The organochlorine o,p'-DDT plays a role in coactivator-mediated MAPK crosstalk in MCF-7 breast cancer cells

Melyssa R. Bratton, Daniel E. Frigo, H. Chris Segar, Kenneth P. Nephew, John A. McLachlan, Thomas E. Wiese, Matthew E. Burow

Research output: Contribution to journalArticle

24 Scopus citations

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. Objectives: 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 (E<inf>2</inf>) 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: E<inf>2</inf> 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 E<inf>2</inf>, 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.

Original languageEnglish (US)
Pages (from-to)1291-1296
Number of pages6
JournalEnvironmental Health Perspectives
Volume120
Issue number9
DOIs
StatePublished - Sep 2012

Keywords

  • Breast cancer
  • CBP
  • Coactivator
  • Crosstalk
  • DDT
  • Dichlorodiphenyltrichloroethane
  • Endocrine-disrupting chemical
  • HIF-1α
  • MAPK
  • Organochlorine
  • p38 kinase
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Public Health, Environmental and Occupational Health

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