Aryl Hydrocarbon Receptor suppresses STING-mediated Type I IFN expression in Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) is one of the most aggressive types of cancer. Despite decades of intense investigation, treatment options remain limited and rapid recurrence with distant metastases remains a significant challenge in the clinic. Cancer cell-intrinsic production of cytokines such as type I interferons (IFN-I) is a known potent modulator of response to therapy in many cancers, including TNBC, and can influence therapeutic outcome. Here, we report that in TNBC systems the aryl hydrocarbon receptor (AhR) suppresses IFN-I expression via inhibition of Stimulator of Interferon Genes (STING), a key mediator of interferon production. Intratumoral STING activity is essential in mediating the efficacy of PARP inhibitors (PARPi) which are used in the treatment of cancers harboring BRCA-1 deficiency. We find that, in TNBC cells, PARPi treatment activates AhR in a BRCA1 deficiency-dependent manner, thus suggesting the presence of a negative feedback loop aimed at modulating PARPi efficacy. Importantly, our results indicate the combined inhibition of PARP and AhR is superior in elevating IFN-I expression as compared to PARPi-alone. Thus, AhR inhibition may allow for enhanced IFN-I production upon PARPi in BRCA1-deficient breast cancers, most of which are of TNBC origin, and may represent a therapeutically viable strategy to enhance PARPi efficacy. Overall design: To investigate the effects of AHR, we have established MDA-MB-231 cells with either GFP-PLKO or shAHR knockdowns of AHR, using 2 different constructs.