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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Eliminating epigenetic barriers induces transient hormone-regulated gene expression in estrogen receptor negative
L Fleury1, M Gerus, A C Lavigne
1Laboratoire de Biologie Moléculaire Eucaryote, Université de Toulouse, Toulouse, France.
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.
Insights
Estrogen receptor-negative breast cancer cells can activate silenced genes. DNA demethylation and histone deacetylation enable estrogen receptor alpha (ERalpha) to bind and express progesterone receptor (PR) in these cells.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Approximately one-third of breast cancers lack estrogen receptor alpha (ERalpha) and its target genes.
- ERalpha-negative tumors present a challenge for endocrine therapy.
- Understanding mechanisms of gene silencing in ERalpha-negative cells is crucial.
Purpose of the Study:
- To investigate the mechanism of hormone-activated gene expression in ERalpha-negative breast cancer cells.
- To identify epigenetic modifications that silence ERalpha target genes.
Main Methods:
- Stable expression of ERalpha in ERalpha-negative MDA-MB231 cell lines.
- Inhibition of DNA methyltransferases (DNMTs) using 5-aza-2'-deoxycytidine.
- Disruption of DNMT1 using small interfering RNAs (siRNAs).
- Treatment with histone deacetylase inhibitor trichostatin A.
- Quantitative comparative analysis of gene expression.
Main Results:
- Stable ERalpha expression alone did not restore progesterone receptor (PR) transcription.
- DNMT inhibition and histone deacetylase inhibition enabled ERalpha-mediated PR expression.
- Demethylation of a CpG island in the PR first exon was necessary for ERalpha binding.
- DNA demethylation was also required for derepression of some ERalpha target genes involved in tumorigenesis.
- PR transcription was transient, lasting only while DNMT inhibitors were present.
Conclusions:
- Epigenetic silencing, specifically DNA methylation, prevents ERalpha access to target gene promoters in ERalpha-negative breast cancer cells.
- Reversal of epigenetic marks can restore hormone-dependent gene expression.
- This suggests a potential therapeutic strategy for ERalpha-negative breast cancers.
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