CEACAM1 controls the EMT switch in murine mammary carcinoma in vitro and in vivo
| Autor: | 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, Kristina Horst, Andrea |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Epithelial-Mesenchymal Transition
Breast Neoplasms Protein Tyrosine Phosphatase Non-Receptor Type 11 In Vitro Techniques Mice breast cancer Antigens CD Cell Line Tumor Biomarkers Tumor CEACAM1 Wnt-pathway EMT WAP-T Animals Humans Neoplasm Invasiveness Neoplasm Metastasis Phosphorylation beta Catenin Carcinoma Mammary Neoplasms Experimental Carcinoembryonic Antigen Up-Regulation Gene Expression Regulation Neoplastic Phenotype Female Cell Adhesion Molecules Research Paper Signal Transduction |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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. Open-Access-Publikationsfonds 2016 peerReviewed |
| Databáze: | OpenAIRE |
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