Abstract 1235: p120ctn is a key effector of Ras-PKC∈-mediated oncogenic signaling

Within the family of protein kinase C (PKC) molecules only the novel isoform member PRKCE (PKC∈) acts as a bona fide oncogene in in-vitro and in-vivo models of tumorigenesis. Previous studies have reported cancer-specific misexpression of PKC∈ at levels well above that of normal adjacent tissue in breast, prostate and lung tumors. We find that oncogenic Ras signaling promotes PKC∈ expression and results in hyperphosphorylation of CTNND1/p120-catenin (p120ctn). In this context, loss of PKC∈ by genetic or pharmacological means results in normalization of morphology and signaling responses. In a KRasD13-dependent breast cancer model loss of PKC∈ function results in growth inhibition in 2-dimensional (2D) and 3-dimensional (3D) culture systems as well as in orthotopic xenografts concomitant with the normalization of a subset of Ras-induced signaling responses. Using phospho-proteomic profiling analysis we observe that CTNND1 (p120ctn) phosphorylation at serine 268 (S268) occurs in a strictly PKC∈ dependent manner. Treatment with a specific PKC∈ inhibitor, PF-5263555, recapitulates the genetic loss of function phenotype and interferes with breast cancer cell growth in-vitro and in-vivo. We also show that PKC∈-mediated phosphorylation at S268 further stabilizes additional p120ctn phosphorylation sites and total protein levels of β-catenin. We demonstrate that p120ctn phosphorylation at S268 represents a specific readout for PKC∈ activity and as such can serve as a suitable biomarker for PKC∈ dysregulation in human cancer and for monitoring therapeutic response. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1235. doi:1538-7445.AM2012-1235