19. Yes-associated protein (YAP), regulated by the salvador-warts-hippo (SWH) pathway, is an ovarian cancer oncogene

Abstract

Background The Salvador-Warts-Hippo (SWH) pathway was first discovered in Drosophila melanogaster as a potent inhibitor of tissue growth. It is highly conserved between species, both in the mechanism of signal transduction and function including inhibiting the nuclear access and expression of the transcriptional co-activator, Yes-associated protein (YAP). The pathway has been observed in several types of human cancers with YAP shown to be important in tumorigenesis and enhancing the transformed phenotype of ovarian cancer cells with conferred chemo-resistance in vitro . Methods We examined for YAP expression in 284 patients with ovarian tumours diagnosed between 1992 and 2006 identified through the Australian Ovarian Cancer Study (AOCS). Immuno-histochemical staining for YAP was performed on tissue micro-arrays constructed from formalin fixed, paraffin embedded (FFPE) tissue. The tumours were scored for cytoplasmic and nuclear staining. Kaplan–Meier curves were used to plot survival curves for samples in each group. Fisher’s exact test was used to test the association between YAP staining and grade, stage and residual disease. Results High nuclear expression of YAP was seen in 14% of all tumours and in a higher proportion of clear cell carcinomas (32%). High nuclear expression was associated with worse progression free survival ( p = 0.017) but not associated with tumour grade, stage or residual disease. Conclusion These results show that high nuclear expression of YAP may be biologically important in ovarian tumours from an early stage conferring a poorer prognosis, and involved in tumor-igenesis of clear cell carcinomas. YAP may be an important therapeutic target in these tumours with enhanced YAP activity.