Functional significance of the aryl hydrocarbon receptor in oncogenic signaling pathways

The aryl hydrocarbon receptor (AhR) is a ubiquitously expressed, ligand-activated transcription factor which has been extensively studied for its role in mediating the toxic effects of several common environmental pollutants. However, more recent findings associating AhR with carcinogenesis and tumor progression have expanded the scope of AhR research and established the preclinical significance of AhR as a possible target for cancer therapy. In this review, the current knowledge of the role of AhR in cancer will be discussed, and evidence from an array of experimental cancer and immune models will be presented. It has been observed that AhR potentiates oncogenic mutations through induction of genetic damage and transactivates EGFR to promote proproliferative signaling along the classical Ras/Raf/MAPK and PI3K/Akt pathways. Furthermore, AhR downregulates E-cadherin via multiple axes to facilitate epithelial-to-mesenchymal transition and contributes to a shift of the tumor immune microenvironment to a predominantly regulatory milieu. The sheer versatility of AhR as a protumor factor should provide sufficient grounds for further investigation of the persisting question of whether targeting AhR can disrupt tumor progression in vivo.