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  • Original Article
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p120 catenin is a key effector of a Ras-PKCɛ oncogenic signaling axis

Abstract

Within the family of protein kinase C (PKC) molecules, the novel isoform PRKCE (PKCɛ) acts as a bona fide oncogene in in vitro and in vivo models of tumorigenesis. Previous studies have reported expression of PKCɛ 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 PKCɛ 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 PKCɛ 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 PKCɛ-dependent manner, and that loss of PKCɛ signaling in TNBC cells leads to reversal of mesenchymal morphology and signaling. In a model of Ras activation, inhibition of PKCɛ is sufficient to block mesenchymal cell morphology. Finally, treatment with a PKCɛ 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 PKCɛ as a tractable therapeutic target for TNBC, where p120ctn phosphorylation may serve as a readout for monitoring patient response.

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Acknowledgements

The authors would like to thank Drs Robert T Abraham and Valeria Fantin for critical review of the manuscript.

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Correspondence to S G Dann.

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All the authors are full time employees of Pfizer, Inc., with no relationships that they believe could be construed as resulting in an actual, potential, or perceived conflict of interest with regard to the manuscript submitted for review.

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Dann, S., Golas, J., Miranda, M. et al. p120 catenin is a key effector of a Ras-PKCɛ oncogenic signaling axis. Oncogene 33, 1385–1394 (2014). https://doi.org/10.1038/onc.2013.91

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