CEACAM1 controls the EMT switch in murine mammary carcinoma in vitro and in vivo
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CEACAM1 controls the EMT switch in murine mammary carcinoma in vitro and in vivo. / Wegwitz, Florian; Lenfert, Eva; Gerstel, Daniela; von Ehrenstein, Lena; Einhoff, Julia; Schmidt, Geske; Logsdon, Matthew; Brandner, Johanna; Tiegs, Gisa; Beauchemin, Nicole; Wagener, Christoph; Deppert, Wolfgang; Horst, Andrea Kristina.
in: ONCOTARGET, Jahrgang 7, Nr. 39, 27.09.2016, S. 63730-63746.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - CEACAM1 controls the EMT switch in murine mammary carcinoma in vitro and in vivo
AU - Wegwitz, Florian
AU - Lenfert, Eva
AU - Gerstel, Daniela
AU - von Ehrenstein, Lena
AU - Einhoff, Julia
AU - Schmidt, Geske
AU - Logsdon, Matthew
AU - Brandner, Johanna
AU - Tiegs, Gisa
AU - Beauchemin, Nicole
AU - Wagener, Christoph
AU - Deppert, Wolfgang
AU - Horst, Andrea Kristina
PY - 2016/9/27
Y1 - 2016/9/27
N2 - We analyzed the molecular basis for carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1)-controlled inhibition of epithelial-mesenchymal transition (EMT) in a mouse model for mammary adenocarcinoma (WAP-T mice). We demonstrate that silencing of CEACAM1 in WAP-T tumor-derived G-2 cells induces epithelial-mesenchymal plasticity (EMP), as evidenced by typical changes of gene expression, morphology and increased invasion. In contrast, reintroduction of CEACAM1 into G-2 cells reversed up-regulation of genes imposing mesenchymal transition, as well as cellular invasion. We identified the Wnt-pathway as target for CEACAM1-mediated repression of EMT. Importantly, β-catenin phosphorylation status and transcriptional activity strongly depend on CEACAM1 expression: CEACAM1high G-2 cells displayed enhanced phosphorylation of β-catenin at S33/S37/T41 and decreased phosphorylation at Y86, thereby inhibiting canonical Wnt/β-catenin signaling. We identified Src-homology 2 domain-containing phosphatase 2 (SHP-2) as a critical binding partner of CEACAM1 that could modulate β-catenin Y86 phosphorylation. Hence, CEACAM1 serves as a scaffold that controls membrane proximal β-catenin signaling. In vivo, mammary tumors of WAP-T/CEACAM1null mice displayed increased nuclear translocation of β-catenin and a dramatically enhanced metastasis rate compared to WAP-T mice. Hence, CEACAM1 controls EMT in vitro and in vivo by site-specific regulation of β-catenin phosphorylation. Survival analyses of human mammary carcinoma patients corroborated these data, indicating that CEACAM1 is a prognostic marker for breast cancer survival.
AB - We analyzed the molecular basis for carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1)-controlled inhibition of epithelial-mesenchymal transition (EMT) in a mouse model for mammary adenocarcinoma (WAP-T mice). We demonstrate that silencing of CEACAM1 in WAP-T tumor-derived G-2 cells induces epithelial-mesenchymal plasticity (EMP), as evidenced by typical changes of gene expression, morphology and increased invasion. In contrast, reintroduction of CEACAM1 into G-2 cells reversed up-regulation of genes imposing mesenchymal transition, as well as cellular invasion. We identified the Wnt-pathway as target for CEACAM1-mediated repression of EMT. Importantly, β-catenin phosphorylation status and transcriptional activity strongly depend on CEACAM1 expression: CEACAM1high G-2 cells displayed enhanced phosphorylation of β-catenin at S33/S37/T41 and decreased phosphorylation at Y86, thereby inhibiting canonical Wnt/β-catenin signaling. We identified Src-homology 2 domain-containing phosphatase 2 (SHP-2) as a critical binding partner of CEACAM1 that could modulate β-catenin Y86 phosphorylation. Hence, CEACAM1 serves as a scaffold that controls membrane proximal β-catenin signaling. In vivo, mammary tumors of WAP-T/CEACAM1null mice displayed increased nuclear translocation of β-catenin and a dramatically enhanced metastasis rate compared to WAP-T mice. Hence, CEACAM1 controls EMT in vitro and in vivo by site-specific regulation of β-catenin phosphorylation. Survival analyses of human mammary carcinoma patients corroborated these data, indicating that CEACAM1 is a prognostic marker for breast cancer survival.
U2 - 10.18632/oncotarget.11650
DO - 10.18632/oncotarget.11650
M3 - SCORING: Journal article
C2 - 27572314
VL - 7
SP - 63730
EP - 63746
JO - ONCOTARGET
JF - ONCOTARGET
SN - 1949-2553
IS - 39
ER -