Glucocorticoid receptor signalling activates YAP in breast cancer

Giovanni Sorrentino, Naomi Ruggeri, Alessandro Zannini, Eleonora Ingallina, Rebecca Bertolio, Carolina Marotta, Carmelo Neri, Elisa Cappuzzello, Mattia Forcato, Antonio Rosato, Miguel Mano, Silvio Bicciato and Giannino Del Sal ()
Additional contact information
Giovanni Sorrentino: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano
Naomi Ruggeri: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano
Alessandro Zannini: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano
Eleonora Ingallina: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano
Rebecca Bertolio: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano
Carolina Marotta: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano
Carmelo Neri: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano
Elisa Cappuzzello: Oncology and Gastroenterology, University of Padova
Mattia Forcato: University of Modena and Reggio Emilia
Antonio Rosato: Oncology and Gastroenterology, University of Padova
Miguel Mano: Center for Neuroscience and Cell Biology (CNC), University of Coimbra
Silvio Bicciato: University of Modena and Reggio Emilia
Giannino Del Sal: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14073

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