Glucocorticoid Receptor Signaling Activates TEAD4 to Promote Breast Cancer Progression

• Published in: Cancer research (Chicago, Ill.) Ill.), 2019-09, Vol.79 (17), p.4399-4411
• Main Authors: He, Lingli, Yuan, Liang, Sun, Yang, Wang, Pingyang, Zhang, Hailin, Feng, Xue, Wang, Zuoyun, Zhang, Wenxiang, Yang, Chuanyu, Zeng, Yi Arial, Zhao, Yun, Chen, Ceshi, Zhang, Lei
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Nucleus - metabolism; Dexamethasone - pharmacology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drug Resistance, Neoplasm - drug effects; Female; Glucocorticoids - metabolism; Glucocorticoids - pharmacology; Humans; Mice, Nude; Muscle Proteins - genetics; Muscle Proteins - metabolism; Niflumic Acid - pharmacology; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Signal Transduction; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-19-0012

The 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 (GC) 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 patients with breast cancer. 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 chemoresistance both and . Pharmacologic inhibition of TEAD4 inhibited GC-induced breast cancer chemoresistance. 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. SIGNIFICANCE: This study provides new insight into the role of glucocorticoid signaling in breast cancer, with potential for clinical translation.