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Targeting G(i/o) protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy
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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492335/ https://www.ncbi.nlm.nih.gov/pubmed/34343132 http://dx.doi.org/10.1172/jci.insight.150532 |
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author | Lyu, Cancan Ye, Yuanchao Lensing, Maddison M. Wagner, Kay-Uwe Weigel, Ronald J. Chen, Songhai |
author_facet | Lyu, Cancan Ye, Yuanchao Lensing, Maddison M. Wagner, Kay-Uwe Weigel, Ronald J. Chen, Songhai |
author_sort | Lyu, Cancan |
collection | PubMed |
description | 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(+) BC by targeting a subgroup of GPCRs that couple to G(i/o) proteins (G(i/o)-GPCRs). In mammary epithelial cells of transgenic mouse models, and BC cell lines, HER2 hyperactivation altered GPCR expression, particularly, G(i/o)-GPCR expression. G(i/o)-GPCR stimulation transactivated EGFR and HER2 and activated the PI3K/AKT and Src pathways. If we uncoupled G(i/o)-GPCRs from their cognate G(i/o) 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(i/o)-GPCR signaling via PTx, PI3K, or Src inhibitors enhanced HER2-targeted therapy. These results indicate that, in BC cells, HER2 hyperactivation drives aberrant G(i/o)-GPCR signaling and G(i/o)-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. |
format | Online Article Text |
id | pubmed-8492335 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-84923352021-10-07 Targeting G(i/o) protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy Lyu, Cancan Ye, Yuanchao Lensing, Maddison M. Wagner, Kay-Uwe Weigel, Ronald J. Chen, Songhai JCI Insight Research Article 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(+) BC by targeting a subgroup of GPCRs that couple to G(i/o) proteins (G(i/o)-GPCRs). In mammary epithelial cells of transgenic mouse models, and BC cell lines, HER2 hyperactivation altered GPCR expression, particularly, G(i/o)-GPCR expression. G(i/o)-GPCR stimulation transactivated EGFR and HER2 and activated the PI3K/AKT and Src pathways. If we uncoupled G(i/o)-GPCRs from their cognate G(i/o) 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(i/o)-GPCR signaling via PTx, PI3K, or Src inhibitors enhanced HER2-targeted therapy. These results indicate that, in BC cells, HER2 hyperactivation drives aberrant G(i/o)-GPCR signaling and G(i/o)-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. American Society for Clinical Investigation 2021-09-22 /pmc/articles/PMC8492335/ /pubmed/34343132 http://dx.doi.org/10.1172/jci.insight.150532 Text en © 2021 Lyu et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Lyu, Cancan Ye, Yuanchao Lensing, Maddison M. Wagner, Kay-Uwe Weigel, Ronald J. Chen, Songhai Targeting G(i/o) protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy |
title | Targeting G(i/o) protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy |
title_full | Targeting G(i/o) protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy |
title_fullStr | Targeting G(i/o) protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy |
title_full_unstemmed | Targeting G(i/o) protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy |
title_short | Targeting G(i/o) protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy |
title_sort | targeting g(i/o) protein–coupled receptor signaling blocks her2-induced breast cancer development and enhances her2-targeted therapy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492335/ https://www.ncbi.nlm.nih.gov/pubmed/34343132 http://dx.doi.org/10.1172/jci.insight.150532 |
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