title: The role of the aryl hydrocarbon receptor in the development of cells with the molecular and functional characteristics of cancer stem-like cells.
abstract: BACKGROUND
  Self-renewing, chemoresistant breast cancer stem cells are believed to contribute significantly to cancer invasion, migration and patient relapse. Therefore, the identification of signaling pathways that regulate the acquisition of stem-like qualities is an important step towards understanding why patients relapse and towards development of novel therapeutics that specifically target cancer stem cell vulnerabilities. Recent studies identified a role for the aryl hydrocarbon receptor (AHR), an environmental carcinogen receptor implicated in cancer initiation, in normal tissue-specific stem cell self-renewal. These studies inspired the hypothesis that the AHR plays a role in the acquisition of cancer stem cell-like qualities.
  
  
  RESULTS
  To test this hypothesis, AHR activity in Hs578T triple negative and SUM149 inflammatory breast cancer cells were modulated with AHR ligands, shRNA or AHR-specific inhibitors, and phenotypic, genomic and functional stem cell-associated characteristics were evaluated. The data demonstrate that (1) ALDH(high) cells express elevated levels of Ahr and Cyp1b1 and Cyp1a1, AHR-driven genes, (2) AHR knockdown reduces ALDH activity by 80%, (3) AHR hyper-activation with several ligands, including environmental ligands, significantly increases ALDH1 activity, expression of stem cell- and invasion/migration-associated genes, and accelerates cell migration, (4) a significant correlation between Ahr or Cyp1b1 expression (as a surrogate marker for AHR activity) and expression of stem cell- and invasion/migration-associated gene sets is seen with genomic data obtained from 79 human breast cancer cell lines and over 1,850 primary human breast cancers, (5) the AHR interacts directly with Sox2, a master regulator of self-renewal; AHR ligands increase this interaction and nuclear SOX2 translocation, (6) AHR knockdown inhibits tumorsphere formation in low adherence conditions, (7) AHR inhibition blocks the rapid migration of ALDH(high) cells and reduces ALDH(high) cell chemoresistance, (8) ALDH(high) cells are highly efficient at initiating tumors in orthotopic xenografts, and (9) AHR knockdown inhibits tumor initiation and reduces tumor Aldh1a1, Sox2, and Cyp1b1 expression in vivo.
  
  
  CONCLUSIONS
  These data suggest that the AHR plays an important role in development of cells with cancer stem cell-like qualities and that environmental AHR ligands may exacerbate breast cancer by enhancing expression of these properties.
authors.affiliation: Department of Environmental Health, Boston University School of Public Health, 72 East Concord Street (R-408), Boston, Massachusetts, 02118, USA.|Boston University Molecular and Translational Medicine Program, 72 E. Concord Street, Boston, MA, 02118, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Stanford
authors.affiliation: Department of Environmental Health, Boston University School of Public Health, 72 East Concord Street (R-408), Boston, Massachusetts, 02118, USA.
authors.forename: Zhongyan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Environmental Health, Boston University School of Public Health, 72 East Concord Street (R-408), Boston, Massachusetts, 02118, USA.|Boston University Molecular and Translational Medicine Program, 72 E. Concord Street, Boston, MA, 02118, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Novikov
authors.affiliation: Department of Medicine, Boston University School of Medicine, Section of Computational Biomedicine, Boston, MA, 02118, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mulas
authors.affiliation: Department of Medicine, Boston University School of Medicine, Section of Hematology and Oncology, 650 Albany Street, Boston, MA, 02118, USA.
authors.forename: Esther
authors.initials: E
authors.lastname: Landesman-Bollag
authors.affiliation: Department of Medicine, Boston University School of Medicine, Section of Computational Biomedicine, Boston, MA, 02118, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Monti
authors.affiliation: Boston University Molecular and Translational Medicine Program, 72 E. Concord Street, Boston, MA, 02118, USA.|Department of Medicine, Boston University School of Medicine, Section of Hematology and Oncology, 650 Albany Street, Boston, MA, 02118, USA.|Boston University and Boston Medical Center, Center for Regenerative Medicine (CReM), 710 Albany Street, Boston, MA, 02118, USA.
authors.forename: Brenden W
authors.initials: BW
authors.lastname: Smith
authors.affiliation: Department of Medicine, Boston University School of Medicine, Section of Hematology and Oncology, 650 Albany Street, Boston, MA, 02118, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Seldin
authors.affiliation: Department of Medicine, Boston University School of Medicine, Section of Hematology and Oncology, 650 Albany Street, Boston, MA, 02118, USA.|Boston University and Boston Medical Center, Center for Regenerative Medicine (CReM), 710 Albany Street, Boston, MA, 02118, USA.
authors.forename: George J
authors.initials: GJ
authors.lastname: Murphy
authors.affiliation: Department of Environmental Health, Boston University School of Public Health, 72 East Concord Street (R-408), Boston, Massachusetts, 02118, USA. dsherr@bu.edu.
authors.forename: David H
authors.initials: DH
authors.lastname: Sherr
mesh_terms: D001940:Breast / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism
chemical_list: D018336:Receptors, Aryl Hydrocarbon
keywords: Aryl hydrocarbon receptor; Breast cancer; Environment; Sox2; Tumor initiating cells