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Safe, S.;  Zhang, L. Aryl Hydrocarbon Receptor in Breast Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/37695 (accessed on 17 June 2024).
Safe S,  Zhang L. Aryl Hydrocarbon Receptor in Breast Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/37695. Accessed June 17, 2024.
Safe, Stephen, Lei Zhang. "Aryl Hydrocarbon Receptor in Breast Cancer" Encyclopedia, https://encyclopedia.pub/entry/37695 (accessed June 17, 2024).
Safe, S., & Zhang, L. (2022, December 01). Aryl Hydrocarbon Receptor in Breast Cancer. In Encyclopedia. https://encyclopedia.pub/entry/37695
Safe, Stephen and Lei Zhang. "Aryl Hydrocarbon Receptor in Breast Cancer." Encyclopedia. Web. 01 December, 2022.
Aryl Hydrocarbon Receptor in Breast Cancer
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The aryl hydrocarbon receptor (AhR) is expressed in breast cancer cells and tumors and in some studies, the AhR is a negative prognostic factor for patient survival. Structurally diverse AhR ligands have been extensively investigated as anticancer agents in breast cancer cells and tumors and show efficacy in both estrogen receptor (ER)-positive and ER -negative breast cancer cells. Moreover, synthetic AhR ligands are being developed and have been in clinical trials for treating breast cancer.

AhR breast cancer agonist ligand

1. Introduction

The aryl hydrocarbon receptor (AhR) is a basic helix-loop-helix protein that binds the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with high affinity and mediates the toxic and biologic effects induced by this compound and structurally-related halogenated aromatics [1][2][3][4][5]. The classical mechanism of AhR-mediated gene expression and functions involves the ligand-dependent formation of the AhR and the AhR nuclear translocator (ARNT) protein as a heterodimer, which in turn binds cognate cis elements in target gene promoters [6]. The cis elements or xenobiotic response elements (XREs) contain a core GCGTG pentanucleotide sequence and variable flanking nucleotides [6][7][8]. This classical mechanism of action of the AHR:ARNT complex which targets sequence-specific cis-elements is similar to that described for many members of the nuclear receptor (NR) superfamily of intracellular receptors such as estrogen receptors (ERs, ESR1) [9][10][11].
Among all intracellular receptors, the AhR is the only receptor identified in molecular toxicology studies focused on determining the mechanism of action of TCDD and structurally related compounds [1][2]. The discovery of the AhR as a “toxicant” receptor has subsequently been a significant hindrance in development and clinical applications of AhR ligands for the treatment of multiple diseases. Overcoming the concerns regarding the potential toxicity of AhR ligands was due to several factors, including the development of AhR knockout (AhRKO) mouse models [12][13][14] and discoveries showing that many AhR ligands are “health promoting” compounds [15][16][17][18][19]. Differences in AhR ligand persistence may be related to their dioxin-like toxicities. The role of the AhR and its ligands as inhibitors of breast cancer in cellular and in vivo models will be investigated. Several studies support a role for AhR ligands as inhibitors of breast cancer and this includes some studies in this laboratory on TCDD and related compounds as antiestrogens associated with ligand-dependent inhibitory AhR-ERα crosstalk [20][21][22]. There is extensive support from cell culture and in vivo studies indicating that the AhR is a target for breast cancer therapy [23] and human clinical trials using the AhR ligand “aminoflavone” have been carried out for treating breast and other cancers [24][25][26][27]. Moreover, studies from several laboratories show that many structural classes of AhR ligands also inhibit some aspects of mammary carcinogenesis [23]. In contrast, there are also reports showing that AhR ligands enhance breast cancer growth and development [28][29][30][31] and there are other examples of AhR/AhR ligands exhibiting both tumor suppressive and tumor promoter-like activities for specific cancers [32][33][34][35][36].

