The VEGF receptor neuropilin 2 promotes homologous recombination by stimulating YAP/TAZ-mediated Rad51 expression

Abstract

Significance VEGF signaling mediated by the NRPs impacts tumor cells, independently of its function in angiogenesis and vascular permeability. VEGF–NRP2 signaling in tumor cells is associated with poor prognosis and therapy resistance in TNBC patients. In light of these observations the question arises, How does VEGF–NRP2 contribute to therapy resistance in TNBC? We discovered that autocrine VEGF–NRP2 signaling contributes to HR DNA repair and therapy resistance in TNBC cells by promoting YAP/TAZ-dependent Rad51 transcription. We also demonstrated that Rad51 is a YAP/TAZ target gene and that VEGF–NRP2–YAP/TAZ–mediated cisplatin resistance occurs through downstream Rad51 expression. These observations establish functions of VEGF–NRP2 signaling and YAP/TAZ in tumor biology and provide an integrated mechanism that governs Rad51 expression and HR in TNBC.