Estrogen regulation of trefoil factor 1 expression by estrogen receptor alpha and Sp proteins

Exp Cell Res. 2005 Jan 1;302(1):96-107. doi: 10.1016/j.yexcr.2004.08.015.


Estrogen-responsive genes in human breast cancer cells often have an estrogen response element (ERE) positioned next to an Sp1 binding site. In chromatin immunoprecipitation (ChIP) assays, we investigated the binding of estrogen receptor alpha (ER), Sp1, and Sp3 to the episomal and native estrogen-responsive trefoil factor 1 (TFF1; formerly pS2) promoter in MCF-7 breast cancer cells. Mutation of the Sp site upstream of the ERE reduced estrogen responsiveness and prevented binding of Sp1 and Sp3, but not ER to the episomal promoter. In the absence of estradiol (E2), Sp1, Sp3, histone deacetylase 1 (HDAC), and HDAC2, and low levels of acetylated H3 and H4 are associated with the native promoter, with the histones being engaged in dynamic reversible acetylation. Following E2 addition, levels of ER and acetylated H3 and H4 bound to the native promoter increases. There is clearance of Sp1, but not of Sp3, from the promoter while HDAC1 and HDAC2 remain bound. These data are consistent with a model in which Sp1 or Sp3 aid in recruitment of HDACs and histone acetyltransferases (HATs) to mediate dynamic acetylation of histones associated with the TFF1 promoter, which is in a state of readiness to respond to events occurring following the addition of estrogen.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylation
  • Binding Sites / genetics
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Carcinoma / genetics
  • Carcinoma / metabolism*
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Estrogens / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Histone Deacetylases / metabolism
  • Humans
  • Mutation / genetics
  • Promoter Regions, Genetic / genetics
  • Protein Binding / genetics
  • Proteins / genetics
  • Proteins / metabolism*
  • Sp1 Transcription Factor / genetics
  • Sp1 Transcription Factor / metabolism*
  • Sp3 Transcription Factor
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Trefoil Factor-1
  • Tumor Suppressor Proteins


  • DNA-Binding Proteins
  • Estrogen Receptor alpha
  • Estrogens
  • Proteins
  • SP3 protein, human
  • Sp1 Transcription Factor
  • TFF1 protein, human
  • Transcription Factors
  • Trefoil Factor-1
  • Tumor Suppressor Proteins
  • Sp3 Transcription Factor
  • Histone Deacetylases