Glucocorticoid receptor signaling activates TEAD4 to promote breast cancer progression.

Hippo pathway plays a critical role in cell growth and tumorigenesis. The activity of TEA domain transcription factor 4 (TEAD4) determines the output of Hippo signaling, however, the regulation and function of TEAD4 has not been explored extensively. Here, we identified glucocorticoids (GCs) as novel activators of TEAD4. GC treatment facilitated glucocorticoid receptor (GR)-dependent nuclear accumulation and transcriptional activation of TEAD4. TEAD4 positively correlated with GR expression in human breast cancer, and high expression of TEAD4 predicted poor survival of breast cancer patients. Mechanistically, GC activation promoted GR interaction with TEAD4, forming a complex that was recruited to the TEAD4 promoter to boost its own expression. Functionally, the activation of TEAD4 by GC promoted breast cancer stem cells maintenance, cell survival, metastasis and chemo-resistance both in vitro and in vivo. Pharmacological inhibition of TEAD4 inhibited GC-induced breast cancer chemo-resistance. In conclusion, our study reveals a novel regulation and functional role of TEAD4 in breast cancer and proposes a potential new strategy for breast cancer therapy.