The role of the aryl hydrocarbon receptor in the development of cells with molecular and functional characteristics of breast cancer stem cells
Stanford, Elizabeth Ann
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Self-renewing, chemoresistant cancer cells that contribute to cancer metastasis and patient relapse have properties similar to those of stem cells, and have been termed "cancer stem cells" (CSCs) in the literature. The identification of signaling pathways that regulate CSC development and/or function is an important step towards understanding why patients relapse, and towards development of novel therapeutics that specifically target CSC vulnerabilities. Recent studies have 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 CSC development. To test this hypothesis, AHR activity in Hs578T triple negative and SUM149 inflammatory breast cancer cells was modulated with AHR ligands, shRNA, or AHR-specific inhibitors and their phenotypic, genomic, and functional CSC characteristics were evaluated. Aldehyde dehydrogenase (ALDH) was used as an epithelial stem cell marker for flow cytometry. Results demonstrate that: 1) ALDHhigh cells express elevated levels of Ahr and the AHR-driven gene that encodes cytochrome p450 isoform 1b1 (Cyp1b1), 2) AHR knockdown reduces ALDH activity, 3) AHR hyper-activation significantly increases ALDH1 activity, expression of stem cell- and invasion/migration-associated genes, and accelerates cell migration, 4) a highly significant correlation between Ahr or Cyp1b1 expression (as a surrogate marker for AHR activity) and expression of the CSC- and invasion/migration-associated gene sets was seen with genomic data obtained from 79 human breast cancer cell lines and over 1850 primary human breast cancers, 5) the AHR interacts directly with the transcription factors Sox2 and Runx1, and AHR ligands increase this interaction, 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, and 8) AHR knockdown inhibits tumor growth and reduces tumor Aldh1a1, Sox2, and Cyp1b1 expression in orthotopic xenografts. These data suggest that the AHR plays an important role in development of CSCs in a large fraction of human breast cancers and that environmental AHR ligands may exacerbate breast cancer by enhancing expression of CSC-like properties.