De Pradip, Carlson Jennifer, Leyland-Jones Brian and Dey Nandini
The Wnt-beta-catenin pathway (WP) regulates different aspects of cell fate, migration and polarity. Inappropriate deregulation of this pathway leads to oncogenic and metastatic changes. The Triple Negative (TN) subset of BC (the absence of hormone receptors and absence of amplification/overexpression of HER2 receptors) exhibits aggressive clinical behavior and has poor clinical outcome. We have recently identified WP as one of the key signature pathways in TNBC associated with metastasis [1,2]. Here we report for the first time that WP controls metastasis-associated phenotype of Vascular Mimicry (VM) in TNBC. We have established 2D and 3D models to study VM in this subset of BC and characterized different TNBC cell lines in terms of VM and identified the role of WP in the regulation of VM. To establish the role of WP in the regulation of VM in TNBC, we have used (1) a pharmacological inhibitor of beta-catenin which is a functional readout of WP and (2) signaling modulators of WP. Since PI3K-pathway is an upstream regulator of WP, we have also used inhibitors of PI3K-pathway to test our hypothesis. Mechanistically (1) sulindac sulfide (pharmacological inhibitor of beta-catenin) and XAV939 (modulator of WP) mediated decrease in beta-catenin, (2) XAV939 mediated increase in axin and (3) LY294002 or SF1126 (pan PI3K inhibitors) mediated decrease in pGSK3beta caused an abrogation of VM in various TNBC cell lines including BT20, HCC1937, SUM149,
MDA-MB231 and MDA-MB468. Finally we obtained genetic proof-of-concept using beta-catenin SiRNA. SiRNAmediated downregulation of WP abrogated VM demonstrating the involvement of WP in VM. Functionally, our data show that VM in brain specific metastatic TNBC cells is mediated via activation of WP.
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