Giovanni Sorrentino 1 , Naomi Ruggeri 1 , Alessandro Zannini 1 , Eleonora Ingallina 1 , 2 , Rebecca Bertolio 1 , Carolina Marotta 1 , Carmelo Neri 1 , 2 , Elisa Cappuzzello 3 , Mattia Forcato 4 , Antonio Rosato 3 , 5 , Miguel Mano 6 , 7 , Silvio Bicciato 4 , Giannino Del Sal a , 1 , 2
19 January 2017
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.
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.