vasculogenic mimicry (VM), in which tumour cells acquire endothelial properties and establish a pseudo-vascular architecture. VM is frequently observed in aggressive tumour subtypes and is associated with a poor prognosis. From our data, Neuropilin-1 (NRP1) is highly expressed and regulates aggressive hallmarks of Claudin-low breast cancer.
According to the above evidence, this study investigated the function of NRP1 in the VM of claudin-low breast cancer models. In MDA-MB-231 and SUM159 claudin-low cell lines, Matrigel-based tube formation assays and RT-qPCR were performed following NRP1 knockout (CRISPR-Cas9) and inhibition (monoclonal antibody Vesencumab). The formation of VM tubes was substantially reduced, and VM-associated mesenchymal markers (VIM, ZEB1, SNAI1/2) and extracellular matrix markers (MMP-2, MMP-14, and EPHA2) were suppressed by NRP1 knockout and inhibition. Additionally, our preliminary data from claudin-low xenografts indicate that NRP1 inhibitor therapy in mice results in a decrease in p42/44 MAPK-positive VM structures, as well as an increase in survival time and a reduction in tumour growth. These data indicate that the inhibition of VM by targeting NRP1 may be beneficial in the prevention of aggressive claudin-low tumour growth and metastasis.