Activation of the Aryl-Hydrocarbon Receptor Inhibits Invasive and Metastatic Features of Human Breast Cancer Cells and Promotes Breast Cancer Cell Differentiation

Hall, Julie M.; Barhoover, Melissa A.; Kazmin, Dmitri; McDonnell, Donald P.; Greenlee, William F.; Thomas, Russell S.

doi:10.1210/jcem.95.1.9993

Cited by 18 publications

(26 citation statements)

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“…Collectively, the documented role of AHR, including its antiapoptotic effect, would be expected to further increase cell proliferation and survival during tumor progression. Conversely, AHR has been suggested to have a role as a tumor suppressor, which becomes suppressed or defected during the process of tumor formation under certain circumstances (32,33). Although this is a seemingly opposite functional impact on tumorigenesis, AHR is known to On the basis of the cut-off values of fold differences, the study population was dichotomized into the "high" and "low" expression group.…”

Section: Discussionmentioning

confidence: 99%

Intestine-Specific Homeobox Gene ISX Integrates IL6 Signaling, Tryptophan Catabolism, and Immune Suppression

et al. 2017

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The intestine-specific homeobox transcription factor intestine-specific homeobox (ISX) is an IL6-inducible proto-oncogene implicated in the development of hepatocellular carcinoma, but its mechanistic contributions to this process are undefined. In this study, we provide evidence that ISX mediates a positive feedback loop integrating inflammation, tryptophan catabolism, and immune suppression. We found that ISX-mediated IL6-induced expression of the tryptophan catabolic enzymes Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase in hepatocellular carcinoma cells, resulting in an ISX-dependent increase in the tryptophan catabolite kynurenine and its receptor aryl hydrocarbon receptor (AHR). Activation of this kynurenine/AHR signaling axis acted through a positive feedback mechanism to increase ISX expression and enhance cellular proliferation and tumorigenic potential. RNAi-mediated attenuation of ISX or AHR reversed these effects. In an IDO1-dependent manner, ectopic expression of ISX induced expression of genes encoding the critical immune modulators CD86 (B7-2) and programmed death ligand-1 (PD-L1), through which ISX conferred a significant suppressive effect on the CD8 T-cell response. In hepatocellular carcinoma specimens, expression of IDO1, kynurenine, AHR, and PD-L1 correlated negatively with survival. Overall, our results identified a feed-forward mechanism of immune suppression in hepatocellular carcinoma organized by ISX, which involves kynurenine-AHR signaling and PD-L1, offering insights into immune escape by hepatocellular carcinoma, which may improve its therapeutic management. .

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Section: Discussionmentioning

confidence: 99%

Intestine-Specific Homeobox Gene ISX Integrates IL6 Signaling, Tryptophan Catabolism, and Immune Suppression

et al. 2017

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“…Paradoxically, the AhR appears to facilitate growth in the absence of ligand, while the agonist-activated receptor displays marked anti-proliferative effects in cancer cells. For example, transfection of breast cancer cells with AhR siRNA is growthinhibitory [64,65]. Similarly, AhR-deficient hepatoma cells (AhR-D) proliferate at a slower rate than wild-type cells (Hepa 1c1c7), and ectopic expression of the AhR in the AhR-D cells increases their growth to the rate of wild-type cells [66].…”

Section: The Effects Of Ahr On Proliferation and The Cell Cyclementioning

confidence: 99%

“…There is emerging evidence that ligand activation of the AhR can inhibit multiple aspects of the metastatic process. In a panel of breast cancer cell lines that represent the 3 major breast cancer subtypes (ER and PR-positive, HER2-positive, and triple-receptor negative), it was found that agonist-activated AhR inhibited cell invasiveness and motility and prevented anchorage-independent growth [65]. Knockdown of the AhR with siRNAs demonstrated that the inhibition of invasiveness was receptor-dependent and endogenous receptor activity was protective in each cell type examined [65].…”

Section: Evidence For a Protective Role Of The Ahr In Breast Cancer Cmentioning

confidence: 99%

“…In a panel of breast cancer cell lines that represent the 3 major breast cancer subtypes (ER and PR-positive, HER2-positive, and triple-receptor negative), it was found that agonist-activated AhR inhibited cell invasiveness and motility and prevented anchorage-independent growth [65]. Knockdown of the AhR with siRNAs demonstrated that the inhibition of invasiveness was receptor-dependent and endogenous receptor activity was protective in each cell type examined [65]. Likewise, AhR agonists were found to promote differentiation of breast cancer cells and mammary cancer stem cells into cells that displayed the phenotypic markers of normal breast epithelial gland cells [65].…”

