Gene expression profiling reveals that the regulation of estrogen-responsive element-independent genes by 17 beta-estradiol-estrogen receptor beta is uncoupled from the induction of phenotypic changes in cell models

J Mol Endocrinol. 2008 May;40(5):211-29. doi: 10.1677/JME-07-0156.


Estrogen hormone 17beta-estradiol (E(2)) is involved in the physiology and pathology of many tissues. E(2) information is conveyed by the transcription factors estrogen receptors (ER) alpha and beta that mediate a complex array of nuclear and non-nuclear events. The interaction of ER with specific DNA sequences, estrogen-responsive elements (EREs), constitutes a critical nuclear signaling pathway. In addition, E(2)-ER regulates transcription through interactions with transfactors bound to their cognate regulatory elements on DNA, hence the ERE-independent signaling pathway. However, the relative importance of the ERE-independent pathway in E(2)-ERbeta signaling is unclear. To address this issue, we engineered an ERE-binding defective ERbeta mutant (ERbeta(EBD)) by changing critical residues in the DNA-binding domain required for ERE binding. Biochemical and functional studies revealed that ERbeta(EBD) signaled exclusively through the ERE-independent pathway. Using the adenovirus infected ER-negative cancer cell models, we found that although E(2)-ERbeta(EBD) regulated the expression of a number of genes identified by microarrays, it was ineffective in altering cellular proliferation, motility, and death in contrast to E(2)-ERbeta. Our results indicate that genomic responses from the ERE-independent pathway to E(2)-ERbeta are not sufficient to alter the cellular phenotype. These findings suggest that the ERE-dependent pathway is a required signaling route for E(2)-ERbeta to induce cellular responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • DNA, Neoplasm / metabolism
  • Estradiol / physiology*
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / metabolism
  • Estrogen Receptor beta / physiology*
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic / physiology
  • HeLa Cells
  • Humans
  • Models, Biological*
  • Phenotype*
  • Protein Binding / genetics
  • Response Elements / genetics
  • Response Elements / physiology*


  • DNA, Neoplasm
  • Estrogen Receptor beta
  • Estradiol