Transcriptomics

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


ABSTRACT: Canonical Wnt signaling plays crucial roles in the progression of many cancer types. In canonical Wnt signaling, β-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-catenin’s different output is not known. Also not known is the functional contribution of β-catenin’s 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 β-catenin that abolish its function completely or specifically target the N or C-terminal transcriptional outputs. Notably, the complete lack of β-catenin resulted in apoptosis of mammary tumor cells in vivo and in vitro. In contrast, the loss of β-catenin’s 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 β-catenin’s 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE148843 | GEO | 2020/04/18

REPOSITORIES: GEO

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