Abstract
BackgroundSelf-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.ResultsTo 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 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 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 tumor Aldh1a1, Sox2, and Cyp1b1 expression in vivo.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0240-y) contains supplementary material, which is available to authorized users.
Highlights
Self-renewing, chemoresistant breast cancer stem cells are believed to contribute significantly to cancer invasion, migration and patient relapse
Our results show that the aryl hydrocarbon receptor (AHR) is involved in the control of phenotypic, genomic, and functional cancer stem cell markers in ER−/PR−/Her2− cells, strongly implicating an important role for the AHR in acquisition of stem cell-like qualities, encouraging development of AHR-targeted therapeutics, and raising the possibility that environmental AHR ligands may drive breast cancer stem-like cells’ (BCSLC) development or activity
AHR expression is elevated in ALDH1high triple negative breast cancer (TNBC) We have previously published data demonstrating elevated expression of transcriptionally (‘constitutively’) active AHR in human breast cancer cell lines [10, 15, 42, 43]
Summary
Self-renewing, chemoresistant breast cancer stem cells are believed to contribute significantly to cancer invasion, migration and patient relapse. 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 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. Recent data suggest alternative, non-genotoxic pathways involving cellular receptors that can be activated by environmental ligands. One such receptor is the aryl hydrocarbon receptor (AHR). The AHR has been best studied for its ability to be activated by dioxins, polychlorinated biphenyls, and polycyclic aromatic hydrocarbons [9], all of which are high priority chemicals on the U.S Agency for Toxic Substances and Disease Registry list of pollutants of greatest concern to human health (http://www.atsdr.cdc.gov/SPL/resources)
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