title: The organochlorine o,p'-DDT plays a role in coactivator-mediated MAPK crosstalk in MCF-7 breast cancer cells.
abstract: BACKGROUND
  The organochlorine dichlorodiphenyltrichloroethane (DDT), a known estrogen mimic and endocrine disruptor, has been linked to animal and human disorders. However, the detailed mechanism(s) by which DDT affects cellular physiology remains incompletely defined.
  
  
  OBJECTIVE
  We and others have shown that DDT activates cell-signaling cascades, culminating in the activation of estrogen receptor-dependent and -independent gene expression. Here, we identify a mechanism by which DDT alters cellular signaling and gene expression, independent of the estrogen receptor.
  
  
  METHODS
  We performed quantitative polymerase chain reaction array analysis of gene expression in MCF-7 breast cancer cells using either estradiol (E₂) or o,p´-DDT to identify distinct cellular gene expression responses. To elucidate the mechanisms by which DDT regulates cell signaling, we used molecular and pharmacological techniques.
  
  
  RESULTS
  E₂ and DDT treatment both altered the expression of many of the genes assayed, but up-regulation of vascular endothelial growth factor A (VEGFA) was observed only after DDT treatment, and this increase was not affected by the pure estrogen receptor α antagonist ICI 182780. Furthermore, DDT increased activation of the HIF-1 response element (HRE), a known enhancer of the VEGFA gene. This DDT-mediated increase in HRE activity was augmented by the coactivator CBP (CREB-binding protein) and was dependent on the p38 pathway.
  
  
  CONCLUSIONS
  DDT up-regulated the expression of several genes in MCF-7 breast cancer cells that were not altered by treatment with E₂, including VEGFA. We propose that this DDT-initiated, ER-independent stimulation of gene expression is due to DDT's ability to initiate crosstalk between MAPK (mitogen-activated protein kinase) signaling pathways and transcriptional coactivators.
authors.affiliation: Department of Pharmacology, Tulane University, New Orleans, Louisiana, USA.
authors.forename: Melyssa R
authors.initials: MR
authors.lastname: Bratton
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Frigo
authors.forename: H Chris
authors.initials: HC
authors.lastname: Segar
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.forename: John A
authors.initials: JA
authors.lastname: McLachlan
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wiese
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Burow
mesh_terms: D003634:DDT / Q000494:pharmacology*; D052244:Endocrine Disruptors / Q000494:pharmacology*; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007306:Insecticides / Q000494:pharmacology; D061986:MCF-7 Cells; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome
chemical_list: D052244:Endocrine Disruptors; D007306:Insecticides; D004958:Estradiol; D003634:DDT; C016340:o,p'-DDT; D020928:Mitogen-Activated Protein Kinases