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

Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):14174-14180. doi: 10.1073/pnas.1821194116. Epub 2019 Jun 24.


Vascular endothelial growth factor (VEGF) signaling in tumor cells mediated by neuropilins (NRPs) contributes to the aggressive nature of several cancers, including triple-negative breast cancer (TNBC), independently of its role in angiogenesis. Understanding the mechanisms by which VEGF-NRP signaling contributes to the phenotype of such cancers is a significant and timely problem. We report that VEGF-NRP2 promote homologous recombination (HR) in BRCA1 wild-type TNBC cells by contributing to the expression and function of Rad51, an essential enzyme in the HR pathway that mediates efficient DNA double-strand break repair. Mechanistically, we provide evidence that VEGF-NRP2 stimulates YAP/TAZ-dependent Rad51 expression and that Rad51 is a direct YAP/TAZ-TEAD transcriptional target. We also discovered that VEGF-NRP2-YAP/TAZ signaling contributes to the resistance of TNBC cells to cisplatin and that Rad51 rescues the defects in DNA repair upon inhibition of either VEGF-NRP2 or YAP/TAZ. These findings reveal roles for VEGF-NRP2 and YAP/TAZ in DNA repair, and they indicate a unified mechanism involving VEGF-NRP2, YAP/TAZ, and Rad51 that contributes to resistance to platinum chemotherapy.

Keywords: DNA repair; VEGF–neuropilin; YAP/TAZ; breast cancer.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • BRCA1 Protein / genetics
  • Cell Line, Tumor
  • DNA Repair / genetics
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Homologous Recombination / genetics
  • Humans
  • Neuropilin-2 / genetics*
  • Neuropilins / genetics
  • Platinum / pharmacology
  • Rad51 Recombinase / genetics*
  • Signal Transduction / drug effects
  • Transcription Factors / genetics
  • Triple Negative Breast Neoplasms / genetics*
  • Triple Negative Breast Neoplasms / pathology
  • Vascular Endothelial Growth Factor A / genetics*
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • BRCA1 Protein
  • BRCA1 protein, human
  • Neuropilin-2
  • Neuropilins
  • Transcription Factors
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • neuropilin-2, human
  • Platinum
  • Rad51 Recombinase