Article ; Online: Aryl hydrocarbon receptor suppresses STING-mediated type I IFN expression in triple-negative breast cancer.
2024 Volume 14, Issue 1, Page(s) 5731
Abstract: 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. Cancer cell- ... ...
| Abstract | 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. 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 BRCA1 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 that 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. |
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| MeSH term(s) | Humans ; BRCA2 Protein/genetics ; Interferon Type I/biosynthesis ; Interferon Type I/immunology ; Interferon Type I/metabolism ; Receptors, Aryl Hydrocarbon/genetics ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/pathology |
| Chemical Substances | AHR protein, human ; BRCA2 Protein ; Interferon Type I ; Receptors, Aryl Hydrocarbon ; STING1 protein, human |
| Language | English |
| Publishing date | 2024-03-08 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 2615211-3 |
| ISSN | 2045-2322 ; 2045-2322 |
| ISSN (online) | 2045-2322 |
| ISSN | 2045-2322 |
| DOI | 10.1038/s41598-024-54732-3 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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