Breast Cancer Research and Treatment

, Volume 120, Issue 2, pp 317–326 | Cite as

SOX9 mediates the retinoic acid-induced HES-1 gene expression in human breast cancer cells

  • Patrick Müller
  • Justin D. Crofts
  • Ben S. Newman
  • Laura C. Bridgewater
  • Chin-Yo Lin
  • Jan-Åke Gustafsson
  • Anders Ström
Preclinical study

Abstract

We have previously shown that the anti-proliferative effect of retinoic acid in human breast cancer cell line MCF-7 is dependent on HES-1 expression. Here we show that retinoic acid induces HES-1 expression via upregulation of transcription factor SOX9. By expressing a dominant negative form of SOX9, disrupting endogenous SOX9 activity, the retinoic acid-induced HES-1 mRNA expression was inhibited. We found an enhancer regulating HES-1 expression: two SOX9 binding sites upstream of the HES-1 gene that were capable of binding SOX9 in vitro. By performing chromatin immunoprecipitation, we showed that SOX9 binding to the HES-1 enhancer was induced by retinoic acid in vivo. In reporter assays, transfection of a SOX9 expression plasmid increased the activity of the HES-1 enhancer. The enhancer responded to retinoic acid; furthermore, the expression of a dominant negative SOX9 abolished this response. Taken together, we present here a novel transcriptional mechanism in regulating hormone-dependent cancer cell proliferation.

Keywords

atRA HES-1 SOX9 Proliferation 

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Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Patrick Müller
    • 1
  • Justin D. Crofts
    • 2
  • Ben S. Newman
    • 2
  • Laura C. Bridgewater
    • 2
  • Chin-Yo Lin
    • 2
  • Jan-Åke Gustafsson
    • 1
    • 3
  • Anders Ström
    • 3
  1. 1.Department of Biosciences and NutritionKarolinska InstitutetHuddingeSweden
  2. 2.Department of Microbiology and Molecular BiologyBrigham Young UniversityProvoUSA
  3. 3.Center for Nuclear Receptors and Cell Signaling, Department of Cell Biology and BiochemistryUniversity of HoustonHoustonUSA

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