Title

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

UMMS Affiliation

Department of Molecular, Cell and Cancer Biology; Medical Scientist Training Program; Department of Radiation Oncology

Publication Date

2019-07-09

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Cancer Biology | Neoplasms

Abstract

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

DOI of Published Version

10.1073/pnas.1821194116

Source

Elaimy AL, Amante JJ, Zhu LJ, Wang M, Walmsley CS, FitzGerald TJ, Goel HL, Mercurio AM. 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. PMID: 31235595; PMCID: PMC6628806. Link to article on publisher's site

Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America

Related Resources

Link to Article in PubMed

PubMed ID

31235595

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