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      Glucocorticoid receptor signalling activates YAP in breast cancer

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          Abstract

          The Hippo pathway is an oncosuppressor signalling cascade that plays a major role in the control of cell growth, tissue homoeostasis and organ size. Dysregulation of the Hippo pathway leads to aberrant activation of the transcription co-activator YAP (Yes-associated protein) that contributes to tumorigenesis in several tissues. Here we identify glucocorticoids (GCs) as hormonal activators of YAP. Stimulation of glucocorticoid receptor (GR) leads to increase of YAP protein levels, nuclear accumulation and transcriptional activity in vitro and in vivo. Mechanistically, we find that GCs increase expression and deposition of fibronectin leading to the focal adhesion-Src pathway stimulation, cytoskeleton-dependent YAP activation and expansion of chemoresistant cancer stem cells. GR activation correlates with YAP activity in human breast cancer and predicts bad prognosis in the basal-like subtype. Our results unveil a novel mechanism of YAP activation in cancer and open the possibility to target GR to prevent cancer stem cells self-renewal and chemoresistance.

          Abstract

          Activation of YAP contributes to tumorigenesis in several tissues. Here, the authors show that in breast cancer cells glucocorticoids induce expression of fibronectin that in turn activates focal adhesion kinase/Src signalling to promote YAP nuclear translocation and transcriptional activity.

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          Most cited references27

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          Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling.

          The Hippo pathway is crucial in organ size control, and its dysregulation contributes to tumorigenesis. However, upstream signals that regulate the mammalian Hippo pathway have remained elusive. Here, we report that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) signaling. Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription coactivators, which are oncoproteins repressed by Lats1/2. YAP and TAZ are involved in LPA-induced gene expression, cell migration, and proliferation. In contrast, stimulation of Gs-coupled receptors by glucagon or epinephrine activates Lats1/2 kinase activity, thereby inhibiting YAP function. Thus, GPCR signaling can either activate or inhibit the Hippo-YAP pathway depending on the coupled G protein. Our study identifies extracellular diffusible signals that modulate the Hippo pathway and also establishes the Hippo-YAP pathway as a critical signaling branch downstream of GPCR. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP.

            The Drosophila TEAD ortholog Scalloped is required for Yki-mediated overgrowth but is largely dispensable for normal tissue growth, suggesting that its mammalian counterpart may be exploited for selective inhibition of oncogenic growth driven by YAP hyperactivation. Here we test this hypothesis genetically and pharmacologically. We show that a dominant-negative TEAD molecule does not perturb normal liver growth but potently suppresses hepatomegaly/tumorigenesis resulting from YAP overexpression or Neurofibromin 2 (NF2)/Merlin inactivation. We further identify verteporfin as a small molecule that inhibits TEAD-YAP association and YAP-induced liver overgrowth. These findings provide proof of principle that inhibiting TEAD-YAP interactions is a pharmacologically viable strategy against the YAP oncoprotein.
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              Focal adhesion regulation of cell behavior.

              Focal adhesions lie at the convergence of integrin adhesion, signaling and the actin cytoskeleton. Cells modify focal adhesions in response to changes in the molecular composition, two-dimensional (2D) vs. three-dimensional (3D) structure, and physical forces present in their extracellular matrix environment. We consider here how cells use focal adhesions to regulate signaling complexes and integrin function. Furthermore, we examine how this regulation controls complex cellular behaviors in response to matrices of diverse physical and biochemical properties. One event regulated by the physical structure of the ECM is phosphorylation of focal adhesion kinase (FAK) at Y397, which couples FAK to several signaling pathways that regulate cell proliferation, survival, migration, and invasion.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                19 January 2017
                2017
                : 8
                : 14073
                Affiliations
                [1 ]Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano , Trieste 34149, Italy
                [2 ]Dipartimento di Scienze della Vita, Università degli Studi di Trieste , Trieste 34127, Italy
                [3 ]Department of Surgery, Oncology and Gastroenterology, University of Padova , Padova 35124, Italy
                [4 ]Department of Life Sciences, University of Modena and Reggio Emilia , Modena 41125, Italy
                [5 ]Veneto Institute of Oncology IOV-IRCCS , Padova 35128, Italy
                [6 ]Center for Neuroscience and Cell Biology (CNC), University of Coimbra , Coimbra 3060-197, Portugal
                [7 ]International Centre for Genetic Engineering and Biotechnology (ICGEB) , Trieste 34149, Italy
                Author notes
                [*]

                These authors contributed equally to this work

                Author information
                http://orcid.org/0000-0002-7383-6576
                http://orcid.org/0000-0003-1922-4824
                http://orcid.org/0000-0002-1944-7078
                Article
                ncomms14073
                10.1038/ncomms14073
                5253666
                28102225
                fb1863ae-8060-423b-ace6-1c6166e70f62
                Copyright © 2017, The Author(s)

                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/

                History
                : 02 August 2016
                : 24 November 2016
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