TNFAIP2 promotes HIF1α transcription and breast cancer angiogenesis by activating the Rac1-ERK-AP1 signaling axis

Abstract Angiogenesis is well known to play a critical role in breast cancer. We previously reported that TNFAIP2 activates Rac1 to promote triple-negative breast cancer (TNBC) cell proliferation, migration, and chemoresistance. However, the potential contribution of TNFAIP2 to tumor angiogenesis remains unknown. In this study, we demonstrated that TNFAIP2 promotes TNBC angiogenesis by activating the Rac1-ERK-AP1-HIF1α signaling axis. Under hypoxia, TNFAIP2 activates Rac1 and ERK sequentially. Following that, ERK activates the AP-1 (c-Jun/Fra1) transcription factor. By employing chromatin immunoprecipitation and luciferase reporter assays, we showed that AP-1 directly interacts with the HIF1α gene promoter, thereby enhancing its transcription. The combined application of ERK inhibitors, U0126 or trametinib, with the VEGFR inhibitor Apatinib, additively suppresses angiogenesis and tumor growth of HCC1806 in nude mice. These findings provide new therapeutic strategies for TNBC.