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HES-1 inhibits 17β-estradiol and heregulin-β1-mediated upregulation of E2F-1

Oncogene volume 23, pages 8826–8833 (2004)Cite this article

Abstract

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-β1 treatment of T47D cells was inhibited by all-trans retinoic acid and this effect was mediated by HES-1. Interestingly, heregulin-β1-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-β1 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-β1-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.

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Abbreviations

E2:

17β-estradiol

atRA:

all-trans retinoic acid

HRG:

heregulin-β1 EGF-domain

Tet:

tetracycline

dnHES-1:

dominant-negative HES-1

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Acknowledgements

We thank Per Berthelson for help with transfections. Joseph R Nevins for the cyclin E reporter and Maria Bondesson for the E2F-1 reporter and E2F-1 expression plasmids. This study was supported by grants from the Swedish Cancer Fund and Karo Bio AB (to J-ÅG), Magnus Bergvall's Foundation (to AS) and National Institutes of Health, USA (to JW).

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Authors and Affiliations

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

    Johan Hartman, Patrick Müller, Jan-Åke Gustafsson & Anders Ström

  2. Department of Obstetrics and Gynecology, Graduate School of Medicine, University of Tennessee Medical Center, Knoxville, 37920, TN, USA

    James S Foster & Jay Wimalasena

  3. Department of Medical Nutrition, Karolinska Institutet, Novum, S-141 86, Huddinge, Sweden

    Jan-Åke Gustafsson

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  1. Johan Hartman
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  2. Patrick Müller
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  3. James S Foster
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  4. Jay Wimalasena
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Correspondence to Anders Ström.

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Hartman, J., Müller, P., Foster, J. et al. HES-1 inhibits 17β-estradiol and heregulin-β1-mediated upregulation of E2F-1. Oncogene 23, 8826–8833 (2004). https://doi.org/10.1038/sj.onc.1208139

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