Related Experiment Video

Updated: Aug 6, 2026

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
11:32

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
PubMed

Insights

Researchers identified endothelin receptor type A (EDNRA) as a key driver in triple-negative breast cancer (TNBC) by activating Hippo/Yes-associated protein (YAP) signaling. Blocking EDNRA with atrasentan shows promise for treating 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 in TNBC.
  • To identify and characterize the role of EDNRA in YAP-driven TNBC.

Main Methods:

  • Bioinformatic analysis of TCGA data for Hippo/YAP signatures.
  • siRNA screening to identify GPCRs involved in connective tissue growth factor (CTGF) signaling.
  • Experimental validation using cell lines and xenografts involving EDNRA manipulation and atrasentan treatment.
  • Molecular analyses including immunoblotting, RT-qPCR, reporter assays, and ChIP-qPCR to elucidate signaling pathways.

Main Results:

  • EDNRA expression positively correlated with Hippo/YAP signatures, adverse clinical features, and poor outcomes in TNBC.
  • EDNRA depletion or atrasentan blockade inhibited TNBC cell proliferation, migration, stemness, and xenograft growth.
  • EDNRA signaling activates YAP/TEAD through Gαq/11-Rho/ROCK-LATS pathway, forming a positive feedback loop with YAP/TEAD4 enhancing EDNRA transcription.
  • Atrasentan demonstrated synergistic effects with paclitaxel in TNBC.

Conclusions:

  • EDNRA is a druggable upstream regulator of YAP in TNBC.
  • Targeting EDNRA represents a promising therapeutic strategy for YAP-driven TNBC.
  • The identified EDNRA-YAP feedback loop offers a novel therapeutic vulnerability.
Keywords:
EDNRAG protein‐coupled receptorHippo/YAP signalingpositive feedback looptriple‐negative breast cancer

More Related Videos

An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation08:48

An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation

Published on: June 30, 2015

Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model09:29

Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model

Published on: March 20, 2020

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Hedgehog Signaling Pathway02:33

Hedgehog Signaling Pathway

The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins - Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to...
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal01:22

Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal

Erythropoietin-producing hepatocellular carcinoma receptor (Eph) and its ligand, Eph receptor-interacting protein (Ephrin) were first discovered in the human carcinoma cell line, hence the name. Ephrin-Eph interaction guides cells to reach their appropriate location in adult tissues. They also play an essential role in the immune system by helping in immune cell migration, adhesion, and activation. Based on their structure and function, Eph is divided into two classes — EphA and EphB.