The Role of Aryl Hydrocarbon Receptor and Crosstalk with Estrogen Receptor in Response of Breast Cancer Cells to the Novel Antitumor Agents Benzothiazoles and Aminoflavone

Callero, Mariana A.; Loaiza-Perez, Andrea

doi:10.4061/2011/923250

Cited by 35 publications

(50 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The AhR-independency of AF sensitivity in MDA-MB-468 and Cal51 is in discrepancy with the finding that MCF7 cells are sensitive to AF while Ah R100 MCF7 cells are AF resistant. Previous studies had shown that Ah R100 cells exhibited diminished AhR protein levels, mRNA levels, and ability to induce AhR target genes, rendering the cell line resistant to AF [8,18,19]. The difference in AF sensitivity with regards to AhR levels and activity could be cell type specific.…”

Section: Discussionmentioning

confidence: 99%

“…Because flavonoid compounds have been shown to bind the intracellular aryl hydrocarbon receptor (AhR) and activate the AhR signaling pathway, one suggestion to explain AF’s activity pattern is metabolic activation by the AhR and its target genes, specifically the 1A isoforms of cytochome P450 (CYP) enzymes [7,8,16,17]. An AhR-deficient clone of MCF7 that was generated by continuous exposure to 100nM benzo [a] pyrene for six to nine months (Ah R100 ) has been shown to be rendered resistant to AF [8,18,19]. Further, previous studies revealed that AF is metabolized by CYP1A1 and, to a lesser extent, 1A2 and 1B1, and that this metabolism produces hydroxylamine species [7,8,17].…”

Section: Introductionmentioning

confidence: 99%

“…In addition to increasing CYP1A1/1A2/1B1 expression, AF induces nuclear translocation of AhR and stimulates protein-DNA complexes formed on DREs in AF-sensitive MCF7 human breast cancer cells, suggesting that AF is an AhR agonist [8]. Further, localization of AhR in the cellular cytoplasm has been shown to correlate with AF sensitivity [8,19]. Interestingly, it has also been shown that AF inhibits hypoxia inducible factor 1α (HIF1α), a protein which may interact with AhR [30].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Estrogen receptor α and aryl hydrocarbon receptor independent growth inhibitory effects of aminoflavone in breast cancer cells

Brinkman

Ersland

et al. 2014

BMC Cancer

View full text Add to dashboard Cite

BackgroundNumerous studies have implicated the aryl hydrocarbon receptor (AhR) as a potential therapeutic target for several human diseases, including estrogen receptor alpha (ERα) positive breast cancer. Aminoflavone (AF), an activator of AhR signaling, is currently undergoing clinical evaluation for the treatment of solid tumors. Of particular interest is the potential treatment of triple negative breast cancers (TNBC), which are typically more aggressive and characterized by poorer outcomes. Here, we examined AF’s effects on two TNBC cell lines and the role of AhR signaling in AF sensitivity in these model cell lines.MethodsAF sensitivity in MDA-MB-468 and Cal51 was examined using cell counting assays to determine growth inhibition (GI50) values. Luciferase assays and qPCR of AhR target genes cytochrome P450 (CYP) 1A1 and 1B1 were used to confirm AF-mediated AhR signaling. The requirement of endogenous levels of AhR and AhR signaling for AF sensitivity was examined in MDA-MB-468 and Cal51 cells stably harboring inducible shRNA for AhR. The mechanism of AF-mediated growth inhibition was explored using flow cytometry for markers of DNA damage and apoptosis, cell cycle analysis, and β-galactosidase staining for senescence. Luciferase data was analyzed using Student’s T test. Three-parameter nonlinear regression was performed for cell counting assays.ResultsHere, we report that ERα-negative TNBC cell lines MDA-MB-468 and Cal51 are sensitive to AF. Further, we presented evidence suggesting that neither endogenous AhR expression levels nor downstream induction of AhR target genes CYP1A1 and CYP1B1 is required for AF-mediated growth inhibition in these cells. Between these two ERα negative cell lines, we showed that the mechanism of AF action differs slightly. Low dose AF mediated DNA damage, S-phase arrest and apoptosis in MDA-MB-468 cells, while it resulted in DNA damage, S-phase arrest and cellular senescence in Cal51 cells.ConclusionsOverall, this work provides evidence against the simplified view of AF sensitivity, and suggests that AF could mediate growth inhibitory effects in ERα-positive and negative breast cancer cells, as well as cells with impaired AhR expression and signaling. While AF could have therapeutic effects on broader subtypes of breast cancer, the mechanism of cytotoxicity is complex, and likely, cell line- and tumor-specific.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Estrogen receptor α and aryl hydrocarbon receptor independent growth inhibitory effects of aminoflavone in breast cancer cells

Brinkman

Ersland

et al. 2014

BMC Cancer

View full text Add to dashboard Cite

show abstract

“…The AhR-mediated regulation of metabolism of polycyclic aromatic hydrocarbons (PAH) has been implicated in a variety of cancers [2], [3]. PAH-induced AhR activation increases the transcription of a variety of genes encoding phase I drug metabolizing enzymes, such as CYP1A1 and CYP1B1, and phase II drug metabolizing enzymes, such as glutathione-S-transferase A1 (GSTA1) and UDP glucuronosyl transferase 1A2 (UGT1A2).…”

