The transcriptional regulators TAZ and YAP direct transforming growth factor ß-induced tumorigenic phenotypes in breast cancer cells.

Uncontrolled transforming growth factor-ß (TGFß) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGFß-mediated cues are directed to induce tumorigenic events is poorly understood, particularly given that TGFß has clear tumor suppressing activity in other contexts. Here, we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGFß-induced tumorigenic phenotypes in breast cancer cells. Interactions between TAZ/YAP, TGFß-activated SMAD2/3, and TEAD transcription factors reveal convergent roles for these factors in the nucleus. Genome-wide expression analyses indicate that TAZ/YAP, TEADs, and TGFß-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by TAZ/YAP, TEAD, and TGFß, such as the novel targets NEGR1 and UCA1, are necessary for maintaining tumorigenic activity in metastatic breast cancer cells. Nuclear TAZ/YAP also cooperate with TGFß signaling to promote phenotypic and transcriptional changes in nontumorigenic cells to overcome TGFß-repressive effects. Our work thus identifies cross-talk between nuclear TAZ/YAP and TGFß signaling in breast cancer cells, revealing novel insight into late-stage disease-driving mechanisms.