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

Nature Cell Biology volume 8, pages 1398–1406 (2006)Cite this article

Abstract

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.

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Figure 1: Wnt-mediated induction of β-catenin–TCF–dependent invasion.
Figure 2: Axin2-dependent induction of Snail1-mediated EMT.
Figure 3: Axin2-dependent regulation of GSK3β localization.
Figure 4: Regulation of Axin2 nucleo-cytoplasmic trafficking.
Figure 5: β-cateninS33Y-mediated EMT through the Axin2-dependent regulation of nuclear GSK3β and Snail1 levels.

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Acknowledgements

We thank S. I. Jee for technical assistance with mRNA in situ hybridization and immunohistochemical staining. This study was supported by grants from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A050550), the Basic Research Program of the Korea Science & Engineering Foundation (R01-2006-10203), the Korea Research Foundation (KRF-2005-005-J05903; J.I.Y.), and National Institutes of Health (NIH) grant 5 R01 CA71699 (S.J.W.).

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Authors and Affiliations

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

    Jong In Yook, Hyun Sil Kim, Nam Hee Kim, So Young Cha, Joo Kyung Ryu & Jin Kim

  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, 48109–2216, MI, USA

    Xiao-Yan Li, Ichiro Ota, Casey Hu & Stephen J. Weiss

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

    Yoon Jung Choi

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

    Eric R. Fearon

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Contributions

J.I.Y and X.-Y.L. were responsible for overall experimental work and design, I.O. and C.H. for CAM experiments, H.S.K., Y.J.C. and J.K for histochemistry of tissue samples, N.H.K., S.Y.C. and J.K.R. for DNA cloning, and E.R.F and S.J.W. for project planning and data analysis.

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Correspondence to Stephen J. Weiss.

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The authors declare no competing financial interests.

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Supplementary Figures S1, S2, S3 and S4 (PDF 836 kb)

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Yook, J., Li, XY., Ota, I. et al. A Wnt–Axin2–GSK3β cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol 8, 1398–1406 (2006). https://doi.org/10.1038/ncb1508

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