24559095
BACKGROUND	Yes-associated protein ( YAP1 ) is frequently reported to function as an oncogene in many types of cancer , but in breast cancer results remain controversial .
BACKGROUND	We set out to clarify the role of YAP1 in breast cancer by examining gene and protein expression in subgroups of patient material and by downregulating YAP1 in vitro and studying its role in response to the widely used anti-estrogen tamoxifen .
METHODS	YAP1 protein intensity was scored as absent , weak , intermediate or strong in two primary breast cancer cohorts ( n = 144 and n = 564 ) and mRNA expression of YAP1 was evaluated in a gene expression dataset ( n = 1107 ) .
METHODS	Recurrence-free survival was analysed using the log-rank test and Cox multivariate analysis was used to test for independence .
METHODS	WST-1 assay was employed to measure cell viability and a luciferase ERE ( estrogen responsive element ) construct was used to study the effect of tamoxifen , following downregulation of YAP1 using siRNAs .
RESULTS	In the ER + ( Estrogen Receptor positive ) subgroup of the randomised cohort , YAP1 expression was inversely correlated to histological grade and proliferation ( p = 0.001 and p = 0.016 , respectively ) whereas in the ER - ( Estrogen Receptor negative ) subgroup YAP1 expression correlated positively to proliferation ( p = 0.005 ) .
RESULTS	Notably , low YAP1 mRNA was independently associated with decreased recurrence-free survival in the gene expression dataset , specifically for the luminal A subgroup ( p < 0.001 ) which includes low proliferating tumours of lower grade , usually associated with a good prognosis .
RESULTS	This subgroup specificity led us to hypothesize that YAP1 may be important for response to endocrine therapies , such as tamoxifen , extensively used for luminal A breast cancers .
RESULTS	In a tamoxifen randomised patient material , absent YAP1 protein expression was associated with impaired tamoxifen response which was significant upon interaction analysis ( p = 0.042 ) .
RESULTS	YAP1 downregulation resulted in increased progesterone receptor ( PgR ) expression and a delayed and weaker tamoxifen in support of the clinical data .
CONCLUSIONS	Decreased YAP1 expression is an independent prognostic factor for recurrence in the less aggressive luminal A breast cancer subgroup , likely due to the decreased tamoxifen sensitivity conferred by YAP1 downregulation .

