A Wnt–Axin2–GSK3β cascade regulates Snail1 activity in breast cancer cells.

Accumulating evidence indicates that hyperactive Wnt signalling occurs in association with the development and progression of human breast cancer. As a consequence of engaging the canonical Wnt pathway, a β-catenin–T-cell factor (TCF) transcriptional complex is generated, which has been postulated to trigger the epithelial–mesenchymal transition (EMT) that characterizes the tissue-invasive phenotype. However, the molecular mechanisms by which the β-catenin–TCF complex induces EMT-like programmes remain undefined. Here, we demonstrate that canonical Wnt signalling engages tumour cell dedifferentiation and tissue-invasive activity through an Axin2-dependent pathway that stabilizes the Snail1 zinc-transcription factor, a key regulator of normal and neoplastic EMT programmes. Axin2 regulates EMT by acting as a nucleocytoplasmic chaperone for GSK3β, the dominant kinase responsible for controlling Snail1 protein turnover and activity. As dysregulated Wnt signalling marks a diverse array of cancerous tissue types, the identification of a β-catenin–TCF-regulated Axin2–GSK3β–Snail1 axis provides new mechanistic insights into cancer-associated EMT programmes. [ABSTRACT FROM AUTHOR]

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