Wnt signaling in triple-negative breast cancer

Author(s): SÖ-G Pohl ¹ ^, ² ^, ³ , N Brook ¹ ^, ² ^, ³ , M Agostino ¹ ^, ² ^, ³ ^, ⁴ , F Arfuso ¹ ^, ² ^, ³ , A P Kumar ² ^, ³ ^, ⁵ ^, ⁶ ^, ⁷ ^, ^* , A Dharmarajan ¹ ^, ² ^, ³ ^, ^*

Publication date (Electronic): 03 April 2017

Journal: Oncogenesis

Publisher: Nature Publishing Group

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Abstract

Wnt signaling regulates a variety of cellular processes, including cell fate, differentiation, proliferation and stem cell pluripotency. Aberrant Wnt signaling is a hallmark of many cancers. An aggressive subtype of breast cancer, known as triple-negative breast cancer (TNBC), demonstrates dysregulation in canonical and non-canonical Wnt signaling. In this review, we summarize regulators of canonical and non-canonical Wnt signaling, as well as Wnt signaling dysfunction that mediates the progression of TNBC. We review the complex molecular nature of TNBC and the emerging therapies that are currently under investigation for the treatment of this disease.

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Most cited references 101

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Identification of c-MYC as a target of the APC pathway.

T C He, A B Sparks, C Rago … (1998)

The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that is inactivated in most colorectal cancers. Mutations of APC cause aberrant accumulation of beta-catenin, which then binds T cell factor-4 (Tcf-4), causing increased transcriptional activation of unknown genes. Here, the c-MYC oncogene is identified as a target gene in this signaling pathway. Expression of c-MYC was shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c-MYC promoter. These results provide a molecular framework for understanding the previously enigmatic overexpression of c-MYC in colorectal cancers.

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Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.

Shih-Min A Huang, Yuji M. Mishina, Shanming Liu … (2009)

The stability of the Wnt pathway transcription factor beta-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits beta-catenin-mediated transcription. XAV939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.

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YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response.

Luca Azzolin, Tito Panciera, Sandra Soligo … (2014)

The Hippo transducers YAP/TAZ have been shown to play positive, as well as negative, roles in Wnt signaling, but the underlying mechanisms remain unclear. Here, we provide biochemical, functional, and genetic evidence that YAP and TAZ are integral components of the β-catenin destruction complex that serves as cytoplasmic sink for YAP/TAZ. In Wnt-ON cells, YAP/TAZ are physically dislodged from the destruction complex, allowing their nuclear accumulation and activation of Wnt/YAP/TAZ-dependent biological effects. YAP/TAZ are required for intestinal crypt overgrowth induced by APC deficiency and for crypt regeneration ex vivo. In Wnt-OFF cells, YAP/TAZ are essential for β-TrCP recruitment to the complex and β-catenin inactivation. In Wnt-ON cells, release of YAP/TAZ from the complex is instrumental for Wnt/β-catenin signaling. In line, the β-catenin-dependent maintenance of ES cells in an undifferentiated state is sustained by loss of YAP/TAZ. This work reveals an unprecedented signaling framework relevant for organ size control, regeneration, and tumor suppression. Copyright © 2014 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Oncogenesis

Journal ID (iso-abbrev): Oncogenesis

Title: Oncogenesis

Publisher: Nature Publishing Group

ISSN (Electronic): 2157-9024

Publication date (Print): April 2017

Publication date (Electronic): 03 April 2017

Publication date PMC-release: 1 April 2017

Volume: 6

Issue: 4

Page: e310

Affiliations

[1 ]Stem Cell and Cancer Biology Laboratory , Perth, WA, Australia

[2 ]School of Biomedical Sciences, Curtin University , Perth, WA, Australia

[3 ]Curtin Health Innovation Research Institute, Curtin University , Perth, WA, Australia

[4 ]Curtin Institute for Computation, Curtin University , Perth, WA, Australia

[5 ]Cancer Science Institute of Singapore, National University of Singapore , Singapore, Singapore

[6 ]Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Centre for Translational Medicine , Singapore, Singapore

[7 ]Department of Biological Sciences, University of North Texas , Denton, TX, USA

Author notes

[* ]Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Centre for Translational Medicine , 14 Medical Drive, #11-01M, Singapore 117599, Singapore. E-mail: csiapk@ 123456nus.edu.sg

[* ]School of Biomedical Sciences, Curtin University , Kent Street, Bentley, Perth, WA 6102, Australia. E-mail: a.dharmarajan@ 123456curtin.edu.au

Article

Publisher Item ID: oncsis201714

DOI: 10.1038/oncsis.2017.14

PMC ID: 5520491

PubMed ID: 28368389

SO-VID: 392282d6-062d-483e-8760-68f63a3bf9a2

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Oncogenesis is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Wnt signaling in triple-negative breast cancer

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Karger: Oncology

Most cited references 101

Identification of c-MYC as a target of the APC pathway.

Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.

YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response.

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