title: Glucocorticoid receptor signalling activates YAP in breast cancer.
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.
authors.affiliation: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano, Trieste 34149, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sorrentino
authors.affiliation: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano, Trieste 34149, Italy.
authors.forename: Naomi
authors.initials: N
authors.lastname: Ruggeri
authors.affiliation: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano, Trieste 34149, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zannini
authors.affiliation: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano, Trieste 34149, Italy.|Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Trieste 34127, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Ingallina
authors.affiliation: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano, Trieste 34149, Italy.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bertolio
authors.affiliation: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano, Trieste 34149, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Marotta
authors.affiliation: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano, Trieste 34149, Italy.|Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Trieste 34127, Italy.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Neri
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova 35124, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Cappuzzello
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena 41125, Italy.
authors.forename: Mattia
authors.identifier: 0000-0002-7383-6576
authors.initials: M
authors.lastname: Forcato
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova 35124, Italy.|Veneto Institute of Oncology IOV-IRCCS, Padova 35128, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
authors.affiliation: Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra 3060-197, Portugal.|International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste 34149, Italy.
authors.forename: Miguel
authors.identifier: 0000-0003-1922-4824
authors.initials: M
authors.lastname: Mano
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena 41125, Italy.
authors.forename: Silvio
authors.identifier: 0000-0002-1944-7078
authors.initials: S
authors.lastname: Bicciato
authors.affiliation: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano, Trieste 34149, Italy.|Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Trieste 34127, Italy.
authors.forename: Giannino
authors.initials: G
authors.lastname: Del Sal
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D005938:Glucocorticoids; D010750:Phosphoproteins; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human