HES-1 inhibits 17beta-estradiol and heregulin-beta1-mediated upregulation of E2F-1

Oncogene. 2004 Nov 18;23(54):8826-33. doi: 10.1038/sj.onc.1208139.


We have previously shown that expression of the transcription factor HES-1 is required for the growth-inhibitory effect of all-trans retinoic acid on MCF-7 cells. In this study, we have used T47D cells with tetracyclin-regulated expression of wild-type or a dominant-negative form of HES-1. Expression of HES-1 in T47D cells inhibited G1/S-phase transition and activation of Cdk2 elicited by estrogen. Estrogen treatment of T47D cells caused increased expression of E2F-1, and this expression was inhibited by cotreatment with all-trans retinoic acid. We show that the effect is mediated through HES-1, which directly downregulates E2F-1 expression through a CACGAG-site within the E2F-1 promoter. Furthermore, proliferation caused by heregulin-beta1 treatment of T47D cells was inhibited by all-trans retinoic acid and this effect was mediated by HES-1. Interestingly, heregulin-beta1-mediated upregulation of E2F-1 expression was directly inhibited by HES-1 through the same CACGAG-site as seen with estrogen-stimulated induction. In addition, we found that two important downstream target genes of estrogen and heregulin-beta1 that are regulated through E2F-1, cyclin E and NPAT, were both regulated in a similar fashion by all-trans retinoic acid, and these effects were antagonized by dominant-negative HES-1. These findings establish that HES-1 inhibits both estrogen- and heregulin-beta1-stimulated growth of breast cancer cells, and further suggest that growth inhibition induced in these cells by all-trans retinoic acid occurs via HES-1-mediated downregulation of E2F-1 expression.

Publication types

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

MeSH terms

  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors
  • Blotting, Western
  • Cell Cycle Proteins / physiology*
  • Cell Line, Tumor
  • DNA Primers
  • DNA, Complementary
  • DNA-Binding Proteins / physiology*
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • Electrophoretic Mobility Shift Assay
  • Estradiol / physiology*
  • Flow Cytometry
  • Homeodomain Proteins / physiology*
  • Humans
  • Neuregulin-1 / physiology*
  • Polymerase Chain Reaction
  • Transcription Factor HES-1
  • Transcription Factors / physiology*
  • Up-Regulation / physiology*


  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • DNA Primers
  • DNA, Complementary
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Homeodomain Proteins
  • Neuregulin-1
  • Transcription Factor HES-1
  • Transcription Factors
  • HES1 protein, human
  • heregulin beta1
  • Estradiol