PFKFB4 promotes angiogenesis via IL-6/STAT5A/P-STAT5 signaling in breast cancer

Breast cancer has become the most newly-diagnosed cancer and the 5 th leading cause of cancer death worldwide. The 5-year survival rate of breast cancer is about 90%. However, the 5-year survival rate drops to <30% when metastasis to distant sites occurs. The blood vessel formation (i.e., angiogenesis) plays a crucial role during the metastatic process. In this study, we investigated the role of PFKFB4 in angiogenesis of breast cancer. Employing in vitro HUVEC tube formation or in vivo orthotopic mouse model, and gene editing or specific small inhibitors strategy, and utilizing qPCR, western blot, ELISA, or immunofluorescent/immunohistochemistry staining methods, we found the following: 1) PFKFB4 upregulates IL-6 expression via NF-B signaling in breast cancer cells; 2) PFKFB4-induced lactate secretion contributes to NF-B activation in breast cancer cells; 3) IL-6 elicits angiogenesis via STAT5A/P-STAT5 in HUVEC; 4) 5-MPN (a specific PFKFB4 inhibitor) suppresses angiogenesis in vitro and in vivo. Our findings suggest a potential strategy whereby 5-MPN may lead to an improved therapeutic outcome for breast cancer patients.