The Aryl Hydrocarbon Receptor: A Target for Breast Cancer Therapy

Powell, Joann B.; Goode, Gennifer D.; Eltom, Sakina E.

doi:10.4236/jct.2013.47137

Cited by 47 publications

(35 citation statements)

References 73 publications

(72 reference statements)

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“…In addition, a highly significant correlation between the AhR expression and invasive breast carcinoma was reported [41]. Recent studies have demonstrated that activation of AhR dramatically increased CSCs development and characteristics [21, 42].…”

Section: Discussionmentioning

confidence: 99%

Aryl hydrocarbon receptor/cytochrome P450 1A1 pathway mediates breast cancer stem cells expansion through PTEN inhibition and β-Catenin and Akt activation

2017

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BackgroundBreast cancer stem cells (CSCs) are small sub-type of the whole cancer cells that drive tumor initiation, progression and metastasis. Recent studies have demonstrated a role for the aryl hydrocarbon receptor (AhR)/cytochrome P4501A1 pathway in CSCs expansion. However, the exact molecular mechanisms remain unclear.MethodsThe current study was designed to a) determine the effect of AhR activation and inhibition on breast CSCs development, maintenance, self-renewal, and chemoresistance at the in vitro and in vivo levels and b) explore the role of β-Catenin, PI3K/Akt, and PTEN signaling pathways. To test this hypothesis, CSC characteristics of five human breast cancer cells; SKBR-3, MCF-7, and MDA-MB231, HS587T, and T47D treated with AhR activators or inhibitor were determined using Aldefluor assay, side population, and mammosphere formation. The mRNA, protein expression, cellular content and localization of the target genes were determined by RT-PCR, Western blot analysis, and Immunofluorescence, respectively. At the in vivo level, female Balb/c mice were treated with AhR/CYP1A1 inducer and histopathology changes and Immunohistochemistry examination for target proteins were determined.ResultsThe constitutive mRNA expression and cellular content of CYP1A1 and CYP1B1, AhR-regulated genes, were markedly higher in CSCs more than differentiating non-CSCs of five different human breast cancer cells. Activation of AhR/CYP1A1 in MCF-7 cells by TCDD and DMBA, strong AhR activators, significantly increased CSC-specific markers, mammosphere formation, aldehyde dehydrogenase (ALDH) activity, and percentage of side population (SP) cells, whereas inactivation of AhR/CYP1A1 using chemical inhibitor, α-naphthoflavone (α-NF), or by genetic shRNA knockdown, significantly inhibited the upregulation of ALDH activity and SP cells. Importantly, inactivation of the AhR/CYP1A1 significantly increased sensitization of CSCs to the chemotherapeutic agent doxorubicin. Mechanistically, Induction of AhR/CYP1A1 by TCDD and DMBA was associated with significant increase in β-Catenin mRNA and protein expression, nuclear translocation and its downstream target Cyclin D1, whereas AhR or CYP1A1 knockdown using shRNA dramatically inhibited β-Catenin cellular content and nuclear translocation. This was associated with significant inhibition of PTEN and induction of total and phosphorylated Akt protein expressions. Importantly, inhibition of PI3K/Akt pathway by LY294002 completely blocked the TCDD-induced SP cells expansion. In vivo, IHC staining of mammary gland structures of untreated and DMBA (30 mg/kg, IP)- treated mice, showed tremendous inhibition of PTEN expression accompanied with an increase in the expression p-Akt, β-Catenin and stem cells marker ALDH1.ConclusionsThe present study provides the first evidence that AhR/CYP1A1 signaling pathway is controlling breast CSCs proliferation, development, self-renewal and chemoresistance through inhibition of the PTEN and activation of β-Catenin and Akt pathways.

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Section: Discussionmentioning

confidence: 99%

Aryl hydrocarbon receptor/cytochrome P450 1A1 pathway mediates breast cancer stem cells expansion through PTEN inhibition and β-Catenin and Akt activation

2017

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“…The AhR has been previously described in the initiation and progression of breast cancer (Nebert et al, 2004;Schlezinger et al, 2006;Vinothini and Nagini, 2010;Powell et al, 2013;Go et al, 2015). The metabolism of environmental toxins by the AhR leads credence to the proposal that the initial insult that caused the breast cancer was a fat-soluble xenobiotic element that was metabolized to a DNA-damaging compound.…”

Section: Discussionmentioning

confidence: 86%

(Z)-2-(3,4-Dichlorophenyl)-3-(1H-Pyrrol-2-yl)Acrylonitrile Exhibits Selective Antitumor Activity in Breast Cancer Cell Lines via the Aryl Hydrocarbon Receptor Pathway

et al. 2017

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We have previously reported the synthesis and breast cancer selectivity of ()-2-(3,4-dichlorophenyl)-3-(1-pyrrol-2-yl)acrylonitrile (ANI-7) in cancer cell lines. To further evaluate the selectivity of ANI-7, we have expanded upon the initial cell line panel to now include the breast cancer cell lines (MCF7, MCF7/VP16, BT474, T47D, ZR-75-1, SKBR3, MDA-MB-468, BT20, MDA-MB-231); normal breast cells (MCF-10A); and cell lines derived from colon (HT29), ovarian (A2780), lung (H460), skin (A431), neuronal (BE2C), glial (U87, SJG2), and pancreatic (MIA) cancers. We now show that ANI-7 is up to 263-fold more potent at inhibiting the growth of breast cancer cell lines (MCF7, MCF7/VP16, BT474, T47D, ZR-75-1, SKBR3, MDA-MB-468) than normal breast cells (MCF-10A) or cell lines derived from other tumor types. Measures of growth inhibition, cell cycle analysis, morphologic assessment, Western blotting, receptor binding, gene expression, small interfering RNA technology, reporter activity, and enzyme inhibition assays were exploited to define the mechanism of action of ANI-7. In this work, we report that ANI-7 mediates its effects via the activation of the aryl hydrocarbon receptor (AhR) pathway and the subsequent induction of CYP1-metabolizing mono-oxygenases. The metabolic conversion of ANI-7 induces DNA damage, checkpoint activation, S-phase cell cycle arrest, and cell death in sensitive breast cancer cell lines. Basal expression of AhR, the AhR nuclear translocator, and the CYP1 family members do not predict for sensitivity; however, inherent expression of the phase II-metabolizing enzyme sulfur transferase 1A1 does. For the first time, we identify ()-2-(3,4-dichlorophenyl)-3-(1-pyrrol-2-yl)acrylonitrile as a new AhR ligand.

