Glucocorticoid Receptor Signaling Activates TEAD4 to Promote Breast Cancer Progression.

Lingli He,Pingyang Wang,Yang Sun,Liang Yuan,Lei Zhang,Xue Feng,Hailin Zhang,Wenxiang Zhang,Yi Arial Zeng,Ceshi Chen,Yun Zhao,Chuanyu Yang,Zuoyun Wang

doi:10.1158/0008-5472.can-19-0012

Abstract

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 in vitro and in vivo. 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.

Highlights

The Hippo signaling pathway, originally discovered in Drosophila melanogaster and highly conserved in mammals, plays key roles in cell proliferation, cell fate determination, organ size control, and tumor suppression [1,2,3]
To confirm the upregulation of TEAD4 was triggered by GCs but dexamethasone, 1 mg/mL hydrocortisone was used in MDA-MB-231 cells
Regardless the change in Yes associated-protein (YAP)/TAZ expression, TEAD4 was activated in BT-549 and MDA-MB-453 cells (Fig. 1C), implying that the GC-related regulation of TEAD4 is a general phenomenon in breast cancer cells

Summary

Introduction

The Hippo signaling pathway, originally discovered in Drosophila melanogaster and highly conserved in mammals, plays key roles in cell proliferation, cell fate determination, organ size control, and tumor suppression [1,2,3]. Activated TEADs stimulates the expression of genes involved in cell proliferation and metastasis (CYR61, CTGF, BIRC5, ANKRD1, vimentin, and N-cadherin) and promote tumorigenesis and progression [2, 6]. Regulators, such as energy/osmotic stress [7, 8], cell contact/mechanical force [9, 10] and hormones [11] trigger Hippo pathway by controlling YAP/TAZ activity, whereas YAP/TAZ require TEADs binding to regulate target genes [12]. It is of importance to understand the regulation and function of TEADs

Methods

Results

Conclusion