Letter abstract
Nature Cell Biology 8, 1398 - 1406 (2006)
Published online: 29 October 2006 | doi:10.1038/ncb1508
A Wnt–Axin2–GSK3
cascade regulates Snail1 activity in breast cancer cells
Jong In Yook1, Xiao-Yan Li2, Ichiro Ota2, Casey Hu2, Hyun Sil Kim1, Nam Hee Kim1, So Young Cha1, Joo Kyung Ryu1, Yoon Jung Choi3, Jin Kim1, Eric R. Fearon4 & Stephen J. Weiss2
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 
-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 -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 GSK3, 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 -catenin–TCF-regulated Axin2–GSK3–Snail1 axis provides new mechanistic insights into cancer-associated EMT programmes.
- Department of Oral Pathology, Oral Cancer Research Institute, College of Dentistry Yonsei University, Seoul 120–752, Korea.
- Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109–2216, USA.
- Department of Pathology, National Health Insurance Corporation Ilsan Hospital, Kyungki-do, 419–719, Korea.
- Department of Internal Medicine, Human Genetics, and Pathology, University of Michigan, Ann Arbor, MI 48109–2216, USA.
Correspondence to: Stephen J. Weiss2 e-mail: sjweiss@umich.edu
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