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“…A recent reduction in mortality rates, in the face of increased diagnoses, has been attributed to advances in early identification and treatment . Despite this reduction in mortality, the treatment of many types of breast cancer is complex and difficult . Ongoing improvements in the long‐term treatment and survival of women with breast cancer is further complicated by disease relapse and drug resistance …”

Section: Breast Cancer Backgroundmentioning

confidence: 99%

“…The aryl hydrocarbon receptor (AhR) is a member of the basic helix‐loop‐helix/Per‐ARNT‐SIM (bHLH/PAS) transcription factor family, and it has been previously suggested that it is a possible druggable target . It is ligand activated by a variety of synthetic and natural compounds .…”

Section: Aryl Hydrocarbon Receptormentioning

confidence: 99%

The aryl hydrocarbon receptor (AhR) as a breast cancer drug target

Baker

Sakoff

McCluskey

2019

Medicinal Research Reviews

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Breast cancer is the most common cancer in women, with more than 1.7 million diagnoses worldwide per annum. Metastatic breast cancer remains incurable, and the presence of triplenegative phenotypes makes targeted treatment impossible. The aryl hydrocarbon receptor (AhR), most commonly associated with the metabolism of xenobiotic ligands, has emerged as a promising biological target for the treatment of this deadly disease. Ligands for the AhR can be classed as exogenous or endogenous and may have agonistic or antagonistic activity. It has been well reported that agonistic ligands may have potent and selective growth inhibition activity in a number of oncogenic cell lines, and one (aminoflavone) has progressed to phase I clinical trials for breast cancer sufferers. In this study, we examine the current state of the literature in this area and elucidate the promising advances that are being made in hijacking the cytosolic-to-nuclear pathway of the AhR for the possible future treatment of breast cancer. K E Y W O R D S aryl hydrocarbon receptor, breast cancer, cancer drugs Abbreviations: 3MC, 3-methylcholanthrene; AF, aminoflavone; AF-1, activation function domain 1; AF-2, activation function domain 2; AhR, aryl hydrocarbon receptor; AhRR, aryl hydrocarbon receptor repressor; AIP, aryl hydrocarbon receptor-interacting protein; ANI-7, (Z)-2-(3,4-dichlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile; ARNT, aryl hydrocarbon receptor nuclear translocator; BaP, benzo[a]pyrene; BE, botanical estrogen; bHLH, basic helixloop-helix; βNF, β-naphthoflavone; BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; DNF, dinaphtho[1,2-b;1′2'-d] furan; ER, estrogen receptor; FDA, US Food and Drug Administration; FICZ, 6-formylindolo[3,2-b]carbazole; HAHs, halogenated aromatic hydrocarbons; HER-2, human epidermal growth factor receptor 2; HR, hormone receptor; Hsp90, heat shock protein 90; ITE, 2-(1′H-indole-3′-carbonyl)-thiazole-4carboxylic acid ester; LBD, ligand-binding domain; NLS, nuclear localization sequences; NSAID, nonsteroidal anti-inflammatory drug; p23, prostaglandin E synthase 3; PAHs, polycyclic aromatic hydrocarbons; PAS, period-aryl hydrocarbon receptor nuclear translocator-single minded; PAS-A, period-aryl hydrocarbon receptor nuclear translocator-single minded domain A; PAS-B, period-aryl hydrocarbon receptor nuclear translocator-single minded domain B; PCB, 3,3′,4,4′,5-pentachlorobiphenyl; PPI, proton pump inhibitor; PR, progesterone receptor; PR-A, progesterone receptor form A; PR-B, progesterone receptor form B; PR-C, progesterone receptor form C; ROS, reductive oxidative species; SERMs, selective estrogen receptor modulators; SULT1A1, sulfotransferase 1A1; TAD, transactivation domain; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDF, 2,3,7,8-tetrachlorodibenzofuran; TNBC, triplenegative breast cancer; Tregs, regulatory T cells; XAP-2, hepatitis B virus X-associated protein 2; XRE, xenobiotic response element. | BREAST CANCER BACKGROUNDBreast cancer is the most common cancer in women. Of...

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The Aryl Hydrocarbon Receptor: A Target for Breast Cancer Therapy

Cited by 47 publications

References 73 publications

Aryl hydrocarbon receptor/cytochrome P450 1A1 pathway mediates breast cancer stem cells expansion through PTEN inhibition and β-Catenin and Akt activation

Aryl hydrocarbon receptor/cytochrome P450 1A1 pathway mediates breast cancer stem cells expansion through PTEN inhibition and β-Catenin and Akt activation

(Z)-2-(3,4-Dichlorophenyl)-3-(1H-Pyrrol-2-yl)Acrylonitrile Exhibits Selective Antitumor Activity in Breast Cancer Cell Lines via the Aryl Hydrocarbon Receptor Pathway

The aryl hydrocarbon receptor (AhR) as a breast cancer drug target

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