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Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
Published on: March 27, 2020
EDNRA Forms a Positive Feedback Loop with the Hippo/YAP Axis to Drive Triple-Negative Breast Cancer Progression
Zehao Hong1, Boyang Li1, Jiahui Xu1
1Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 24, 2026
Summary
Researchers identified endothelin receptor type A (EDNRA) as a key driver in triple-negative breast cancer (TNBC). Blocking EDNRA with atrasentan suppressed tumor growth and sensitized cells to chemotherapy, offering a new therapeutic strategy for YAP-driven TNBC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Sustained Hippo/Yes-associated protein (YAP) activation is crucial for triple-negative breast cancer (TNBC) progression.
- Identifying druggable upstream regulators of YAP in TNBC is a critical unmet need.
Purpose of the Study:
- To investigate G protein-coupled receptors (GPCRs) as potential upstream regulators of YAP activation in TNBC.
- To identify and characterize novel therapeutic targets for YAP-driven TNBC.
Main Methods:
- TCGA data analysis, GPCR annotation, and siRNA screening identified EDNRA.
- Functional studies involved knockdown, overexpression, ET-1 stimulation, and atrasentan blockade in TNBC cells and xenografts.
- YAP regulation was assessed using immunoblotting, RT-qPCR, TEAD reporter assays, and molecular interaction studies.
Main Results:
- EDNRA expression correlated with YAP signatures, adverse clinical features, and poor prognosis in TNBC.
- EDNRA depletion or atrasentan treatment inhibited TNBC cell proliferation, migration, stemness, and xenograft growth.
- EDNRA activated YAP/TEAD signaling via Gαq/11-Rho/ROCK-LATS pathway, forming a positive feedback loop with YAP/TEAD4.
Conclusions:
- EDNRA is a druggable upstream regulator of YAP in TNBC, representing a potential therapeutic vulnerability.
- Atrasentan blockade of EDNRA suppressed tumor progression and sensitized TNBC to paclitaxel, demonstrating synergistic potential.
Keywords:
EDNRAG protein‐coupled receptorHippo/YAP signalingpositive feedback looptriple‐negative breast cancerMore Related Videos
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