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A WntAxin2GSK3 cascade regulates Snail1 activity in breast cancer cells
Jong In Yook1, Xiao-Yan Li2, Ichiro Ota 2, Casey Hu2, Hyun Sil Kim1, Nam Hee Kim1, So Young Cha1, Joo Kyung Ryu1, Yoon Jung Choi3, Jin Kim1, Eric R. Fearon4 and Stephen J. Weiss2, 5
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 -cateninT-cell factor (TCF) transcriptional complex is generated, which has been postulated to trigger the epithelialmesenchymal 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 theSnail1 zinc-transcription factor, a key regulator of normal and neoplastic EMT programmes. Axin2 regulates EMT by actingas 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 -cateninTCF-regulated Axin2GSK3Snail1 axis provides new mechanistic insights into cancer-associated EMT programmes.
Within the mammary gland, the canonical Wnt signalling pathway has a dominant role in regulating epithelialmesenchymal cell interactions critical for morphogenesis13. In this signalling system, Wnt ligands bind to a coreceptor complex consisting of a seven-transmembrane-domain,Frizzled receptor and one of the LDL receptor-related proteins (LRPs),LRP5 or LRP6 (ref. 3). A signalling cascade is then engaged that leads to the formation of a bipartite complex between the adhesion molecule, -catenin, and transcription factors of the TCF family3. In turn, the -cateninTCF complex activates expression of a cohort of target genes that impact on cellular function3. Although the -cateninTCF complex has an important role in regulating normal cell function, increasing evidence indicates that canonical Wnt signalling can be disrupted in various cancerous states, including breast cancer39. As hyperactive Wnt
1398 NATURE CELL BIOLOGY VOLUME 8 | NUMBER 12 | DECEMBER 2006
2006
signalling can trigger EMT-like programmes311, the constitutive activation of the canonical Wnt pathway in human breast cancer may highlight a key role for aberrant activation of the -cateninTCF cascade and tumour progression. Here, we demonstrate that -cateninTCF-dependent signalling activates an EMT programme in human...