Abstract
Endogenous ligand-activated AHR plays an important role in numerous biological processes. As the known number of AHR-mediated processes grows, so too does the importance of determining what endogenous AHR ligands are produced, how their production is regulated, and what biological consequences ensue. Consequently, our studies were designed primarily to determine if ER-/PR-/Her2- breast cancer cells have the potential to produce endogenous AHR ligands and, if so, how production of these ligands is controlled. We postulated that: 1) malignant cells produce tryptophan-derived AHR ligand(s) through the kynurenine pathway, 2) these metabolites have the potential to drive AHR-dependent breast cancer migration, 3) the AHR controls expression of a rate-limiting kynurenine pathway enzyme(s) in a closed amplification loop, and 4) environmental AHR ligands mimic the effects of endogenous ligands. Data presented here indicate that primary human breast cancers, and their metastases, express high levels of AHR and TDO; representative ER-/PR-/Her2- cell lines express TDO and produce sufficient intracellular kynurenine and xanthurenic acid concentrations to chronically activate the AHR. TDO over-expression, or excess kynurenine or xanthurenic acid, accelerate migration in an AHR-dependent fashion. Environmental AHR ligands TCDD and B[a]P mimic this effect. AHR knockdown or inhibition significantly reduces TDO2 expression. These studies identify, for the first time, a positive amplification loop in which AHR -dependent TDO2 expression contributes to endogenous AHR ligand production. The net biologic effect of AHR activation by endogenous ligands, which can be mimicked by environmental ligands, is an increase in tumor cell migration, a measure of tumor aggressiveness.
- Comparative genome analyses
- Immunocytochemistry
- Mass Spectroscopy
- Nuclear receptors (AHR, PXR, CAR, FXR, etc.)
- Metastasis
- The American Society for Pharmacology and Experimental Therapeutics