Mutant p53 Cooperates with the SWI/SNF Chromatin Remodeling Complex to Regulate VEGFR2 in Breast Cancer Cells. Homo sapiens

Mutant p53 impacts the expression of numerous genes at the level of transcription tomediate oncogenesis. We identified vascular endothelial growth factor receptor 2(VEGFR2), the primary functional VEGF receptor that mediates endothelial cellvascularization, as a mutant p53 transcriptional target in multiple breast cancer cell lines.Up-regulation of VEGFR2 mediates the role of mutant p53 in increasing cellular growthin 2D and 3D culture conditions. Mutant p53 binds near the VEGFR2 promotertranscriptional start site and plays a role in maintaining an open conformation at thatlocation. Relatedly, mutant p53 interacts with the SWI/SNF complex which is required forremodeling the VEGFR2 promoter. By both querying individual genes regulated bymutant p53 and performing RNA-sequencing, the results indicate that over fifty percentof all mutant p53-regulated gene expression is mediated by SWI/SNF. We surmise thatmutant p53 impacts transcription of VEGFR2 as well as myriad other genes by promoterremodeling through interaction with and likely regulation of the SWI/SNF chromatinremodeling complex. Therefore, not only might mutant p53 expressing tumors besusceptible to anti VEGF therapies, impacting SWI/SNF tumor suppressor function inmutant p53 tumors may have therapeutic potential.