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Open AccessArticle

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

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Department of Pathology and Laboratory Medicine, Boston University School of Medicine, 72 East Concord St., Boston, MA 02118, USA
2
Biological Sciences and Biotechnology Programs, Northeastern University, Boston, MA 02115, USA
3
Molecular and Translational Medicine Program, Department of Medicine, Boston University School of Medicine, 72 East Concord St., Boston, MA 02118, USA
4
Sage Therapeutics, 215 1rst St., Cambridge, MA 02142, USA
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Department of Environmental Health, Boston University School of Public Health, 72 East Concord St., Boston, MA 02118, USA
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Departments of Pharmacology and Medicine, Cancer Center, Boston University School of Medicine, 72 East Concord St., Boston, MA 02118, USA
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Department of Pediatrics, University of California, San Diego, CA 92093, USA
8
Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, 72 East Concord St., Boston, MA 02118, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(5), 1388; https://doi.org/10.3390/ijms19051388
Received: 2 April 2018 / Revised: 27 April 2018 / Accepted: 30 April 2018 / Published: 7 May 2018
(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Biology and Toxicology)
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. View Full-Text
Keywords: aryl hydrocarbon receptor; cancer; AHR agonist; AHR antagonist; cancer therapeutics aryl hydrocarbon receptor; cancer; AHR agonist; AHR antagonist; cancer therapeutics
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Narasimhan, S.; Stanford Zulick, E.; Novikov, O.; Parks, A.J.; Schlezinger, J.J.; Wang, Z.; Laroche, F.; Feng, H.; Mulas, F.; Monti, S.; Sherr, D.H. Towards Resolving the Pro- and Anti-Tumor Effects of the Aryl Hydrocarbon Receptor. Int. J. Mol. Sci. 2018, 19, 1388.

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