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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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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DOI: https://doi.org/10.1038/sj.onc.1208139
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