title: CEACAM1 controls the EMT switch in murine mammary carcinoma in vitro and in vivo.
abstract: 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.
authors: Clinic for General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Georg-August-University of Göttingen, D-37077 Göttingen, Germany.|Institute for Tumor Biology, University Medical Center-Hamburg-Eppendorf, D-20251 Hamburg, Germany.
authors: Florian
authors: F
authors: Wegwitz
authors: Institute for Tumor Biology, University Medical Center-Hamburg-Eppendorf, D-20251 Hamburg, Germany.
authors: Eva
authors: E
authors: Lenfert
authors: Center for Diagnostics, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany.
authors: Daniela
authors: D
authors: Gerstel
authors: Institute for Tumor Biology, University Medical Center-Hamburg-Eppendorf, D-20251 Hamburg, Germany.
authors: Lena
authors: L
authors: von Ehrenstein
authors: Institute for Tumor Biology, University Medical Center-Hamburg-Eppendorf, D-20251 Hamburg, Germany.|Pharmaceutical Institute, Christian-Albrechts-University Kiel, D-24118 Kiel, Germany.
authors: Julia
authors: J
authors: Einhoff
authors: Clinic for General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Georg-August-University of Göttingen, D-37077 Göttingen, Germany.
authors: Geske
authors: G
authors: Schmidt
authors: Clinic for General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Georg-August-University of Göttingen, D-37077 Göttingen, Germany.
authors: Matthew
authors: M
authors: Logsdon
authors: Dermatology and Venerology Department and Clinic, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany.
authors: Johanna
authors: J
authors: Brandner
authors: Institute for Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany.
authors: Gisa
authors: G
authors: Tiegs
authors: Goodman Cancer Research Centre and Departments of Biochemistry, Medicine and Oncology, McGill University, Montreal, H3G1Y6, Canada.
authors: Nicole
authors: N
authors: Beauchemin
authors: Center for Diagnostics, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany.
authors: Christoph
authors: C
authors: Wagener
authors: Institute for Tumor Biology, University Medical Center-Hamburg-Eppendorf, D-20251 Hamburg, Germany.
authors: Wolfgang
authors: W
authors: Deppert
authors: Institute for Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany.
authors: Andrea Kristina
authors: AK
authors: Horst
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002272:Carcinoembryonic Antigen / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D066298:In Vitro Techniques; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010641:Phenotype; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C069847:CD66 antigens; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D015815:Cell Adhesion Molecules; D051176:beta Catenin; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: CEACAM1; EMT; WAP-T; Wnt-pathway; breast cancer