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

Overview of attention for article published in Molecular Cancer, January 2017
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Mentioned by

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3 tweeters

Citations

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41 Dimensions

Readers on

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39 Mendeley
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Title
Aryl hydrocarbon receptor/cytochrome P450 1A1 pathway mediates breast cancer stem cells expansion through PTEN inhibition and β-Catenin and Akt activation
Published in
Molecular Cancer, January 2017
DOI 10.1186/s12943-016-0570-y
Pubmed ID
Authors

Abdullah Al-Dhfyan, Ali Alhoshani, Hesham M. Korashy

Abstract

Breast 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. The 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. The 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. The 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.

Twitter Demographics

The data shown below were collected from the profiles of 3 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 39 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 39 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 11 28%
Student > Ph. D. Student 7 18%
Student > Master 7 18%
Student > Doctoral Student 2 5%
Other 2 5%
Other 5 13%
Unknown 5 13%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 13 33%
Pharmacology, Toxicology and Pharmaceutical Science 8 21%
Agricultural and Biological Sciences 3 8%
Immunology and Microbiology 3 8%
Veterinary Science and Veterinary Medicine 2 5%
Other 3 8%
Unknown 7 18%

Attention Score in Context

This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 30 January 2017.
All research outputs
#4,535,609
of 8,982,225 outputs
Outputs from Molecular Cancer
#309
of 800 outputs
Outputs of similar age
#157,018
of 309,036 outputs
Outputs of similar age from Molecular Cancer
#8
of 30 outputs
Altmetric has tracked 8,982,225 research outputs across all sources so far. This one is in the 48th percentile – i.e., 48% of other outputs scored the same or lower than it.
So far Altmetric has tracked 800 research outputs from this source. They receive a mean Attention Score of 3.1. This one has gotten more attention than average, scoring higher than 60% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 309,036 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 48th percentile – i.e., 48% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 30 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 73% of its contemporaries.