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

Cancan Lyu1, Yuanchao Ye1, Maddison M Lensing1

  • 1Departments of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.

JCI Insight
|August 3, 2021
PubMed

Insights

Targeting G-protein coupled receptors (GPCRs) that signal through Gi/o proteins may block breast cancer (BC) progression. Inhibiting these Gi/o-GPCRs enhances HER2-targeted therapy efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • G-protein coupled receptors (GPCRs) are crucial drug targets, but targeting individual GPCRs shows limited efficacy in cancer therapy.
  • GPCRs are implicated in tumor development and progression, particularly in breast cancer (BC).
  • HER2-positive (HER2+) BC involves hyperactivation of numerous GPCRs, complicating targeted treatment strategies.

Purpose of the Study:

  • To investigate a novel therapeutic strategy for HER2+ BC by targeting a specific subgroup of GPCRs coupled to Gi/o proteins (Gi/o-GPCRs).
  • To elucidate the role of Gi/o-GPCR signaling in HER2-driven BC progression and resistance to HER2-targeted therapies.

Main Methods:

  • Utilized transgenic mouse models and BC cell lines to analyze GPCR expression alterations in response to HER2 hyperactivation.
  • Investigated the effects of inhibiting Gi/o-GPCRs using pertussis toxin (PTx) on BC cell proliferation, migration, tumor formation, and metastasis.
  • Assessed the impact of targeting Gi/o-GPCR signaling pathways (PTx, PI3K, Src inhibitors) on the efficacy of HER2-targeted therapy.

Main Results:

  • HER2 hyperactivation in BC cells led to altered expression of GPCRs, especially Gi/o-GPCRs.
  • Stimulation of Gi/o-GPCRs resulted in transactivation of EGFR and HER2, activating PI3K/AKT and Src pathways.
  • Inhibition of Gi/o-GPCRs by PTx suppressed BC cell proliferation, migration, tumor growth, and metastasis.
  • Targeting Gi/o-GPCR signaling pathways potentiated the effectiveness of HER2-targeted therapies.

Conclusions:

  • Aberrant Gi/o-GPCR signaling, driven by HER2 hyperactivation, promotes BC progression and resistance to HER2-targeted therapy.
  • Gi/o-GPCR signals converge on PI3K/AKT and Src pathways, contributing to cancer growth and therapeutic resistance.
  • Pharmacologically deactivating GPCR signaling offers a promising approach to inhibit tumor growth and improve therapeutic outcomes in BC.
Keywords:
Breast cancerG protein–coupled receptorsOncologySignal transductionTherapeutics

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