{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:01:15Z","timestamp":1790730075034,"version":"4.1.0"},"reference-count":52,"publisher":"American Society for Clinical Investigation","issue":"18","license":[{"start":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T00:00:00Z","timestamp":1632268800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NCI","award":["R01CA207889"],"award-info":[{"award-number":["R01CA207889"]}]},{"name":"DOD","award":["BC151478"],"award-info":[{"award-number":["BC151478"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,22]]},"abstract":"<jats:p>\n                    GPCRs are highly desirable drug targets for human disease. Although GPCR dysfunction drives development and progression of many tumors, including breast cancer (BC), targeting individual GPCRs has limited efficacy as a cancer therapy because numerous GPCRs are activated. Here, we sought a new way of blocking GPCR activation in HER2\n                    <jats:sup>+<\/jats:sup>\n                    BC by targeting a subgroup of GPCRs that couple to G\n                    <jats:sub>i\/o<\/jats:sub>\n                    proteins (G\n                    <jats:sub>i\/o<\/jats:sub>\n                    -GPCRs). In mammary epithelial cells of transgenic mouse models, and BC cell lines, HER2 hyperactivation altered GPCR expression, particularly, G\n                    <jats:sub>i\/o<\/jats:sub>\n                    -GPCR expression. G\n                    <jats:sub>i\/o<\/jats:sub>\n                    -GPCR stimulation transactivated EGFR and HER2 and activated the PI3K\/AKT and Src pathways. If we uncoupled G\n                    <jats:sub>i\/o<\/jats:sub>\n                    -GPCRs from their cognate G\n                    <jats:sub>i\/o<\/jats:sub>\n                    proteins by pertussis toxin (PTx), then BC cell proliferation and migration was inhibited in vitro and HER2-driven tumor formation and metastasis were suppressed in vivo. Moreover, targeting G\n                    <jats:sub>i\/o<\/jats:sub>\n                    -GPCR signaling via PTx, PI3K, or Src inhibitors enhanced HER2-targeted therapy. These results indicate that, in BC cells, HER2 hyperactivation drives aberrant G\n                    <jats:sub>i\/o<\/jats:sub>\n                    -GPCR signaling and G\n                    <jats:sub>i\/o<\/jats:sub>\n                    -GPCR signals converge on the PI3K\/AKT and Src signaling pathways to promote cancer progression and resistance to HER2-targeted therapy. Our findings point to a way to pharmacologically deactivate GPCR signaling to block tumor growth and enhance therapeutic efficacy.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.150532","type":"journal-article","created":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T17:13:51Z","timestamp":1628615631000},"source":"Crossref","is-referenced-by-count":19,"title":["Targeting Gi\/o protein\u2013coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy"],"prefix":"10.1172","volume":"6","author":[{"given":"Cancan","family":"Lyu","sequence":"first","affiliation":[{"name":"Departments of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanchao","family":"Ye","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maddison M.","family":"Lensing","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5081-0226","authenticated-orcid":true,"given":"Kay-Uwe","family":"Wagner","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald J.","family":"Weigel","sequence":"additional","affiliation":[{"name":"Department of Surgery, Roy J. and Lucille A. 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