Tumor-Suppressive Functions of the Aryl Hydrocarbon Receptor (AhR) and AhR as a Therapeutic Target in Cancer

SIMPLE SUMMARY: Cancer is driven by the excessive activity of growth-promoting genes and deficient activity of the genes that restrain cell growth. Genes that suppress cell growth possess tumor-suppressive activity. Knowing how these tumor-suppressive genes function and pharmacological methods to restore or elicit their growth-inhibiting activity is of keen interest for therapeutic development. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, and the activation of AhR by different molecules drives a wide range of biological effects, with both adverse and beneficial outcomes. Certain molecules that bind to AhR elicit tumor-suppressive effects (e.g., selective growth inhibition of cancer cells, apoptosis). Loss of AhR expression leads to increased tumorigenesis in different mouse models. Therapeutic targeting of the receptor requires insights into the molecular mechanisms that lead to tumor suppression, the determinants of the response to AhR ligands, and the cancer types that are responsive to AhR-selective modulators. ABSTRACT: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in regulating a wide range of biological responses. A diverse array of xenobiotics and endogenous small molecules bind to the receptor and drive unique phenotypic responses. Due in part to its role in mediating toxic responses to environmental pollutants, AhR activation has not been traditionally viewed as a viable therapeutic approach. Nonetheless, the expression and activation of AhR can inhibit the proliferation, migration, and survival of cancer cells, and many clinically approved drugs transcriptionally activate AhR. Identification of novel select modulators of AhR-regulated transcription that promote tumor suppression is an active area of investigation. The development of AhR-targeted anticancer agents requires a thorough understanding of the molecular mechanisms driving tumor suppression. Here, we summarized the tumor-suppressive mechanisms regulated by AhR with an emphasis on the endogenous functions of the receptor in opposing carcinogenesis. In multiple different cancer models, the deletion of AhR promotes increased tumorigenesis, but a precise understanding of the molecular cues and the genetic targets of AhR involved in this process is lacking. The intent of this review was to synthesize the evidence supporting AhR-dependent tumor suppression and distill insights for development of AhR-targeted cancer therapeutics.