Journal article
Targeting G(i/o) protein-coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy
JCI insight, Vol.6(18), e150532
09/22/2021
DOI: 10.1172/jci.insight.150532
PMCID: PMC8492335
PMID: 34343132
Abstract
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.
Details
- Title: Subtitle
- Targeting G(i/o) protein-coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy
- Creators
- Cancan Lyu - Roy J. and Lucille A. Carver College of MedicineYuanchao Ye - Roy J. and Lucille A. Carver College of MedicineMaddison M. Lensing - Roy J. and Lucille A. Carver College of MedicineKay-Uwe Wagner - Wayne State UniversityRonald J. Weigel - Roy J. and Lucille A. Carver College of MedicineSonghai Chen - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.6(18), e150532
- DOI
- 10.1172/jci.insight.150532
- PMID
- 34343132
- PMCID
- PMC8492335
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- Publisher
- Amer Soc Clinical Investigation Inc
- Number of pages
- 17
- Grant note
- R01CA207889 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA BC151478 / Department of Defense Breast Cancer Research Program breakthrough award level 2; United States Department of Defense P30 CA086862 / National Cancer Institute core grant; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 09/22/2021
- Academic Unit
- Molecular Physiology and Biophysics; Anatomy and Cell Biology; Iowa Neuroscience Institute; Surgery; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984284337802771
Metrics
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