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Aryl hydrocarbon receptor suppresses STING-mediated type I IFN expression in triple-negative breast cancer

Jeffrey C Martin1, Tatiane da Silva Fernandes1, Kanita A Chaudhry1,2

  • 1Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Scientific Reports
|March 8, 2024
PubMed

Insights

Aryl hydrocarbon receptor (AhR) suppresses type I interferons (IFN-I) in triple-negative breast cancer (TNBC). Inhibiting AhR alongside PARP inhibitors enhances IFN-I, potentially improving treatment efficacy for BRCA1-deficient breast cancers.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Triple-negative breast cancer (TNBC) is aggressive with limited treatment options.
  • Type I interferons (IFN-I) modulate cancer therapy response.
  • STImulator of Interferon Genes (STING) is crucial for interferon production and PARP inhibitor (PARPi) efficacy.

Purpose of the Study:

  • Investigate the role of aryl hydrocarbon receptor (AhR) in regulating IFN-I production in TNBC.
  • Determine the interplay between AhR, STING, and PARPi efficacy in BRCA1-deficient TNBC.
  • Explore combined AhR and PARPi inhibition as a therapeutic strategy.

Main Methods:

  • Utilized TNBC cell systems.
  • Assessed AhR activity and IFN-I expression.
  • Investigated the effect of PARPi treatment on AhR activation.
  • Evaluated the impact of combined AhR and PARPi inhibition.

Main Results:

  • AhR suppresses IFN-I expression by inhibiting STING in TNBC.
  • PARPi treatment activates AhR in a BRCA1-dependent manner, creating a negative feedback loop.
  • Combined inhibition of AhR and PARP significantly increases IFN-I expression compared to PARPi alone.

Conclusions:

  • AhR acts as a negative regulator of IFN-I production in TNBC via STING inhibition.
  • Targeting AhR in combination with PARPi may enhance therapeutic outcomes in BRCA1-deficient breast cancers, predominantly TNBC.
  • AhR inhibition represents a potential strategy to improve PARPi efficacy in specific breast cancer subtypes.
Keywords:
Aryl hydrocarbon receptorBRCA1/2 mutationsPARP inhibitorsTriple-negative breast cancerType I interferonscGAS-STING

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