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Aryl Hydrocarbon Receptor/Cytochrome P4501 Pathway Mediates Breast Cancer Stem Cells Expansion through β‐Catenin/Akt Activation and Pten Inhibition
Author(s) -
AlDhfyan Abdullah O,
Alhoshani Ali R.,
Korashy Hesham M.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.671.5
Subject(s) - aryl hydrocarbon receptor , pten , cancer research , pi3k/akt/mtor pathway , cancer stem cell , chemistry , protein kinase b , population , side population , biology , signal transduction , stem cell , microbiology and biotechnology , medicine , biochemistry , transcription factor , gene , environmental health
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 P4501 pathway in CSCs expansion. However, the exact molecular mechanisms remain unclear. Thus the current study was designed to determine the effect of AhR activation and inhibition on breast CSCs development, maintenance, self‐renewal, and chemoresistance and to explore the role of β‐catenin, PI3K/Akt, and Pten signaling pathways. To test this hypothesis, CSCc characteristics in three human breast cancer cells SKBR‐3, MCF‐7, and MDA‐MB‐231, treated with AhR activators or inhibitors were determined using Aldefluor assay, side population, and mammosphere formation. The mRNA and protein expression of the target genes were determined by RT‐PCR and Western blot analysis respectively. Our results showed that the constitutive mRNA expression and cellular content of CYP1A1 and CYP1B1 were markedly higher in CSCs more than differentiating non‐CSCs of the three different human breast cancer cells. Activation of AhR/CYP1 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/CYP1 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 conclusions, the present study provides the first evidence that AhR/CYP1A1 signaling pathway is controlling breast CSCs proliferation, development, self‐renewal and chemoresistance through activation of β‐catenin and Akt and inhibition of the Pten pathways. Support or Funding Information National Plan for Science, Technology and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, Kingdom of Saudi Arabia, Award Number (12‐MED3131‐02).