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Eliminating epigenetic barriers induces transient hormone-regulated gene expression in estrogen receptor negative breast cancer cells

Oncogene volume 27, pages 4075–4085 (2008)Cite this article

Abstract

In breast cancer, approximately one-third of tumors express neither the estrogen receptor (ERα) nor estrogen-regulated genes such as the progesterone receptor gene (PR). Our study provides new insights into the mechanism allowing hormone-activated expression of ERα target genes silenced in ERα-negative mammary tumor cells. In cell lines derived from ERα-negative MDA-MB231 cells, stable expression of different levels of ERα from a transgene did not result in transcription of PR. A quantitative comparative analysis demonstrates that inhibiting DNA methyltransferases using 5-aza-2′-deoxycytidine or specific disruption of DNMT1 by small interfering RNAs and treatment with the histone-deacetylase inhibitor trichostatin A enabled ERα-mediated hormone-dependent expression of endogenous PR. We show that demethylation of a CpG island located in the first exon of PR was a prerequisite for ERα binding to these regulatory sequences. Although not a general requirement, DNA demethylation is also necessary for derepression of a subset of ERα target genes involved in tumorigenesis. PR transcription did not subsist 4 days after removal of the DNA methyltransferase blocking agents, suggesting that hormone-induced expression of ERα target genes in ERα-negative tumor cells is transient. Our observations support a model where an epigenetic mark confers stable silencing by precluding ERα access to promoters.

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Acknowledgements

We thank F Gannon for cell line MDA-66, F Vignon for cell line HE-5, D Trouche and members of his group for insightful discussions and assistance and D Trouche for critical reading of the manuscript. This work was partially supported by the following grants: ANR JC08_42115, La Ligue contre le Cancer, comité du Tarn and comité de Haute Garonne, INCa, contract no. PL 06-045 and Region Midi-Pyrénées.

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  1. M Gerus and A C Lavigne: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratoire de Biologie Moléculaire Eucaryote, Université de Toulouse, Toulouse, France

    L Fleury, M Gerus, A C Lavigne, H Richard-Foy & K Bystricky

  2. UMR 5099, CNRS, Toulouse, France

    L Fleury, M Gerus, A C Lavigne, H Richard-Foy & K Bystricky

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Correspondence to K Bystricky.

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Fleury, L., Gerus, M., Lavigne, A. et al. Eliminating epigenetic barriers induces transient hormone-regulated gene expression in estrogen receptor negative breast cancer cells. Oncogene 27, 4075–4085 (2008). https://doi.org/10.1038/onc.2008.41

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