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Article

The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGFβ Signaling

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School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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Division of Experimental Oncology, IRCCS Istituto Scientfico San Raffaele, 20132, Milan, Italy
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School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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School of Veterinary Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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St John’s Institute of Dermatology, School of Basic and Medical Biosciences, King’s College London, London SE1 9RT, UK
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Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA
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Department of Pathobiology & Population Sciences, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire AL9 7TA, UK
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School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(8), 2047; https://doi.org/10.3390/cancers12082047
Received: 27 May 2020 / Revised: 7 July 2020 / Accepted: 13 July 2020 / Published: 24 July 2020
Downregulation of the cylindromatosis (CYLD) tumor suppressor has been associated with breast cancer development and progression. Here, we report a critical role for CYLD in maintaining the phenotype of mammary epithelial cells in vitro and in vivo. CYLD downregulation or inactivation induced an epithelial to mesenchymal transition of mammary epithelial cells that was dependent on the concomitant activation of the transcription factors Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and transforming growth factor beta (TGFβ)signaling. CYLD inactivation enhanced the nuclear localization of YAP/TAZ and the phosphorylation of Small Mothers Against Decapentaplegic (SMAD)2/3 proteins in confluent cell culture conditions. Consistent with these findings were the hyperplastic alterations of CYLD-deficient mouse mammary epithelia, which were associated with enhanced nuclear expression of the YAP/TAZ transcription factors. Furthermore, in human breast cancer samples, downregulation of CYLD expression correlates with enhanced YAP/TAZ-regulated target gene expression. Our results identify CYLD as a critical regulator of a signaling node that prevents the coordinated activation of YAP/TAZ and the TGFβ pathway in mammary epithelial cells, in order to maintain their phenotypic identity and homeostasis. Consequently, they provide a novel conceptual framework that supports and explains a causal implication of deficient CYLD expression in aggressive human breast cancers. View Full-Text
Keywords: breast cancer; EMT; TGFβ; YAP; TAZ; CYLD breast cancer; EMT; TGFβ; YAP; TAZ; CYLD
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MDPI and ACS Style

Pseftogas, A.; Xanthopoulos, K.; Poutahidis, T.; Ainali, C.; Dafou, D.; Panteris, E.; Kern, J.G.; Varelas, X.; Hardas, A.; Gonidas, C.; Tsingotjidou, A.; Hatzivassiliou, E.; Mosialos, G. The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGFβ Signaling. Cancers 2020, 12, 2047. https://doi.org/10.3390/cancers12082047

AMA Style

Pseftogas A, Xanthopoulos K, Poutahidis T, Ainali C, Dafou D, Panteris E, Kern JG, Varelas X, Hardas A, Gonidas C, Tsingotjidou A, Hatzivassiliou E, Mosialos G. The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGFβ Signaling. Cancers. 2020; 12(8):2047. https://doi.org/10.3390/cancers12082047

Chicago/Turabian Style

Pseftogas, Athanasios, Konstantinos Xanthopoulos, Theofilos Poutahidis, Chrysanthi Ainali, Dimitra Dafou, Emmanuel Panteris, Joseph G. Kern, Xaralabos Varelas, Alexander Hardas, Christos Gonidas, Anastasia Tsingotjidou, Eudoxia Hatzivassiliou, and George Mosialos. 2020. "The Tumor Suppressor CYLD Inhibits Mammary Epithelial to Mesenchymal Transition by the Coordinated Inhibition of YAP/TAZ and TGFβ Signaling" Cancers 12, no. 8: 2047. https://doi.org/10.3390/cancers12082047

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