Towards Resolving the Pro- and Anti-Tumor Effects of the Aryl Hydrocarbon Receptor

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 contra...

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Bibliographic Details
Published in:International journal of molecular sciences 2018-05, Vol.19 (5), p.1388
Main Authors: Narasimhan, Supraja, Stanford Zulick, Elizabeth, Novikov, Olga, Parks, Ashley J, Schlezinger, Jennifer J, Wang, Zhongyan, Laroche, Fabrice, Feng, Hui, Mulas, Francesca, Monti, Stefano, Sherr, David H
Format: Article
Language:English
Subjects:
Aggression
Antagonists
Aromatic compounds
Breast cancer
Cancer
Colonies
CRISPR
Dioxins
E-cadherin
ErbB-2 protein
Fibronectin
Hydrocarbons
Inflammation
Inhibitors
Metastases
Metastasis
Molecular chains
Pharmacology
siRNA
Thrombospondin
Tumors
Xenografts
Xenotransplantation
Zebrafish
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Summary: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., , , Thrombospondin, ) and an increase in , previously associated with decreased tumor aggression. Paradoxically, AHR agonists (2,3,7,8-tetrachlorodibenzo- -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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms19051388