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      Wnt signalling is a bi-directional vulnerability of cancer cells

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          Abstract

          Wnt signalling is involved in the formation, metastasis and relapse of a wide array of cancers. However, there is ongoing debate as to whether activation or inhibition of the pathway holds the most promise as a therapeutic treatment for cancer, with conflicting evidence from a variety of tumour types. We show that Wnt/β-catenin signalling is a bi-directional vulnerability of neuroblastoma, malignant melanoma and colorectal cancer, with hyper-activation or repression of the pathway both representing a promising therapeutic strategy, even within the same cancer type. Hyper-activation directs cancer cells to undergo apoptosis, even in cells oncogenically driven by β-catenin. Wnt inhibition blocks proliferation of cancer cells and promotes neuroblastoma differentiation. Wnt and retinoic acid co-treatments synergise, representing a promising combination treatment for MYCN-amplified neuroblastoma. Additionally, we report novel cross-talks between MYCN and β-catenin signalling, which repress normal β-catenin mediated transcriptional regulation. A β-catenin target gene signature could predict patient outcome, as could the expression level of its DNA binding partners, the TCF/LEFs. This β-catenin signature provides a tool to identify neuroblastoma patients likely to benefit from Wnt-directed therapy. Taken together, we show that Wnt/β-catenin signalling is a bi-directional vulnerability of a number of cancer entities, and potentially a more broadly conserved feature of malignant cells.

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

          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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            Molecular genetics of colorectal cancer.

            Over the past three decades, molecular genetic studies have revealed some critical mutations underlying the pathogenesis of the sporadic and inherited forms of colorectal cancer (CRC). A relatively limited number of oncogenes and tumor-suppressor genes-most prominently the APC, KRAS, and p53 genes-are mutated in a sizeable fraction of CRCs, and a larger collection of genes that are mutated in subsets of CRC have begun to be defined. Together with DNA-methylation and chromatin-structure changes, the mutations act to dysregulate conserved signaling networks that exert context-dependent effects on critical cell phenotypes, including the regulation of cellular metabolism, proliferation, differentiation, and survival. Much work remains to be done to fully understand the nature and significance of the individual and collective genetic and epigenetic defects in CRC. Some key concepts for the field have emerged, two of which are emphasized in this review. Specifically, the gene defects in CRC often target proteins and pathways that exert pleiotropic effects on the cancer cell phenotype, and particular genetic and epigenetic alterations are linked to biologically and clinically distinct subsets of CRC.
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              Wnt signaling and cancer.

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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                13 September 2016
                11 August 2016
                : 7
                : 37
                : 60310-60331
                Affiliations
                1 Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland
                2 Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
                3 School of Medicine, University College Dublin, Belfield, Dublin, Ireland
                4 Division of NB Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
                5 Department of Paediatric Haematology and Oncology and Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Cologne, Germany
                6 VTT Technical Research Centre of Finland, Espoo, Finland
                7 Current address: The Whitney Laboratory for Marine Bioscience, University of Florida, St. Augustine, Florida, USA
                8 Current address: European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
                Author notes
                Correspondence to: David J. Duffy, david.duffy@ 123456ucd.ie
                Article
                11203
                10.18632/oncotarget.11203
                5312386
                27531891
                2db07576-973f-4b96-844d-baf12a7d16e3
                Copyright: © 2016 Duffy et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 November 2015
                : 26 July 2016
                Categories
                Research Paper

                Oncology & Radiotherapy
                neuroblastoma,melanoma,colorectal cancer,myc (c-myc),mrna sequencing (mrna-seq)

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