title: Cytochrome P450 2E1 (CYP2E1) regulates the response to oxidative stress and migration of breast cancer cells.
abstract: BACKGROUND
  The cytochrome P450 (CYP) enzymes are a class of heme-containing enzymes involved in phase I metabolism of a large number of xenobiotics. The CYP family member CYP2E1 metabolises many xenobiotics and pro-carcinogens, it is not just expressed in the liver but also in many other tissues such as the kidney, the lung, the brain, the gastrointestinal tract and the breast tissue. It is induced in several pathological conditions including cancer, obesity, and type II diabetes implying that this enzyme is implicated in other biological processes beyond its role in phase I metabolism. Despite the detailed description of the role of CYP2E1 in the liver, its functions in other tissues have not been extensively studied. In this study, we investigated the functional significance of CYP2E1 in breast carcinogenesis.
  
  
  METHODS
  Cellular levels of reactive oxygen species (ROS) were measured by H2DCFDA (2 2.9.2 2',7'-dichlorodihydrofluorescein diacetate) staining and autophagy was assessed by tracing the cellular levels of autophagy markers using western blot assays. The endoplasmic reticulum stress and the unfolded protein response (UPR) were detected by luciferase assays reflecting the splicing of mRNA encoding the X-box binding protein 1 (XBP1) transcription factor and cell migration was evaluated using the scratch wound assay. Gene expression was recorded with standard transcription assays including luciferase reporter and chromatin immunoprecipitation.
  
  
  RESULTS
  Ectopic expression of CYP2E1 induced ROS generation, affected autophagy, stimulated endoplasmic reticulum stress and inhibited migration in breast cancer cells with different metastatic potential and p53 status. Furthermore, evidence is presented indicating that CYP2E1 gene expression is under the transcriptional control of the p53 tumor suppressor.
  
  
  CONCLUSIONS
  These results support the notion that CYP2E1 exerts an important role in mammary carcinogenesis, provide a potential link between ethanol metabolism and breast cancer and suggest that progression, and metastasis, of advanced stages of breast cancer can be modulated by induction of CYP2E1 activity.
authors.forename: Travis
authors.initials: T
authors.lastname: Leung
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Rajendran
authors.forename: Subir
authors.initials: S
authors.lastname: Singh
authors.forename: Richa
authors.initials: R
authors.lastname: Garva
authors.forename: Marija
authors.initials: M
authors.lastname: Krstic-Demonacos
authors.forename: Constantinos
authors.initials: C
authors.lastname: Demonacos
mesh_terms: D001343:Autophagy; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D059865:Endoplasmic Reticulum Stress; D000431:Ethanol / Q000493:pharmacokinetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; C110332:CYP2F1 protein, human; D000072467:Cytochrome P450 Family 2