Original Article

Oncogene (2008) 27, 4075–4085; doi:10.1038/onc.2008.41; published online 3 March 2008

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

L Fleury1,2, M Gerus1,2,3, A C Lavigne1,2,3, H Richard-Foy1,2 and K Bystricky1,2

  1. 1Laboratoire de Biologie Moléculaire Eucaryote, Université de Toulouse, Toulouse, France
  2. 2UMR 5099, CNRS, Toulouse, France

Correspondence: Dr K Bystricky, Laboratoire de Biologie Moléculaire Eucaryote, Université de Toulouse, IBCG, 118 route de Narbonne, Toulouse, Midi Pyrenees 31062, France. E-mail: kerstin@ibcg.biotoul.fr

3These authors contributed equally to this work.

Received 28 August 2007; Revised 27 December 2007; Accepted 31 January 2008; Published online 3 March 2008.

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Abstract

In breast cancer, approximately one-third of tumors express neither the estrogen receptor (ERalpha) nor estrogen-regulated genes such as the progesterone receptor gene (PR). Our study provides new insights into the mechanism allowing hormone-activated expression of ERalpha target genes silenced in ERalpha-negative mammary tumor cells. In cell lines derived from ERalpha-negative MDA-MB231 cells, stable expression of different levels of ERalpha 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 ERalpha-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 ERalpha binding to these regulatory sequences. Although not a general requirement, DNA demethylation is also necessary for derepression of a subset of ERalpha 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 ERalpha target genes in ERalpha-negative tumor cells is transient. Our observations support a model where an epigenetic mark confers stable silencing by precluding ERalpha access to promoters.

Keywords:

breast cancer, chromatin, ERalpha, PR, methylation

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