Abstract
We have postulated that the aryl hydrocarbon receptor (AHR) drives the later, more lethal stages of some cancers when chronically activated by endogenous ligands. However, other studies have suggested that, under some circumstances, the AHR can oppose tumor aggression. Resolving this apparent contradiction is critical to the design of AHR-targeted cancer therapeutics. Molecular (siRNA, shRNA, AHR repressor, CRISPR-Cas9) and pharmacological (AHR inhibitors) approaches were used to confirm the hypothesis that AHR inhibition reduces human cancer cell invasion (irregular colony growth in 3D Matrigel cultures and Boyden chambers), migration (scratch wound assay) and metastasis (human cancer cell xenografts in zebrafish). Furthermore, these assays were used for a head-to-head comparison between AHR antagonists and agonists. AHR inhibition or knockdown/knockout consistently reduced human ER−/PR−/Her2− and inflammatory breast cancer cell invasion, migration, and metastasis. This was associated with a decrease in invasion-associated genes (e.g., Fibronectin, VCAM1, Thrombospondin, MMP1) and an increase in CDH1/E-cadherin, previously associated with decreased tumor aggression. Paradoxically, AHR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin and/or 3,3′-diindolylmethane) similarly inhibited irregular colony formation in Matrigel and blocked metastasis in vivo but accelerated migration. These data demonstrate the complexity of modulating AHR activity in cancer while suggesting that AHR inhibitors, and, under some circumstances, AHR agonists, may be useful as cancer therapeutics.
Highlights
The earliest studies on the aryl hydrocarbon receptor (AHR) focused on its role as an environmental chemical sensor and mediator of the toxic effects of polycyclic aromatic hydrocarbons, dioxins, and planar polychlorinated biphenyls, many of which are classified as human carcinogens [1]
We postulated that constitutive AHR activity, driven in part by the production of μM quantities of the endogenous tryptophan-derived ligands kynurenine and xanthurenic acid [17], is causally linked to breast cancer invasion [12,21]
To confirm the role of the AHR in an aggressive cancer phenotype, AHR expression or activity was downregulated in human ER−/PR−/Her2− BP1 and Hs578T cell lines by transfection of an AHR repressor plasmid (AHRR), AHR-specific siRNA or by AHR deletion through CRISPR-Cas9-mediated AHR gene editing
Summary
The earliest studies on the aryl hydrocarbon receptor (AHR) focused on its role as an environmental chemical sensor and mediator of the toxic effects of polycyclic aromatic hydrocarbons, dioxins, and planar polychlorinated biphenyls, many of which are classified as human carcinogens [1]. Because AHR activity is highly context (tissue type, cell type, ligand)-specific [10,26], predicting how the “Janus-faced” AHR [27] will act in any given system can be problematic It is sometimes unclear if the AHR promotes or inhibits tumor aggression in any given tumor type. In support of the AHR driving tumor aggression, AHR knockdown in lung adenocarcinoma [28] or oral squamous cell carcinoma [17], or depletion of putative endogenous AHR ligands in glioblastoma [18] decreases anchorage-independent growth and/or invasion. A direct comparison between outcomes in these system has been confounded by the use of a variety of readouts (e.g., tumor growth or migration assays), AHR modulators (inhibitors, agonists, molecular knockdowns) and tumor types
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