Targeting Cross‐Talks of Notch and VEGF to Tweak the EMT and EPT Dynamics in Triple Negative Breast Cancer Cells

Abstract

AbstractThe associations of the Notch pathway with the major oncogenic pathways (especially the receptor tyrosine kinases, RTKs) are primarily responsible for inducing EMT (epithelial to mesenchymal transition), angiogenesis, and chemoresistance. In this study, Axitinib is used in combination with LY411575 (γ‐secretase inhibitor) and it is observed that the co‐treatment synergistically induced apoptosis (by 37.36% in MDAMB231 and 27.9% in MDAMB468), arrests cells at the G2/M phase, decreases the stemness properties of the triple‐negative breast cancer (TNBC) cells. It also diminishes the spheroid forming ability, enhances the expression of epithelial markers, such as E‐cadherin (by 2.2 fold in MDAMB231 and 2.51 fold in MDAMB468), and downregulated the expression of mesenchymal markers. Additionally, the protein expression profile of the pro‐oncogenic and pro‐survival genes also reduces significantly after the administration of co‐therapy, which is highlighted by a reduction in the levels of pEGFR, pFAK, pMAPK, NF‐κB, etc. Moreover, the expression of pericyte markers (such as PDGFRs, α‐SMA, c‐kit, and NG2) reduces significantly in both TNBC cells upon co‐treatment, thereby hinting toward the inhibition of epithelial‐to‐pericyte transition (EPT). The current work endows with the effectiveness of the co‐therapy on the EMT and EPT dynamics of TNBC upon inhibition of the major crosstalk between the Vascular endothelial growth factor (VEGF)t and Notch pathway.