Research Papers:

CEACAM1 controls the EMT switch in murine mammary carcinoma in vitro and in vivo

Wegwitz Florian _, Eva Lenfert, Daniela Gerstel, Lena von Ehrenstein, Julia Einhoff, Geske Schmidt, Matthew Logsdon, Johanna Brandner, Gisa Tiegs, Nicole Beauchemin, Christoph Wagener, Wolfgang Deppert and Andrea Kristina Horst

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Oncotarget. 2016; 7:63730-63746. https://doi.org/10.18632/oncotarget.11650

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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

Correspondence to:

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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