title: Endogenous aryl hydrocarbon receptor promotes basal and inducible expression of tumor necrosis factor target genes in MCF-7 cancer cells.
abstract: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that upon activation by the toxicant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) stimulates gene expression and toxicity. AHR is also important for normal mouse physiology and may play a role in cancer progression in the absence of environmental toxicants. The objective of this report was to identify AHR-dependent genes (ADGs) whose expression is regulated by AHR in the absence of toxicants. RNA-Seq analysis revealed that AHR regulated the expression of over 600 genes at an FDR<10% in MCF-7 breast cancer cells upon knockdown with short interfering RNA. Pathway analysis revealed that a significant number of ADGs were components of TCDD and tumor necrosis factor (TNF) pathways. We also demonstrated that siRNA knockdown of AHR modulated TNF induction of MNSOD and cytotoxicity in MCF-7 cells. Collectively, the major new findings of this report are: (1) endogenous AHR promotes the expression of xenobiotic metabolizing enzymes even in the absence of toxicants and drugs, (2) AHR by modulating the basal expression of a large fraction of TNF target genes may prime them for TNF stimulation and (3) AHR is required for TNF induction of MNSOD and the cellular response to cytotoxicity in MCF-7 cells. This latter result provides a potentially new role for AHR in MCF-7 cancer progression as a mediator of TNF and antioxidant responses.
authors: Departments of Pharmacology, Physiology and Toxicology Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA. Electronic address: salisburyt@marshall.edu.
authors: Travis B
authors: TB
authors: Salisbury
authors: Departments of Pharmacology, Physiology and Toxicology Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA. Electronic address: tomblin36@marshall.edu.
authors: Justin K
authors: JK
authors: Tomblin
authors: Biochemistry and Microbiology and Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA. Electronic address: primeran@marshall.edu.
authors: Donald A
authors: DA
authors: Primerano
authors: Biochemistry and Microbiology and Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA.
authors: Goran
authors: G
authors: Boskovic
authors: Biochemistry and Microbiology and Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA. Electronic address: fanj@marshall.edu.
authors: Jun
authors: J
authors: Fan
authors: Medical Oncology and Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA.
authors: Inderjit
authors: I
authors: Mehmi
authors: Department of Biology, West Virginia State University, Institute, WV 25112, USA. Electronic address: fletcherjackie@gmail.com.
authors: Jackie
authors: J
authors: Fletcher
authors: Departments of Pharmacology, Physiology and Toxicology Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA. Electronic address: santanam@marshall.edu.
authors: Nalini
authors: N
authors: Santanam
authors: Departments of Pharmacology, Physiology and Toxicology Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA. Electronic address: hurn@marshall.edu.
authors: Estil
authors: E
authors: Hurn
authors: Department of Science and Mathematics, Glenville State College, Glenville, WV 26351, USA. Electronic address: Gary.Morris@glenville.edu.
authors: Gary Z
authors: GZ
authors: Morris
authors: Biochemistry and Microbiology and Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA. Electronic address: denvir@marshall.edu.
authors: James
authors: J
authors: Denvir
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008658:Inactivation, Metabolic; D061986:MCF-7 Cells / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004798:Enzymes; D000072317:Polychlorinated Dibenzodioxins; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D013482:Superoxide Dismutase; D014409:Tumor Necrosis Factor-alpha; C111235:AHR protein, human
keywords: Aryl hydrocarbon receptor (AHR); Breast cancer; Gene expression; Tumor necrosis factor; Xenobiotics