e12579 Background: Tryptophan (Trp) is an essential amino acid metabolized through the kynurenine, serotonin, and indole pathways. Dysregulation of Trp metabolism has been implicated in cancer progression. Several Trp-derived metabolites serve as ligands for the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that is critical to immune response and tumorigenesis. Although AhR is broadly expressed across breast cancer subtypes, its precise role in breast cancer remains unclear. Thus, investigating Trp metabolism in relation to AhR activation may provide novel insights into how the Trp-AhR axis interfaces with immune regulation in breast cancer. Methods: Serum samples were obtained from patients with breast cancer (n = 13) and age-matched individuals with fibroadenoma (n = 9). Eighteen Trp metabolites were quantified using ultra-high performance liquid chromatography. Differential metabolite levels were analyzed, followed by Pearson correlation analysis of individual metabolites relative to Trp to assess pathway-specific metabolic flux. To evaluate transcriptional regulation, RNA-seq data for key Trp-metabolizing enzymes and AhR were retrieved from The Cancer Genome Atlas (TCGA) Breast Invasive Carcinoma cohort. Correlation analyses were performed between AhR expression, Trp metabolic enzymes, and immune checkpoint–related genes. Results: Serum Trp metabolism was significantly altered in breast cancer compared with fibroadenoma. Trp levels were reduced, while cinnavalininate, 5-HIAA, and picolinic acid demonstrated the most pronounced differences. Correlation analyses revealed preferential engagement of the kynurenine and serotonin pathways in breast cancer. Consistent with serum metabolite profiles, TCGA analysis showed differential mRNA expression of key Trp-metabolizing enzymes in breast cancer relative to benign tumors. AhR expression was significantly reduced in breast cancer. Despite modest effect sizes, AhR expression positively correlated with multiple Trp metabolic enzymes, including IDO, HAAO, and MAO-A. Notably, AhR expression strongly correlated with immune checkpoint–related genes, including PD-L1, and CTLA-4 ligands (CD80, CD86). Conclusions: Trp metabolism is significantly disrupted in breast cancer and is coupled to altered AhR signaling. The association between AhR, Trp metabolic enzymes, and immune checkpoint gene expression highlights a previously underappreciated role for the Trp-AhR axis in immune regulation within the breast cancer microenvironment. Although preliminary, these results support further investigation of AhR-coupled Trp metabolism as a potential therapeutic target for immunomodulatory strategies in breast cancer.
Wu et al. (Thu,) studied this question.