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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
10:36

Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer

Published on: March 17, 2016

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

Johan Hartman1, Patrick Müller, James S Foster

  • 1Center for Biotechnology, Department of BioSciences, Karolinska Institutet, Novum, S-141 57 Huddinge Sweden.

Oncogene
|October 7, 2004
PubMed

Insights

All-trans retinoic acid inhibits breast cancer cell growth by downregulating E2F-1 expression via the transcription factor HES-1. This mechanism affects key cell cycle genes, impacting estrogen and heregulin signaling pathways.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The transcription factor HES-1 is crucial for the growth-inhibitory effects of all-trans retinoic acid (ATRA) in breast cancer cells.
  • Estrogen and heregulin-beta1 are known to stimulate breast cancer cell proliferation.

Purpose of the Study:

  • To investigate the role of HES-1 in mediating the effects of ATRA on estrogen- and heregulin-beta1-stimulated breast cancer cell growth.
  • To elucidate the molecular mechanisms by which HES-1 regulates E2F-1 expression and downstream targets.

Main Methods:

  • Utilized T47D breast cancer cells with tetracycline-regulated expression of HES-1 (wild-type and dominant-negative).
  • Assessed cell cycle progression (G1/S transition) and Cdk2 activation.
  • Quantified E2F-1, cyclin E, and NPAT expression following treatment with ATRA, estrogen, or heregulin-beta1.
  • Performed promoter analysis to identify HES-1 binding sites.

Main Results:

  • HES-1 expression inhibited G1/S transition and estrogen-induced Cdk2 activation.
  • ATRA treatment downregulated estrogen- and heregulin-beta1-induced E2F-1 expression, an effect mediated by HES-1.
  • HES-1 directly repressed E2F-1 transcription via a CACGAG-site in the E2F-1 promoter.
  • ATRA inhibited heregulin-beta1-stimulated proliferation via HES-1.
  • Downstream targets of E2F-1, cyclin E and NPAT, were similarly regulated by ATRA and antagonized by dominant-negative HES-1.

Conclusions:

  • HES-1 plays a critical role in inhibiting both estrogen- and heregulin-beta1-stimulated breast cancer cell growth.
  • ATRA induces growth inhibition in these cells through HES-1-mediated downregulation of E2F-1 expression.
  • The HES-1/E2F-1 pathway represents a key mechanism in breast cancer cell proliferation and a potential therapeutic target.

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