title: 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.
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Dann
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Golas
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Miranda
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Shi
authors.affiliation: Pfizer Structural Biology and Biophysics, Groton, CT, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Jin
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: E
authors.initials: E
authors.lastname: Rosfjord
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: E
authors.initials: E
authors.lastname: Upeslacis
authors.affiliation: Pfizer Oncology Research Unit, Pearl River, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Klippel
mesh_terms: D051177:Catenins / Q000502:physiology*; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D009857:Oncogenes; D010766:Phosphorylation; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D051177:Catenins; D050719:Crk-Associated Substrate Protein; D051744:Protein Kinase C-epsilon; D018631:ras Proteins