{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:18:08Z","timestamp":1790018288768,"version":"4.0.1"},"reference-count":42,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Sustained Hippo\/Yes\u2010associated protein (YAP) activation drives triple\u2010negative breast cancer (TNBC), but druggable upstream regulators remain unclear. We investigated G protein\u2010coupled receptors (GPCRs) as membrane inputs for YAP activation. TCGA\u2010based Hippo\/YAP signature analysis, marketed\u2010drug GPCR annotation, and siRNA screening using connective tissue growth factor (CTGF) identified endothelin receptor type A (EDNRA). EDNRA function was tested by knockdown, overexpression, endothelin\u20101 (ET\u20101) stimulation, and atrasentan blockade in TNBC cells and xenografts. YAP regulation was examined by immunoblotting, RT\u2010qPCR, TEAD reporter assays, subcellular localization, docking, co\u2010immunoprecipitation, mutagenesis, ChIP\u2010qPCR, and CRISPRi. EDNRA correlated with Hippo\/YAP signatures, adverse clinical features, and poor outcome. EDNRA depletion or atrasentan suppressed proliferation, migration, stem\u2010like populations, and xenograft growth, whereas EDNRA overexpression or ET\u20101 had opposite effects. Mechanistically, EDNRA reduced YAP Ser127 phosphorylation, promoted nuclear YAP accumulation, and enhanced TEAD transcription through G\u03b1q\/11\u2013Rho\/ROCK\u2013LATS signaling. Mutating predicted EDNRA\u2013G\u03b1q\/11 interface residues impaired YAP activation and tumor\u2010promoting activity. Reciprocally, YAP\/TEAD4 enhanced EDNRA transcription through an enhancer\u2010associated region. Atrasentan also sensitized TNBC cells to paclitaxel and produced positive zero interaction potency (ZIP) synergy scores. EDNRA establishes a druggable positive feedback loop with Hippo\/YAP signaling and represents a potential therapeutic vulnerability in YAP\u2010driven TNBC.<\/jats:p>","DOI":"10.1002\/advs.76784","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T12:22:03Z","timestamp":1784895723000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["EDNRA Forms a Positive Feedback Loop with the Hippo\/YAP Axis to Drive Triple\u2010Negative Breast Cancer Progression"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3007-0034","authenticated-orcid":false,"given":"Zehao","family":"Hong","sequence":"first","affiliation":[{"name":"Department of Breast Surgery The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4367-2367","authenticated-orcid":false,"given":"Boyang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruonan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghao","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenlu","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boxiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cancer Research Institute The Affiliated Cancer Hospital of Xinjiang Medical University  Urumqi Xinjiang Uygur Autonomous Region China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy Yue","family":"Lau","sequence":"additional","affiliation":[{"name":"Department of Public Health Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Aldridge","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Minnesota Medical School Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Whitmore","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Minnesota Medical School Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7413-2463","authenticated-orcid":false,"given":"Yi","family":"Chen","sequence":"additional","affiliation":[{"name":"Cancer Research Institute The Affiliated Cancer Hospital of Xinjiang Medical University  Urumqi Xinjiang Uygur Autonomous Region China"},{"name":"Department of Public Health Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"issue":"2","key":"e_1_2_12_2_1","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41571-021-00565-2","article-title":"Treatment Landscape of Triple\u2010Negative Breast Cancer \u2014 Expanded Options, Evolving Needs","volume":"19","author":"Bianchini G.","year":"2022","journal-title":"Nature Reviews Clinical Oncology"},{"issue":"1","key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41523-022-00468-0","article-title":"Triple Negative Breast Cancer: Pitfalls and Progress","volume":"8","author":"Zagami P.","year":"2022","journal-title":"NPJ Breast Cancer"},{"issue":"21","key":"e_1_2_12_4_1","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1056\/NEJMoa2409932","article-title":"Overall Survival with Pembrolizumab in Early\u2010Stage Triple\u2010Negative Breast Cancer","volume":"391","author":"Schmid P.","year":"2024","journal-title":"New England Journal of Medicine"},{"issue":"12","key":"e_1_2_12_5_1","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1016\/j.annonc.2022.09.159","article-title":"Overall Survival in the OlympiA Phase III Trial of Adjuvant Olaparib in Patients with Germline Pathogenic Variants in BRCA1\/2 and High\u2010Risk, Early\u00a0Breast Cancer","volume":"33","author":"Geyer C. 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