Scutellarin suppresses the metastasis of triple-negative breast cancer via targeting TNFα/TNFR2-RUNX1-triggered G-CSF expression in endothelial cells

Triple-negative breast cancer (TNBC) is heterogeneous and aggressive, with high vascularity and frequent metastasis. We have already found natural flavonoid scutellarin (SC) suppressed spontaneous TNBC metastasis via normalizing tumor vasculature in vivo. In this study, supernatant from tumor necrosis factor alpha (TNF alpha)-treated human mammary microvascular endothelial cell (HMMEC) promoted cell migration and pseudopod formation in TNBC cells, but these phenomena were disappeared in SC-co-treated HMMEC. TNF alpha enhanced the expression of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in both HMMEC and human umbilical vein endothelial cell (HUVEC). G-CSF promoted TNBC migration and invasion in vitro, while G-CSF neutralization antibody and SC both inhibited TNBC metastasis in Balb/c mice. SC had no inhibition on the G-CSF-induced TNBC cell migration, but reduced G-CSF content in TNBC tumor tissues and TNF alpha-stimulated endothelial cells (ECs). SC restricted the nuclear translocation of runt-related transcription factor 1 (RUNX1) in TNBC tumor vessels and TNF alpha-treated ECs. RUNX1 was found to directly bind to the promoter of G-CSF in TNBC tumor vessels and regulated G-CSF expression. TNF receptor 2 (TNFR2) was crucial for regulating the TNF alpha-induced RUNX1 activation and G-CSF expression. Notably, SC hindered the interaction between TNF alpha and TNFR2 via binding to TNFR2. This work demonstrated that SC reduced TNBC metastasis by targeting TNF alpha/TNFR2-initiated RUNX1 activation and subsequent G-CSF production in TNBC-associated ECs.

Automated summary

This study found that the natural flavonoid scutellarin (SC) suppressed the metastasis of TNBC by regulating tumor vasculature. SC reduced the production of G-CSF, thereby inhibiting the migration and invasion of TNBC cells. SC also hindered the interaction between TNF alpha and TNFR2, leading to reduced TNBC metastasis.