2. Selective AhR Modulators (SAhRMs)

Initial studies on the AhR and the steroid hormone NRs identified exogenous (e.g.,: TCDD) or endogenous (e.g., steroid hormones) ligands that act primarily as receptor agonists. However, for the AhR and other nuclear receptors, it was soon recognized that many different structural classes of ligands also bound the receptor and could act as tissue/cell-and even gene specific agonists, antagonists or partial agonists/antagonists. For example, the AhR binds structurally diverse industrial and synthetic compounds, PAHs, pharmaceuticals, mycotoxins, multiple classes of health promoting phytochemicals including flavonoids, polyphenolics, heteroaromatics such as indole-3-carbinol (I3C), microbial metabolites, and 1,4-dihyroxy-2-naphthoic acid (DHNA) [15][16][17][18][19] (Figure 1 and Figure 2). In addition, some endogenous compounds, including 6-formyl (3,2-b) carbazole (FICZ), 2-(1′-H-indole-3-carbonyl) thiazole-4-carboxylic acid methyl ester (ITE), tryptophan metabolites such as kynurenine and other gut microbial products, and leukotrienes may play a role as endogenous ligands for the AhR [37][38][39][40][41][42].
Figure 1. The structures of AhR ligands that inhibit DMBA-induced mammary cancer growth in female Sprague Dawley rats [43][44][45][46][47][48] using the Huggins model [49].
Figure 2. The structures of synthetic compounds, including pharmaceuticals that are AhR ligands.
The selectivity of AhR ligands in terms of their tissue-specific agonist or antagonist activity has been reported in breast and other cancer cell lines and also has been recently reviewed [15]. It is striking that the RNAseq analysis of TCDD and related toxicants are highly variable with respect to their differentially expressed genes. A landmark study of 596 drug-related compounds identified a sub-set of 147 compounds that were evaluated in several Ah-responsive assays, including receptor binding, reporter gene activation and CYP1A1 gene expression [50]. They observed multiple differences among these pharmaceutical compounds to activate putative Ah-responsive endpoints. For example, 59% (81/137) of the compounds induced hepatic CYP1A1 mRNA in mice but did not bind or activate the AhR in vitro. Only nine of these compounds exhibited both in vitro and in vivo activity as AhR agonists in the complete panel of assays which included cytochrome P450 induction in mouse cancer cell lines and liver (in vivo). The selectivity of these AhR-active pharmaceuticals has been further investigated in the laboratory in breast and pancreatic cancer cells [51][52][53].
The pharmaceutical-derived AhR agonists identified in the screening study [51], including flutamide, leflunomide, mexiletine hydrochloride, nimodipine, omeprazole, sulindac and tranilast were investigated in breast cancer cells. Their activity as inducers of CYP1A1 and CYP1B1 in MDA-MB-468 and BT474 breast cancer cells was structure, response and cell type-specific. Compared to TCDD, induction of CYP1A1 was more robust in BT474 than MDA-MB-468 cells, whereas for most of these compounds the reverse was true for the induction of CYP1B1. 4-Hydroxytamoxifen induced minimal (<25% of maximal induction observed for 10 nM TCDD) CYP1A1 and CYP1B1 expression in both cell lines and with the exception of induction of CYP1B1 (50% of maximal induction observed for 10 nM TCDD), tranilast was also a weak inducer of CYP1A1 and CYP1B1 [51]. The pattern of CYP1A1/CYP1B1 induction in MDA-MB-231 cells also differed from that observed in MDA-MB-468 and BT474 cells. The selectivity was also observed for the effects of these pharmaceuticals on the invasion (Boyden chamber) of MDA-MB-231 cells. TCDD (minimal), omeprazole and tranilast inhibited invasion at sub-toxic concentrations, whereas no effects were observed for 4-hydroxytamoxifen, flutamide, leflunomide, mexiletine, nimodipine, and sulindac [52]. Using omeprazole as a model, it was also shown that inhibition of MDA-MB-231 cell invasion by omeprazole was reversed by AhR antagonists and AhR knockdown (siAhR) and inhibition of invasion was primarily due to AhR-dependent downregulation of CXCR4, which was observed both in vitro and in vivo [52]. These highly variable ligand-dependent results in breast cancer cells were observed for pharmaceuticals that were all AhR-active in liver and liver cancer cells, demonstrating that these compounds are SAhRMs. Moreover, there is evidence for SAhRM-like activity for many other structural classes of AhR ligands [15][16].

3. AhR in Breast Cancer: Prognostic Significance

There are multiple genes/gene products expressed in breast cancer and other tumors that can predict overall survival or recurrence of disease and they also may be useful for selecting appropriate treatment regimens [54]. These markers, which include receptors, may or may not be indicative of their functional activity or predict effects of therapeutic regimens. There were some differences in the nuclear and extranuclear distribution of AhR protein in non-pathological breast ductal epithelial cells and invasive ductal carcinoma and AhR overexpression was associated with better prognosis of ER-negative and ER-positive invasive ductal carcinoma patients [55]. In another study on 436 breast cancer cases, it was concluded “that AhR expression is not a prognostic factor in breast cancer” [56]. There were correlations between AhR, and levels of several genes associated with inflammation and high levels of AhR repressor (AhRR) mRNA which predicted enhanced patient survival. This might suggest that since AhRR inhibits AhR function due to competition for ARNT, then high AhR levels would be negative prognostic factors; however, this was not observed in a prospective study of 1116 patients where correlations between multiple prognostic factors and their combination with AhR expression were evaluated for their prognostic value. Low cytosolic AhR levels and positive aromatase were associated with more aggressive ER negative (ER-) tumors; however, AhR tumor genotypes did not correlate with AhR protein levels [57]. Another report indicated that the predictive value of the AhR was dependent on the lymph node status of the patient and concluded “that AhR is a marker of poor prognosis for patients with LN-negative luminal-like BCs” [58]. The results suggest that the prognostic value of AhR levels (mRNA and protein), intracellular location and AhR polymorphisms with respect to patient survival/disease recurrence is complex and dependent on many other factors, including prior patient treatment protocols [55][56][57][58].

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