Section: Introductionmentioning

confidence: 99%

Depletion of the Aryl Hydrocarbon Receptor in MDA-MB-231 Human Breast Cancer Cells Altered the Expression of Genes in Key Regulatory Pathways of Cancer

2014

View full text Add to dashboard Cite

The aryl hydrocarbon receptor (AhR), a transcription factor that is best known for its role in mediating the toxic responses elicited by poly aromatic hydrocarbons as well as many other environmental factors; is also involved in breast cancer progression. We previously reported that stable knockdown of AhR decreased the tumorigenic properties of the highly metastatic MDA-MB-231 breast cancer cell line; whereas ectopic overexpression of AhR was sufficient to transform immortalized human mammary epithelial cells to exhibit malignant phenotypes. In the present study we investigated the genes that are differentially regulated by AhR and are controlling cellular processes linked to breast cancer. We used Affymetrix Human GeneChip 1.0-ST whole transcriptome arrays to analyze alterations of gene expression resulting from stable AhR knockdown in the MDA-MB-231 breast cancer cell line. The expression of 144 genes was significantly altered with a ≥2.0-fold change and a multiple test corrected p-value ≤0.05, as a result of AhR knockdown. We demonstrate that AhR knockdown alters the expression of several genes known to be linked to cancer. These genes include those involved in tryptophan metabolism (KYNU), cell growth (MUC1 and IL8), cell survival (BIRC3 and BCL3), cell migration and invasion (S100A4 and ABI3), multi-drug resistance (ABCC3) and angiogenesis (VEGFA and CCL2). The identification of the genes and pathways affected by AhR depletion provides new insight into possible molecular events that could explain the reported phenotypic changes. In conclusion AhR knockdown alters the expression of genes known to enhance or inhibit cancer progression; tipping the balance towards a state that counteracts tumor progression.

show abstract

“…Aminoflavone (AF, NSC686288, and AFP464, NSC 710464) is an anti‐tumor agent with proved efficacy in clinical trials for the treatment of ER+ breast cancer patients. This agent presents a unique mechanism of action activating the aryl hydrocarbon receptor (AhR) signaling pathway which has a crosstalk with the ER signaling pathway [Denison and Nagy, ; Callero and Loaiza‐Pérez, ]. In vitro studies have demonstrated that ER+ breast cancer cell lines and renal cancer cell lines are sensitive to AF [Loaiza‐Pérez et al, ,b; Callero et al, ].…”

mentioning

confidence: 99%

The Immune System As a New Possible Cell Target for AFP 464 in a Spontaneous Mammary Cancer Mouse Model

et al. 2017

Self Cite

View full text Add to dashboard Cite

Aminoflavone (AFP 464, NSC 710464), an antitumor agent which recently entered phase II clinical trials, acts against estrogen-positive breast cancer (ER+). AFP 464, which has a unique mechanism of action by activating aryl hydrocarbon receptor (AhR) signaling pathway, decreased tumor size, and growth rate in the estrogen dependent, Tamoxifen-sensitive spontaneous M05 mouse model. Considering that AhR has recently emerged as a physiological regulator of the innate and adaptive immune responses, we investigated whether AFP 464 modulates the immune response in our mouse model. Studies on the effect of AFP 464 on the immune system were carried in BALB/c mice bearing M05 semi-differentiated mammary adenocarcinomas that express estrogen and progesterone receptors. Splenic cells and tumor inflammatory infiltrates were studied by cytometric analyses. The modulation of splenocytes cytotoxic activity by AFP 464 was also evaluated. We further investigated the effects of AFP 464 on peritoneal macrophages by evaluating metalloproteinase, arginase, and iNOS activities. We found that AFP 464 increased splenic cytotoxic activity, diminished the number of systemic and local Treg lymphocytes, and MDSCs, and induced a M1 phenotype in peritoneal macrophages of M05 tumor bearing mice. Therefore, we conclude that AFP 464 modulates immune response which collaborates with its anti-tumor activity. Our results place the immune system as a novel target for this anti-cancer agent to strengthen the rationale for its inclusion in breast cancer treatment regimens. J. Cell. Biochem. 118: 2841-2849, 2017. © 2017 Wiley Periodicals, Inc.

show abstract

The Role of Aryl Hydrocarbon Receptor and Crosstalk with Estrogen Receptor in Response of Breast Cancer Cells to the Novel Antitumor Agents Benzothiazoles and Aminoflavone

Cited by 35 publications

References 30 publications

Estrogen receptor α and aryl hydrocarbon receptor independent growth inhibitory effects of aminoflavone in breast cancer cells

Estrogen receptor α and aryl hydrocarbon receptor independent growth inhibitory effects of aminoflavone in breast cancer cells

Depletion of the Aryl Hydrocarbon Receptor in MDA-MB-231 Human Breast Cancer Cells Altered the Expression of Genes in Key Regulatory Pathways of Cancer

The Immune System As a New Possible Cell Target for AFP 464 in a Spontaneous Mammary Cancer Mouse Model

Contact Info

Product

Resources

About