| First Author | Dann SG | Year | 2014 |
| Journal | Oncogene | Volume | 33 |
| Issue | 11 | Pages | 1385-94 |
| PubMed ID | 23542175 | Mgi Jnum | J:212374 |
| Mgi Id | MGI:5578713 | Doi | 10.1038/onc.2013.91 |
| Citation | Dann SG, et al. (2014) p120 catenin is a key effector of a Ras-PKCvarepsilon oncogenic signaling axis. Oncogene 33(11):1385-94 |
| abstractText | Within the family of protein kinase C (PKC) molecules, the novel isoform PRKCE (PKCvarepsilon) acts as a bona fide oncogene in in vitro and in vivo models of tumorigenesis. Previous studies have reported expression of PKCvarepsilon in breast, prostate and lung tumors above that of normal adjacent tissue. Data from the cancer genome atlas suggest increased copy number of PRKCE in triple negative breast cancer (TNBC). We find that overexpression of PKCvarepsilon in a non-tumorigenic breast epithelial cell line is sufficient to overcome contact inhibition and results in the formation of cellular foci. Correspondingly, inhibition of PKCvarepsilon in a TNBC cell model results in growth defects in two-dimensional (2D) and three-dimensional (3D) culture conditions and orthotopic xenografts. Using stable isotope labeling of amino acids in a cell culture phosphoproteomic approach, we find that CTNND1/p120ctn phosphorylation at serine 268 (P-S268) occurs in a strictly PKCvarepsilon-dependent manner, and that loss of PKCvarepsilon signaling in TNBC cells leads to reversal of mesenchymal morphology and signaling. In a model of Ras activation, inhibition of PKCvarepsilon is sufficient to block mesenchymal cell morphology. Finally, treatment with a PKCvarepsilon ATP mimetic inhibitor, PF-5263555, recapitulates genetic loss of function experiments impairing p120ctn phosphorylation as well as compromising TNBC cell growth in vitro and in vivo. We demonstrate PKCvarepsilon as a tractable therapeutic target for TNBC, where p120ctn phosphorylation may serve as a readout for monitoring patient response. |
