The Hippo signaling pathway, a conserved regulator of organ size, has emerged as an important regulatory pathway in
cancer. The final transducer effectors of this pathway in mammals are the
oncoproteins TAZ and YAP1, which are transcriptional coactivators of target genes involved in cell proliferation and survival. TAZ has been previously reported to play a role in
tumorigenesis in
breast cancer, but detailed analyses of the different
breast cancer phenotypes have not been conducted thus far. We analyzed TAZ expression by immunohistochemistry in a retrospective series of 640 invasive
breast carcinomas, comprising
estrogen/
progesterone receptor-positive (ER+/PR+), HER2-positive, and triple-negative (TN)
tumors. We found a strong association of TAZ nuclear expression with the TN phenotype (60.5% TAZ-positive, P<0.001), which was strengthened when stratified into the basal-like subtype (70.8% TAZ-positive, P<0.001). Moreover, 90% of metaplastic
breast carcinomas with morphological epithelial-mesenchymal transition features were TAZ-positive. We also investigated whether amplification or differential DNA methylation of the TAZ-encoding locus could account for the observed enhanced TAZ
protein expression in the TN/basal phenotype. Amplification of the TAZ locus was analyzed by fluorescence in situ hybridization in 30 TN
tumors, and we found gene amplification in some cases (6.45%). DNA methylation analysis was performed using the Sequenom MassArray MALDI-TOF platform, and we observed similar low methylation levels both in TN (n=25) and ER+/PR+ (n=26)
tumors. These results were further confirmed using a panel of
breast cancer cell lines and using the TCGA dataset. Finally, patients with strong TAZ expression showed poorer clinical outcomes with respect to both recurrence and overall survival.