Aryl Hydrocarbon Receptor Agonists Induce MicroRNA-335 Expression and Inhibit Lung Metastasis of Estrogen Receptor Negative Breast Cancer Cells

Zhang, Shu; Kim, Kyounghyun; Jin, Un-Ho; Pfent, Catherine; Cao, Huojun; Amendt, Brad A.; Liu, Xinyi; Wilson-Robles, Heather; Safe, Stephen

doi:10.1158/1535-7163.mct-11-0548

Cited by 91 publications

(71 citation statements)

References 46 publications

(44 reference statements)

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“…Previous functional studies with TCDD and MCDF in breast cancer cells showed that both compounds inhibit cell migration in a Boyden chamber assay (Zhang et al, 2012). Figure 6A illustrates the effects of TCDD and the pharmaceutical AHR ligands on this response in MDA-MB-468 cells.…”

Section: Resultsmentioning

confidence: 91%

“…A ChIP assay was used to compare TCDD-induced recruitment of the AHR to the proximal CYP1A1-DRE promoter (Zhang et al, 2012) with that observed for 4-hydroxytamoxifen (Fig. 5A), mexiletine (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous studies demonstrated the effectiveness of AHR agonists for inhibiting ER-positive and ER-negative mammary tumor growth or metastasis, respectively (McDougal et al, 2001;Zhang et al, 2009Zhang et al, , 2012. The effects of AHR agonists in ER-negative breast cancer cells were intriguing because both TCDD and the SAhRM MCDF inhibited tumor cell migration and invasion in vitro and MCDF inhibited lung metastasis in a mouse model administered MDA-MB-231 cells by tail vein injection (Zhang et al, 2012).…”

Section: Discussionmentioning

confidence: 98%

“…The AHR is a ligand-activated receptor that not only plays a role in mediating the toxicity of TCDD and related compounds but is also a potential target for the treatment of several diseases including autoimmune diseases, various inflammatory conditions, and cancer (McDougal et al, 2001;Quintana et al, 2008Quintana et al, , 2010Zhang et al, 2009Zhang et al, , 2012DiNatale et al, 2010bDiNatale et al, , 2011Murray et al, 2010;O'Donnell et al, 2010;Kiss et al, 2011;Li et al, 2011;Opitz et al, 2011;Singh et al, 2011). Depending on the tissue or cell, AHR agonists or antagonists may be required, and there is also evidence that the effects of various AHR-active compounds are structure-dependent.…”

Section: Discussionmentioning

confidence: 99%

“…However, MCDF did not inhibit TCDD-induced antiestrogenic effects in the rodent uterus or human breast cancer cells but acted as an AHR agonist (Astroff and Safe, 1991;Zacharewski et al, 1992), and subsequent studies showed that MCDF also inhibited ERpositive and ER-negative breast cancer cell and tumor growth (McDougal et al, 2001;Zhang et al, 2009Zhang et al, , 2012. Thus, MCDF was one of the first compounds characterized as a selective AHR modulator (SAhRM) that exhibits tissue-selective AHR agonist or antagonist activities (Astroff and Safe, 1991;Zacharewski et al, 1992;McDougal et al, 2001;Zhang et al, 2009Zhang et al, , 2012, and several other AHR antagonists and SAhRMs have been identified (Boitano et al, 2010;Murray et al, 2010Murray et al, , 2011Zhao et al, 2010;Smith et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Aryl Hydrocarbon Receptor (AHR)-Active Pharmaceuticals Are Selective AHR Modulators in MDA-MB-468 and BT474 Breast Cancer Cells

Jin

Lee

Safe

2012

J Pharmacol Exp Ther

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105

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Leflunomide, flutamide, nimodipine, mexiletine, sulindac, tranilast, 4-hydroxytamoxifen, and omeprazole are pharmaceuticals previously characterized as aryl hydrocarbon receptor (AHR) agonists in various cell lines and animal models. In this study, the eight AHR-active pharmaceuticals were investigated in highly aggressive aryl hydrocarbon (Ah)-responsive BT474 and MDA-MB-468 breast cancer cell lines, and their effects on AHR protein, CYP1A1 (protein and mRNA), CYP1B1 (mRNA), and cell migration were determined. 2,3,7,8-Tetrachlorodibenzo-pdioxin (TCDD) was used as a positive control. The AHR agonist activities of the pharmaceuticals depended on structure, response, and cell context. Most compounds induced one or more AHR-mediated responses in BT474 cells, whereas in Ah-responsive MDA-MB-468 cells effects of the AHR-active pharmaceuticals were highly variable. 4-Hydroxytamoxifen, mexiletine, and tranilast did not induce CYP1A1 in MDA-MB-468 cells; moreover, in combination with TCDD, mexiletine was a potent AHR antagonist, tranilast was a partial antagonist, and 4-hydroxytamoxifen also exhibited some AHR antagonist activity. Omeprazole and, to a lesser extent, sulindac and leflunomide were full and partial AHR agonists, respectively, in both breast cancer cell lines. These data indicate that the AHRactive pharmaceuticals are selective AHR modulators, and applications of these drugs for targeting the AHR must be confirmed by studies using the most relevant cell context.

