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

Abstract

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 <i>in vitro</i> HUVEC tube formation or <i>in vivo</i> 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-κB signaling in breast cancer cells; 2) PFKFB4-induced lactate secretion contributes to NF-κB 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 <i>in vitro</i> and <i>in vivo</i>. Our findings suggest a potential strategy whereby 5-MPN may lead to an improved therapeutic outcome for breast cancer patients.