| First Author | Wegwitz F | Year | 2016 |
| Journal | Oncotarget | Volume | 7 |
| Issue | 39 | Pages | 63730-63746 |
| PubMed ID | 27572314 | Mgi Jnum | J:309342 |
| Mgi Id | MGI:6757446 | Doi | 10.18632/oncotarget.11650 |
| Citation | Wegwitz F, et al. (2016) CEACAM1 controls the EMT switch in murine mammary carcinoma in vitro and in vivo. Oncotarget 7(39):63730-63746 |
| abstractText | 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. |
