Mechanisms of Primary and Secondary Estrogen Target Gene Regulation in Breast Cancer Cells

Nucleic Acids Res. 2008 Jan;36(1):76-93. doi: 10.1093/nar/gkm945. Epub 2007 Nov 5.

Abstract

Estrogen receptors (ERs), which mediate the proliferative action of estrogens in breast cancer cells, are ligand-dependent transcription factors that regulate expression of their primary target genes through several mechanisms. In addition to direct binding to cognate DNA sequences, ERs can be recruited to DNA through other transcription factors (tethering), or affect gene transcription through modulation of signaling cascades by non-genomic mechanisms of action. To better characterize the mechanisms of gene regulation by estrogens, we have identified more than 700 putative primary and about 1300 putative secondary target genes of estradiol in MCF-7 cells through microarray analysis performed in the presence or absence of the translation inhibitor cycloheximide. Although siRNA-mediated inhibition of ERalpha expression antagonized the effects of estradiol on up- and down-regulated primary target genes, estrogen response elements (EREs) were enriched only in the vicinity of up-regulated genes. Binding sites for several other transcription factors, including proteins known to tether ERalpha, were enriched in up- and/or down-regulated primary targets. Secondary estrogen targets were particularly enriched in sites for E2F family members, several of which were transcriptionally regulated by estradiol, consistent with a major role of these factors in mediating the effects of estrogens on gene expression and cellular growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Breast Neoplasms / genetics*
  • Cell Line, Tumor
  • E2F Transcription Factors / metabolism
  • Estradiol / pharmacology*
  • Estrogen Receptor alpha / metabolism*
  • Estrogens / pharmacology*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Humans
  • Response Elements
  • Transcription Factors / metabolism

Substances

  • E2F Transcription Factors
  • Estrogen Receptor alpha
  • Estrogens
  • Transcription Factors
  • Estradiol