title: The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene.
abstract: The Salvador-Warts-Hippo (SWH) pathway was first discovered in Drosophila melanogaster as a potent inhibitor of tissue growth. The SWH pathway is highly conserved between D. melanogaster and mammals, both in function and in the mechanism of signal transduction. The mammalian SWH pathway limits tissue growth by inhibiting the nuclear access and expression of the transcriptional co-activator, Yes-associated protein (YAP). Mutation and altered expression of SWH pathway proteins has been observed in several types of human cancer, but the contribution of these events to tumorigenesis has been unclear. Here we show that YAP can enhance the transformed phenotype of ovarian cancer cell lines and that YAP confers resistance to chemotherapeutic agents that are commonly used to treat ovarian cancer. We find that high nuclear YAP expression correlates with poor patient prognosis in a cohort of 268 invasive epithelial ovarian cancer samples. Segregation by histotype shows that the correlation between nuclear YAP and poor survival is predominantly associated with clear cell tumors, independent of stage. Collectively our findings suggest that YAP derepression contributes to the genesis of ovarian clear cell carcinoma and that the SWH pathway is an attractive therapeutic target.
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: George
authors.forename: S
authors.initials: S
authors.lastname: Deb
authors.forename: J L
authors.initials: JL
authors.lastname: Degoutin
authors.forename: E A
authors.initials: EA
authors.lastname: Takano
authors.forename: S B
authors.initials: SB
authors.lastname: Fox
authors.forename: D D L
authors.initials: DD
authors.lastname: Bowtell
authors.forename: K F
authors.initials: KF
authors.lastname: Harvey
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D005260:Female; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D017239:Paclitaxel; D002945:Cisplatin