The role of the aryl hydrocarbon receptor in the development of cells with the molecular and functional characteristics of cancer stem-like cells

Autor: George J. Murphy, Elizabeth A. Stanford, Esther Landesman-Bollag, Stefano Monti, Brenden W. Smith, Olga Novikov, David H. Sherr, David C. Seldin, Zhongyan Wang, Francesca Mulas
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Physiology
Cell
Sox2
Breast Neoplasms
Plant Science
Tumor initiation
Environment
Tumor initiating cells
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
0302 clinical medicine
Breast cancer
SOX2
Structural Biology
Cancer stem cell
Cell Movement
Cell Line
Tumor
medicine
Humans
Breast
Ecology
Evolution
Behavior and Systematics
Aryl hydrocarbon receptor
Agricultural and Biological Sciences(all)
biology
Biochemistry
Genetics and Molecular Biology(all)
Cancer
Cell Biology
respiratory system
medicine.disease
respiratory tract diseases
3. Good health
Gene Expression Regulation
Neoplastic
030104 developmental biology
medicine.anatomical_structure
Receptors
Aryl Hydrocarbon
030220 oncology & carcinogenesis
Immunology
Cancer research
biology.protein
Neoplastic Stem Cells
Female
Stem cell
Signal transduction
General Agricultural and Biological Sciences
Developmental Biology
Biotechnology
Research Article
Zdroj: BMC Biology
ISSN: 1741-7007
Popis: 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 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. 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. Electronic supplementary material The online version of this article (doi:10.1186/s12915-016-0240-y) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
Externí odkaz: