PLX193864

GSE148843: -catenin is a node at orchestrating distinct aspects of epithelial-mesenchymal transition (EMT) and malignant mammary tumor progression

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

Canonical Wnt signaling plays crucial roles in the progression of many cancer types. In canonical Wnt signaling, -catenin acts as a controller determining the transcriptional output: via its N-terminus it recruits the signaling coactivators Bcl9 and Bcl9/9l and via the C-terminus it interacts with the general transcriptional machinery. In the intestine, the C terminal output is essential, while the N-terminus controls only a subset of target genes. In breast cancer, the relative contribution of b-catenins different output is not known. Also not known is the functional contribution of -catenins a role in cadherin-mediated cell adhesion, a function which confounds the analysis of conventional loss of function models. To address these unknowns, we combined the MMTV-PyMT mouse model of metastatic breast cancer with mouse lines carrying mutations in -catenin that abolish its function completely or specifically target the N or C-terminal transcriptional outputs. Notably, the complete lack of -catenin resulted in apoptosis of mammary tumor cells in vivo and in vitro. In contrast, the loss of -catenins transcriptional functions did not provoke apoptosis but did diminish cell proliferation, epithelial-mesenchymal transition (EMT) and cell migration in vitro. This was also reflected in a reduction in primary tumor growth, tumor invasion, and metastasis formation in vivo. Whole transcriptome analysis identified subsets of genes, which were specifically regulated either by -catenins N or C-terminal activities. Intriguingly, the N-terminal output was critical for TGFb-induced EMT and metastasis formation. The observations from the mouse models correlated with expression studies in human breast cancers. SOURCE: Ravi Kiran Reddy KALATHUR (ravikiran.k@gmail.com) - University of Basel