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Ahr and Cancer: from Gene Profiling to Targeted Therapy International Journal of Molecular Sciences Review AhR and Cancer: From Gene Profiling to Targeted Therapy Anaïs Paris 1,†, Nina Tardif 1,† , Marie-Dominique Galibert 1,2,* and Sébastien Corre 1,* 1 CNRS (Centre National de la Recherche Scientifique), IGDR (Institut de Génétique et Développement de Rennes), UMR6290, University Rennes, F-35000 Rennes, France; [email protected] (A.P.); [email protected] (N.T.) 2 Department of Molecular Genetics and Genomics, Hospital University of Rennes (CHU Rennes), F-35000 Rennes, France * Correspondence: [email protected] (M.-D.G.); [email protected] (S.C.) † These authors contributed equally to the work. Abstract: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has been shown to be an essential regulator of a broad spectrum of biological activities required for maintaining the body’s vital functions. AhR also plays a critical role in tumorigenesis. Its role in cancer is complex, encompassing both pro- and anti-tumorigenic activities. Its level of expression and activity are specific to each tumor and patient, increasing the difficulty of understanding the activating or inhibiting roles of AhR ligands. We explored the role of AhR in tumor cell lines and patients using genomic data sets and discuss the extent to which AhR can be considered as a therapeutic target. Keywords: AhR transcription factor; expression; cancer; targeted therapy 1. Introduction The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has multiple critical cellular functions [1]. It belongs to the basic helix-loop-helix/Per-Arnt-Sim Citation: Paris, A.; Tardif, N.; (bHLH/PAS) family and is widely distributed in tissues and among species [2,3]. Evolution Galibert, M.-D.; Corre, S. AhR and of the receptor in the vertebrate branch resulted in its ability to bind to a wide range of Cancer: From Gene Profiling to structurally diverse ligands. Indeed, AhR binds to endogenous (FICZ, kynurenine, etc.) Targeted Therapy. Int. J. Mol. Sci. and exogenous (TCDD, BaP, etc.) low-molecular-weight planar ligands that can exhibit 2021, 22, 752. https://doi.org/ tissue-specific agonist or antagonist activities [4,5]. In the absence of a ligand, AhR makes 10.3390/ijms22020752 up part of a cytosolic multiprotein complex, consisting of c-Src kinase, Hsp90, and the Received: 6 November 2020 chaperones p23 and XAP2 [6,7]. Binding of a ligand to AhR induces conformational Accepted: 8 January 2021 changes, leading to dissociation of the protein complex and nuclear translocation of AhR. Published: 13 January 2021 In the nucleus, AhR dimerizes with its partner protein AhR nuclear translocator (ARNT) and binds to xenobiotic-responsive elements (XREs) in the regulatory region of target genes, Publisher’s Note: MDPI stays neu- inducing their transcription [8,9]. tral with regard to jurisdictional clai- Since the early 90s, AhR has been defined as an essential environmental sensor that ms in published maps and institutio- enables the activation or inhibition of cellular pathways in response to a broad spectrum of nal affiliations. ligands in a cell-type- and context-specific manner [1,10]. More recently, its role in cancer development has been demonstrated, in which it can either act as a positive or negative regulator of carcinogenesis. Here, we summarize the role of AhR in cancer mechanisms, based on previous studies Copyright: © 2021 by the authors. Li- and the analysis of a set of genetic and genomic databases. Then, we discuss the conditions censee MDPI, Basel, Switzerland. required to consider AhR as a therapeutic target. This article is an open access article distributed under the terms and con- 2. Results ditions of the Creative Commons At- 2.1. AhR Mutations, Level of Expression, and Activation in Cancer tribution (CC BY) license (https:// creativecommons.org/licenses/by/ We explored the genetic landscape of AhR alterations in cancer by interrogating 4.0/). available genomic data (TCGA, Sanger, Broad, etc.) searchable on the cBioPortal for cancer Int. J. Mol. Sci. 2021, 22, 752. https://doi.org/10.3390/ijms22020752 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 22 Int. J. Mol. Sci. 2021, 22, 752 2. Results 2 of 22 2.1. AhR Mutations, Level of Expression, and Activation in Cancer We explored the genetic landscape of AhR alterations in cancer by interrogating genomicsavailable genomic online platform data (TCGA, (http://www.cbioportal.org Sanger, Broad, etc.) searchable)[11 on]. Wethe cBioPortal recovered for only cancer a very smallgenomics proportion online ofplatform amplifications, (http://www.cbiopo mutations, orrtal.org) deletions [11]. of theWe AhRrecoveredgene(Figure only a1 A,very top). Onlysmall one proportion somatic of point