Instruct: Identify the main category of Biorxiv papers based on the titles and abstracts
Query: Targeting Gi/o protein-coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy G protein coupled receptors (GPCRs) are among the most desirable drug targets for human disease. Although GPCR dysfunction drives the 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. In this study, we sought a new way of blocking GPCR activation in HER2+-BC by targeting a subgroup of GPCRs that couple to Gi/o proteins (Gi/o-GPCRs). Using cell lines and transgenic mouse models, we showed in mammary epithelial cells, HER2 hyperactivation altered GPCR expression, particularly, Gi/o-GPCRs. Gi/o-GPCR stimulation transactivated EGFR and HER2, which in turn activated the PI3K/AKT and Src pathways. Uncoupling Gi/o-GPCRs from cognate Gi/o proteins by pertussis toxin (PTx) inhibited BC cell proliferation and migration in vitro and suppressed HER2-driven tumor formation and metastasis in vivo. Moreover, targeting Gi/o-GPCR signaling via PTx, PI3K, or Src inhibitors enhanced HER2-targeted therapy. These results indicate that HER2 hyperactivation in BC cells drives aberrant Gi/o-GPCR signaling, and Gi/o-GPCR signals converge on PI3K/AKT and Src signaling pathways to promote cancer progression and the development of resistance to HER2-targeted therapy. Our findings suggest a new way to pharmacologically deactivate GPCR signaling to block tumor growth and enhance therapeutic efficacy.
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The categories of this paper are: microbiology
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The categories of this paper are: zoology
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The categories of this paper are: paleontology
5
The categories of this paper are: cell
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The categories of this paper are: toxicology
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The categories of this paper are: synthetic
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The categories of this paper are: biophysics
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The categories of this paper are: physiology
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The categories of this paper are: systems
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The categories of this paper are: evolutionary
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The categories of this paper are: scientific
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The categories of this paper are: behavior
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The categories of this paper are: animal
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The categories of this paper are: biochemistry
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The categories of this paper are: education
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The categories of this paper are: and