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Wnt/β-catenin signalling in prostate cancer

Abstract

The Wnts are secreted cysteine-rich glycoproteins that have important roles in the developing embryo as well as in tissue homeostasis in adults. Dysregulation of Wnt signalling can lead to several types of cancer, including prostate cancer. A hallmark of the signalling pathway is the stabilization of the transcriptional co-activator β-catenin, which not only regulates expression of many genes implicated in cancer but is also an essential component of cadherin cell adhesion complexes. β-catenin regulates gene expression by binding members of the T-cell-specific transcription factor/lymphoid enhancer-binding factor 1 (TCF/LEF-1) family of transcription factors. In addition, β-catenin associates with the androgen receptor, a key regulator of prostate growth that drives prostate cancer progression. Wnt/β-catenin signalling can be controlled by secreted Wnt antagonists, many of which are downregulated in cancer. Activation of the Wnt/β-catenin pathway has effects on prostate cell proliferation, differentiation and the epithelial–mesenchymal transition, which is thought to regulate the invasive behaviour of tumour cells. However, whether targeting Wnt/β-catenin signalling is a good therapeutic option for prostate cancer remains unclear.

Key Points

  • A hallmark of the Wnt signalling pathway is the stabilization of β-catenin, a transcription factor that regulates many genes implicated in cancer

  • Aberrant expression and localization of β-catenin in prostate cancer is more common than predicted by Wnt pathway mutations

  • Expression of Wnt and secreted Wnt antagonists is frequently altered in prostate cancer, the outcome of which is often inconsistent with the predicted effects of these proteins on β-catenin stability

  • Wnt/β-catenin and androgen receptor signals affect one another in several ways, and this crosstalk is likely to change during disease progression

  • Small-molecule inhibitors of Wnt/β-catenin signalling are anticipated to have therapeutic benefits, particularly for tumours driven by prostate cancer stem or progenitor cells

  • Several mouse models show promise for future studies of the role of Wnt/β-catenin signalling in prostate cancer and for preclinical tests of Wnt inhibitors

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Figure 1: Simplified view of Wnt signalling.
Figure 2: Crosstalk between β-catenin and androgen-receptor signalling.
Figure 3: The role of noncanonical Wnt proteins.

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Acknowledgements

We thank Maria Vivanco (Center for Cooperative Research in Biosciences, CIC bioGUNE) for critical reading of the manuscript, and acknowledge support from the Spanish Ministry of Education and Science (grant SAF2011-30494), The Garfield Weston Foundation, The Dinwoodie Settlement and the Departments of Industry, Tourism and Trade (Etortek) and Innovation Technology of the Government of the Autonomous Community of the Basque Country.

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R. M. Kypta researched the data for and wrote the article. R. M. Kypta and J. Waxman edited the manuscript before submission.

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Correspondence to Robert M. Kypta.

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Supplementary Table 1

Mouse models to study Wnt/β-catenin signaling in prostate cancer (DOC 119 kb)

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Kypta, R., Waxman, J. Wnt/β-catenin signalling in prostate cancer. Nat Rev Urol 9, 418–428 (2012). https://doi.org/10.1038/nrurol.2012.116

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