Targeting Gi/o protein-coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy

JCI Insight. 2021 Sep 22;6(18):e150532. doi: 10.1172/jci.insight.150532.


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 Gi/o proteins (Gi/o-GPCRs). In mammary epithelial cells of transgenic mouse models, and BC cell lines, HER2 hyperactivation altered GPCR expression, particularly, Gi/o-GPCR expression. Gi/o-GPCR stimulation transactivated EGFR and HER2 and activated the PI3K/AKT and Src pathways. If we uncoupled Gi/o-GPCRs from their cognate Gi/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 Gi/o-GPCR signaling via PTx, PI3K, or Src inhibitors enhanced HER2-targeted therapy. These results indicate that, in BC cells, HER2 hyperactivation drives aberrant Gi/o-GPCR signaling and Gi/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.

Keywords: Breast cancer; G protein–coupled receptors; Oncology; Signal transduction; Therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / pharmacology
  • Benzodioxoles / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Drug Synergism
  • Epithelium / metabolism
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Indazoles / pharmacology
  • Lapatinib / pharmacology
  • Mammary Glands, Animal / metabolism*
  • Mice, Transgenic
  • Neoplasm Metastasis
  • Pertussis Toxin
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology
  • Quinazolines / pharmacology
  • Receptor, ErbB-2 / genetics*
  • Receptor, ErbB-2 / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacology
  • Trastuzumab / pharmacology
  • Up-Regulation


  • 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
  • Antineoplastic Agents, Immunological
  • Benzodioxoles
  • Indazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Quinazolines
  • Receptors, G-Protein-Coupled
  • Sulfonamides
  • Lapatinib
  • saracatinib
  • Pertussis Toxin
  • ERBB2 protein, human
  • ErbB Receptors
  • Erbb2 protein, mouse
  • Receptor, ErbB-2
  • Trastuzumab