Section: Evidence For a Protective Role Of The Ahr In Breast Cancer Cmentioning

confidence: 99%

“…Knockdown of the AhR with siRNAs demonstrated that the inhibition of invasiveness was receptor-dependent and endogenous receptor activity was protective in each cell type examined [65]. Likewise, AhR agonists were found to promote differentiation of breast cancer cells and mammary cancer stem cells into cells that displayed the phenotypic markers of normal breast epithelial gland cells [65]. Thus, the AhR plays an important role in mammary epithelial differentiation and, as such, represents a promising therapeutic target for a range of phenotypically distinct human breast cancers.…”

Section: Evidence For a Protective Role Of The Ahr In Breast Cancer Cmentioning

confidence: 99%

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The Aryl-hydrocarbon Receptor (AhR) as a Therapeutic Target in Human Breast Cancer

Hall¹

2013

J Steroids Horm Sci

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Breast cancer is currently the most prevalent malignancy among women in industrialized countries, and 1 in 8 women living in the United States will develop the disease at some point in her lifetime. Although the incidence of breast cancer has increased 0.3% per year since 1990, the mortality rate has decreased by 2% per year since 1990 due to improvements in treatment and early detection. New treatment strategies and a better molecular understanding of the disease will be important to continue the progress science has made against this disease. The aryl-hydrocarbon receptor (AhR) has been traditionally associated with activation by environmental contaminants, acute toxicity, and cancer risks associated with exposures. However, the AhR has been highly conserved throughout evolution suggesting an important biological role for the receptor independent of its response to environmental contaminants. There is a significant body of evidence indicating the AhR plays a role in breast epithelial cell differentiation and that receptor agonists can inhibit breast cancer growth. A 50% reduction in estrousinduced terminal end buds was observed in the mammary glands of AhR knockout animals when compared to wild type suggesting a role for the AhR in mammary development. In 2 independent rodent cancer bioassays, treatment with the AhR agonist 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) significantly reduced the incidence of spontaneous rat mammary tumors. These and other studies support the premise that the AhR plays a fundamental role in breast epithelial cell differentiation. This review provides a brief summary of the current evidence that the AhR may be an important pharmacological target for treating human breast cancer.

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AhR ligand aminoflavone suppresses α6‐integrin–Src–Akt signaling to attenuate tamoxifen resistance in breast cancer cells

Campbell

Mavingire

Khan

et al. 2018

Journal Cellular Physiology

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More than 40% of patients with luminal breast cancer treated with endocrine therapy agent tamoxifen demonstrate resistance. Emerging evidence suggests tumor initiating cells (TICs) and aberrant activation of Src and Akt signaling drive tamoxifen resistance and relapse. We previously demonstrated that aryl hydrocarbon receptor ligand aminoflavone (AF) inhibits the expression of TIC gene α6-integrin and disrupts mammospheres derived from tamoxifen-sensitive breast cancer cells. In the current study, we hypothesize that tamoxifen-resistant (TamR) cells exhibit higher levels of α6-integrin than tamoxifen-sensitive cells and that AF inhibits the growth of TamR cells by suppressing α6-integrin-Src-Akt signaling. In support of our hypothesis, TamR cells and associated mammospheres were found to exhibit elevated α6-integrin expression compared with their tamoxifen-sensitive counterparts. Furthermore, tumor sections from patients who relapsed on tamoxifen showed enhanced α6-integrin expression. Gene expression profiling from the TCGA database further revealed that basal-like breast cancer samples, known to be largely unresponsive to tamoxifen, demonstrated higher α6-integrin levels than luminal breast cancer samples. Importantly, AF reduced TamR cell viability and disrupted TamR mammospheres while concomitantly reducing α6-integrin messenger RNA and protein levels. In addition, AF and small interfering RNA against α6-integrin blocked tamoxifen-stimulated proliferation of TamR MCF-7 cells and further sensitized these cells to tamoxifen. Moreover, AF reduced Src and Akt signaling activation in TamR MCF-7 cells. Our findings suggest elevated α6-integrin expression is associated with tamoxifen resistance and AF suppresses α6-integrin-Src-Akt signaling activation to confer activity against TamR breast cancer.

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Activation of the Aryl-Hydrocarbon Receptor Inhibits Invasive and Metastatic Features of Human Breast Cancer Cells and Promotes Breast Cancer Cell Differentiation

Cited by 18 publications

References 0 publications

Intestine-Specific Homeobox Gene ISX Integrates IL6 Signaling, Tryptophan Catabolism, and Immune Suppression

Intestine-Specific Homeobox Gene ISX Integrates IL6 Signaling, Tryptophan Catabolism, and Immune Suppression

The Aryl-hydrocarbon Receptor (AhR) as a Therapeutic Target in Human Breast Cancer

AhR ligand aminoflavone suppresses α6‐integrin–Src–Akt signaling to attenuate tamoxifen resistance in breast cancer cells

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