The role of the aryl hydrocarbon receptor in the development of cells with the molecular and functional characteristics of cancer stem-like cells. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Stanford, Elizabeth; Wang, Zhongyan; Novikov, Olga; Mulas, Francesca; Landesman-Bollag, Esther; Monti, Stefano; Smith, Brenden; Seldin, David; Murphy, George; Sherr, David
• Is Part Of: BMC biology. Volume 14:Issue 1(2016)
• Page Start: 1
• Page End: 22
• Publication Date: 2016-12
• Subjects: Aryl hydrocarbon receptor -- Breast cancer -- Environment -- Sox2 -- Tumor initiating cells; Biology -- Periodicals; Medical sciences -- Periodicals; Biomedical Research -- Periodicals; 570.5
• DOI: 10.1186/s12915-016-0240-y
• Languages: English
• ISSNs: 1741-7007

Abstract

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) ALDHhigh cells express elevated levels ofAhr andCyp1b1 andCyp1a1, 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 betweenAhr orCyp1b1 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 withSox2, 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 ALDHhigh cells and reduces ALDHhigh cell chemoresistance, (8) ALDHhigh cells are highly efficient at initiating tumors in orthotopic xenografts, and (9) AHR knockdown inhibits tumor initiation and reduces tumorAldh1a1, Sox2, andCyp1b1 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.