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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Aryl Hydrocarbon Receptor (AHR)-Active Pharmaceuticals Are Selective AHR Modulators in MDA-MB-468 and BT474 Breast Cancer Cells

Jin

Lee

Safe

2012

J Pharmacol Exp Ther

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105

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Invasion and migration of MDA‐MB‐231 cells are inhibited by block of AhR and NFAT: role of AhR/NFAT1/β4 integrin signaling

Shadboorestan

Tarfiei

Montazeri

et al. 2018

J of Applied Toxicology

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Benzo[α]pyrene (BaP) can have significant role in the development of breast cancer via aryl hydrocarbon receptor (AhR) activation. AhR activation has been studied in several functions such as survival, migration and invasion of cancer cells. In cancer, integrins contribute to the migration/invasion process and are regulated by nuclear factor of activated T cells (NFAT) and transforming growth factor (TGF) beta pathways. The aim of the present study was to examine the effect of BaP, an activator of AhR and cyclosporine A (CsA), as inhibitor of NFAT on migration and invasion of MDA‐MB‐231 cells. Furthermore, the effects of BaP and CsA were evaluated regarding the crosstalk of AhR, NFAT1 and TGF‐β receptor 1 signaling. Treatment of MDA‐MB‐231 with BaP resulted in significantly more live cells in low doses; however, blocking NFAT with CsA decreased the viability of the cells. Activation of AhR by BaP induced invasion as well as migration in MDA‐MB‐231 cells, which was blocked by AhR antagonist. Unlike BaP, block of NFAT with CsA inhibited cell migration and cell invasion. In these cells, BaP significantly reduced AhR expression while this reduction was reversed by CH‐223191; however, CsA treatment lowered the AhR expression only at low dose. The level of β4 integrin was significantly reduced by CsA at 1 and 2.5 μm. Protein levels of Snail and TGF‐β receptor 1 were not significantly altered by BaP and CsA treatments. Considering these findings, the low AhR expression and high β4 integrin level following BaP and/or CsA treatments may contribute to the higher invasion/migration in MDA‐MB‐231 cells.

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Betulinic acid decreases ER‐negative breast cancer cell growth in vitro and in vivo: Role of Sp transcription factors and microRNA‐27a:ZBTB10

Mertens‐Talcott¹,

Noratto²,

Li³

et al. 2012

Molecular Carcinogenesis

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Betulinic acid (BA), a pentacyclic triterpenoid isolated from tree bark is cytotoxic to cancer cells. There is evidence that specificity proteins (Sps), such as Sp1, Sp3 and Sp4, are overexpressed in tumors and contribute to the proliferative and angiogenic phenotype associated with cancer cells. The objective of this study was to determine the efficacy of BA in decreasing the Sps expression and underlying mechanisms. Results show that BA decreased proliferation and induced apoptosis of estrogen-receptor-negative breast cancer MDA-MB-231 cells. The BA-induced Sp1, Sp3, and Sp4 downregulation was accompanied by increased zinc finger ZBTB10 expression, a putative Sp-repressor (ZBTB10) and decreased microRNA-27a levels, a microRNA involved in the regulation of ZBTB10. Similar results were observed in MDA-MB-231 cells transfected with ZBTB10 expression plasmid. BA induced cell cycle arrest in the G2/M phase and increased Myt-1 mRNA (a microRNA-27a target gene), which causes inhibition in G2/M by phosphorylation of cdc2. The effects of BA were reversed by transient transfection with a mimic of microRNA-27a. In nude mice with xenografted MDA-MB-231 cells, tumor size and weight were significantly decreased by BA treatment. In tumor tissue, ZBTB10 mRNA was increased while mRNA and protein of Sp1, Sp3 and Sp4, as well as mRNA of vascular endothelial growth factor receptor (VEGFR), survivin and microRNA-27a were decreased by BA. In lungs of xenografted mice, human β2-microglobulin mRNA was decreased in BA-treated animals. These results show that the anti-cancer effects of BA are at least in part based on interactions with the microRNA-27a-ZBTB10-Sp1-axis causing increased cell death.

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Aryl Hydrocarbon Receptor Agonists Induce MicroRNA-335 Expression and Inhibit Lung Metastasis of Estrogen Receptor Negative Breast Cancer Cells

Cited by 91 publications

References 46 publications

Aryl Hydrocarbon Receptor (AHR)-Active Pharmaceuticals Are Selective AHR Modulators in MDA-MB-468 and BT474 Breast Cancer Cells

Aryl Hydrocarbon Receptor (AHR)-Active Pharmaceuticals Are Selective AHR Modulators in MDA-MB-468 and BT474 Breast Cancer Cells

Invasion and migration of MDA‐MB‐231 cells are inhibited by block of AhR and NFAT: role of AhR/NFAT1/β4 integrin signaling

Betulinic acid decreases ER‐negative breast cancer cell growth in vitro and in vivo: Role of Sp transcription factors and microRNA‐27a:ZBTB10

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