How the AHR became important in cancer: The role of chronically active AHR in cancer aggression

Sometimes biological research is an act of faith, a belief that untangling complex biologic interactions on a very basic level in-and-of itself eventually leads to larger and broader implications for human health. Indeed, sometimes focusing on the trees leads to a better view of the forest. This has been the case for the aryl hydrocarbon receptor (AHR). For decades, the AHR was studied for its role in environmental chemical toxicity i.e., as a quirk of nature and a mediator of unintended consequences of human pollution. During that period, it was not certain that the AHR had a “normal” physiological function. However, the ongoing accumulation of data from an ever-expanding variety of studies on cancer, cancer immunity, autoimmunity, organ development, and other areas bears witness to a staggering array of AHR-controlled normal and pathological activities. The objective of this review is to discuss how the AHR has gone from a likely contributor to genotoxic environmental carcinogen-induced cancer to a master regulator of malignant cell progression and cancer aggression. Particular focus was placed on the association between AHR activity and poor outcomes, feedback loops that control chronic AHR activity in cancer, and the role of chronically active AHR in driving cancer cell invasion, migration, cancer stem cell characteristics, and survival. The AHR knock-out (KO) in breast cancer cell lines (MDA-MB231 and SUM149) was generated by CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats) gene editing. Each cell line includes Cas9 control and AHR KO with 3 biological replicates. RNA extraction and hybridization on Affymetrix microarrays were processed. The expression profiles between different groups were analyzed and compared.