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

¹  Department of Oral Pathology, Oral Cancer Research Institute, College of Dentistry Yonsei University, Seoul 120–752, Korea.

²  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.

³  Department of Pathology, National Health Insurance Corporation Ilsan Hospital, Kyungki-do, 419–719, Korea.

⁴  Department of Internal Medicine, Human Genetics, and Pathology, University of Michigan, Ann Arbor, MI 48109–2216, USA.

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.

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