CEACAM1 controls the EMT switch in murine mammary carcinoma in vitro and in vivo
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Wegwitz Florian1,2,*, Eva Lenfert2,*, Daniela Gerstel3, Lena von Ehrenstein2, Julia Einhoff2,4, Geske Schmidt1, Matthew Logsdon1, Johanna Brandner5, Gisa Tiegs6, Nicole Beauchemin7, Christoph Wagener3, Wolfgang Deppert2, Andrea Kristina Horst6
1Clinic for General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Georg-August-University of Göttingen, D-37077 Göttingen, Germany
2Institute for Tumor Biology, University Medical Center-Hamburg-Eppendorf, D-20251 Hamburg, Germany
3Center for Diagnostics, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany
4Pharmaceutical Institute, Christian-Albrechts-University Kiel, D-24118 Kiel, Germany
5Dermatology and Venerology Department and Clinic, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany
6Institute for Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany
7Goodman Cancer Research Centre and Departments of Biochemistry, Medicine and Oncology, McGill University, Montreal, H3G1Y6, Canada
*These authors contributed equally to this work
Wegwitz Florian, email: [email protected]
Keywords: CEACAM1, Wnt-pathway, EMT, WAP-T, breast cancer
Received: September 18, 2015 Accepted: August 08, 2016 Published: August 27, 2016
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.
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