amplifications, mutation was mutations, identified or withdeletions a high of frequencythe AhR gene inbladder (Figure cancer.1A, top). Only one somatic point mutation was identified with a high frequency in bladder This mutation (Q383H), located downstream of the PAS-B domain (ligand-binding domain), cancer. This mutation (Q383H), located downstream of the PAS-B domain (ligand-binding has not yet been functionally characterized (Figure1A, bottom). Despite the absence of domain), has not yet been functionally characterized (Figure 1A, bottom). Despite the ab- recurrent genetic abnormalities in cancer, the level of AhR mRNA is elevated in almost sence of recurrent genetic abnormalities in cancer, the level of AhR mRNA is elevated in 70% of various tumor types relative to healthy tissue (Figure1B). Indeed, AhR mRNA almost 70% of various tumor types relative to healthy tissue (Figure 1B). Indeed, AhR is overexpressed in breast cancer [12,13], lung cancer [14], thyroid cancer [15], and oral mRNA is overexpressed in breast cancer [12,13], lung cancer [14], thyroid cancer [15], and squamous cell carcinoma (OSCC) [16]. A high level of AhR protein has also been reported oral squamous cell carcinoma (OSCC) [16]. A high level of AhR protein has also been re- inported pancreatic in pancreatic cancer [17 cancer], endometrial [17], endometria cancer [l18 cancer], and [18], meningioma and meningioma [19]. Median [19]. expressionMedian ofexpressionAhR appears of AhR elevated appears from elevated stage from I, independently stage I, independently of the tumor of the type, tumor suggesting type, sug- that thisgesting increased that this expression increased is expression an early event is an inearly many event cancer in many(Figure cancer1C). (FigureAccordingly, 1C). Ac-AhR expressioncordingly, AhR was expression shown to bewas associated shown to be with associat a poored prognosiswith a poor in prognosis glioma [in20 ].glioma On the contrary,[20]. On theAhR contrary,expression AhR expression was significantly was significantly lower in lower primary in primary peripheral peripheral blood blood chronic myeloidchronic leukemiamyeloid leukemia (CML) cells (CML) than cells in healthy than in controls healthy supportingcontrols supporting the notion the of notion cell specific of functionscell specific of AhRfunctions [21]. of AhR [21]. FigureFigure 1. Status1. Status of of the the aryl aryl hydrocarbon hydrocarbon receptorreceptor (AhR) transcr transcriptioniption factor factor status status in in cancer. cancer. (A ()A The) The frequency frequency of alteration of alteration (top) and mutational status (bottom) of the AhR transcription factor was analyzed in all genetic and genomic data from (top) and mutational status (bottom) of the AhR transcription factor was analyzed in all genetic and genomic data from patients or cancer cell lines from the cBioPortal for cancer genomics (http://www.cbioportal.org). AhR genetic alteration patientsinclude or mutation, cancer cell amplification lines from theand cBioPortal deep deletion. for cancer(B) Analysis genomics of AhR (http://www.cbioportal.org expression in all cancers from). the AhR TCGA genetic compared alteration include mutation, amplification and deep deletion. (B) Analysis of AhR expression in all cancers from the TCGA compared to that in normal tissue using GEPIA 2 (Gene Expression Profiling Interactive Analysis, http://gepia2.cancer-pku.cn). (C) Analysis of AhR expression according to the staging of tumors described in 1B. In addition to the overexpression of AhR mRNA and protein, the activity of the re- ceptor has been found to be significantly elevated in various types of cancer. For example, Int. J. Mol. Sci. 2021, 22, 752 3 of 22 both elevated AhR expression and activity have been observed in papillary thyroid carci- noma (PTC) [22], primary breast cancer [23], and cutaneous squamous-cell carcinoma [24]. Moreover, nuclear localization of AhR has been associated with a worse outcome for pa- tients with high-grade anaplastic meningioma [19] or ovarian cancer [25]. In this context, Kolluri et al. widely described the role of various AhR ligands in the phenotypic control of cancer cells and tumor development [26]. Overall, it is difficult to establish a clear relationship between AhR ligands and their role in controlling proliferation, migration, and tumor cell invasion. Indeed, it appears that the consequences on tumor progression are completely different depending on the tumor type, the function of the ligand (AhR agonist or antagonist), and the cellular and protein context. Bian et al. showed that ITE (2-(1’H- indole-3’-carbonyl)-thiazole-4-carboxylic acid methyl ester), an endogenous AhR ligand, suppresses endometrial cancer cell proliferation
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