| First Author | Buechel D | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 34 | PubMed ID | 34408016 |
| Mgi Jnum | J:309225 | Mgi Id | MGI:6757017 |
| Doi | 10.1073/pnas.2020227118 | Citation | Buechel D, et al. (2021) Parsing beta-catenin's cell adhesion and Wnt signaling functions in malignant mammary tumor progression. Proc Natl Acad Sci U S A 118(34):e2020227118 |
| abstractText | During malignant progression, epithelial cancer cells dissolve their cell-cell adhesion and gain invasive features. By virtue of its dual function, beta-catenin contributes to cadherin-mediated cell-cell adhesion, and it determines the transcriptional output of Wnt signaling: via its N terminus, it recruits the signaling coactivators Bcl9 and Pygopus, and via the C terminus, it interacts with the general transcriptional machinery. This duality confounds the simple loss-of-function analysis of Wnt signaling in cancer progression. In many cancer types including breast cancer, the functional contribution of beta-catenin's transcriptional activities, as compared to its adhesion functions, to tumor progression has remained elusive. Employing the mouse mammary tumor virus (MMTV)-PyMT mouse model of metastatic breast cancer, we compared the complete elimination of beta-catenin with the specific ablation of its signaling outputs in mammary tumor cells. Notably, the complete lack of beta-catenin resulted in massive apoptosis of mammary tumor cells. In contrast, the loss of beta-catenin's transcriptional activity resulted in a reduction of primary tumor growth, tumor invasion, and metastasis formation in vivo. These phenotypic changes were reflected by stalled cell cycle progression and diminished epithelial-mesenchymal transition (EMT) and cell migration of breast cancer cells in vitro. Transcriptome analysis revealed subsets of genes which were specifically regulated by beta-catenin's transcriptional activities upon stimulation with Wnt3a or during TGF-beta-induced EMT. Our results uncouple the signaling from the adhesion function of beta-catenin and underline the importance of Wnt/beta-catenin-dependent transcription in malignant tumor progression of breast cancer. |
