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Cancer Res. 2016 Nov 1;76(21):6278-6289. Epub 2016 Aug 30.

Wnt Signaling Promotes Breast Cancer by Blocking ITCH-Mediated Degradation of YAP/TAZ Transcriptional Coactivator WBP2.

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Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore.
Department of Pathology, National University Hospital, Singapore.
Department of Pathology, Singapore General Hospital, Singapore.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Institute of Molecular and Cell Biology, Agency for Science Technology and Research, Singapore.
Mechanobiology Institute, National University of Singapore, Singapore.
Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
National University Cancer Institute, Singapore.
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.


Cross-talk between the Hippo and Wnt pathways has been implicated recently in breast cancer development, but key intersections have yet to be fully defined. Here we report that WBP2, a transcription coactivator that binds the Hippo pathway transcription factor YAP/TAZ, contributes to Wnt signaling and breast cancer pathogenesis. Clinically, overexpression of WBP2 in breast cancer specimens correlated with malignant progression and poor patient survival. In breast cancer cells, nuclear entry and interaction of WBP2 with β-catenin was stimulated by Wnt3A, thereby activating TCF-mediated transcription and driving malignant invasive character. Mechanistic investigations showed WBP2 levels were controlled by the E3 ligase ITCH, which bound and target WBP2 for ubiquitin-dependent proteasomal degradation. Accordingly, ITCH silencing could elevate WBP2 levels. Wnt signaling upregulated WBP2 by disrupting ITCH-WBP2 interactions via EGFR-mediated tyrosine phosphorylation of WBP2 and TAZ/YAP competitive binding. Conversely, ITCH-mediated downregulation of WBP2 inhibited TCF/β-catenin transcription, in vitro transformation, and in vivo tumorigenesis. We identified somatic mutations in ITCH, which impaired its ability to degrade WBP2 and to block its function in cancer, even while retaining binding capacity to WBP2. Thus, the Wnt pathway appeared to engage WBP2 primarily by affecting its protein stability. Our findings show how WBP2/ITCH signaling functions to link the intricate Wnt and Hippo signaling networks in breast cancer. Cancer Res; 76(21); 6278-89.

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