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.
Highlights
Malignancies of the breast, along with colon cancer, cause the most frequent cancer-associated deaths in women
Dichotomous roles have been assigned to carcinoembryonic-related antigen cell adhesion molecule 1 (CEACAM1) in tumor development and progression: on the one hand, its expression has been correlated to increased tumor invasion in melanoma, lung carcinoma, in carcinomas of the thyroid, liver and colon; in these specimens, CEACAM1 is up- regulated during progression of the disease and has been established as an independent prognostic marker
In early stages, CEACAM1-L is down-regulated in tumor cells of different organs including neoplastic lesions of the colon, stomach, bladder and prostate [59,60,61,62,63,64,65]
Summary
Malignancies of the breast, along with colon cancer, cause the most frequent cancer-associated deaths in women. Epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) are principal tissue plasticity programs in embryogenesis, wound healing, fibrosis, cancer progression and metastasis [2]. This epithelial-mesenchymal plasticity (EMP) is a critical determinant of tumor invasion, stemness and chemoresistance of breast cancer cells, and its pivotal importance for disease outcome has been highlighted by numerous reports [3,4,5,6,7,8,9]. We demonstrated that expression of mutant p53 in WAP-T tumors is mechanistically linked with EMP and enhanced metastasis [18, 19] This aggressive tumor phenotype was inversely correlated with the expression of carcinoembryonic-related antigen cell adhesion molecule 1 (CEACAM1)
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