CEACAM1 controls the EMT switch in murine mammary carcinoma in vitro and in vivo
2016 | journal article. A publication with affiliation to the University of Göttingen.
Jump to: Cite & Linked | Documents & Media | Details | Version history
Cite this publication
CEACAM1 controls the EMT switch in murine mammary carcinoma in vitro and in vivo
Wegwitz, F.; Lenfert, E.; Gerstel, D.; von Ehrenstein, L.; Einhoff, J.; Schmidt, G. & Logsdon, M. et al. (2016)
Oncotarget, 7(39) pp. 63730-63746. DOI: https://doi.org/10.18632/oncotarget.11650
Documents & Media
Details
- Authors
- 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 R.; Horst, Andrea Kristina
- 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, beta-catenin phosphorylation status and transcriptional activity strongly depend on CEACAM1 expression: CEACAM1high G-2 cells displayed enhanced phosphorylation of beta-catenin at S33/S37/T41 and decreased phosphorylation at Y86, thereby inhibiting canonical Wnt/beta-catenin signaling. We identified Src-homology 2 domain-containing phosphatase 2 (SHP-2) as a critical binding partner of CEACAM1 that could modulate beta-catenin Y86 phosphorylation. Hence, CEACAM1 serves as a scaffold that controls membrane proximal beta-catenin signaling. In vivo, mammary tumors of WAP-T/ CEACAM1null mice displayed increased nuclear translocation of beta-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 beta-catenin phosphorylation. Survival analyses of human mammary carcinoma patients corroborated these data, indicating that CEACAM1 is a prognostic marker for breast cancer survival.
- Issue Date
- 2016
- Status
- published
- Publisher
- Impact Journals Llc
- Journal
- Oncotarget
- ISSN
- 1949-2553
- Sponsor
- Open-Access-Publikationsfonds 2016