Transcriptional activation of estrogen receptor alpha in human breast cancer cells by histone deacetylase inhibition

Recent findings have established a connection between DNA methylation and t ranscriptionally inactive chromatin characterized by deacetylated histones, Because the absence of estrogen receptor alpha (ER alpha) gene expression has been associated with aberrant methylation of its CpG island in a signif icant fraction of breast cancers, we tested whether histone deacetylase act ivity contributes to the transcriptional inactivation of the methylated ER gene in a panel of ER-negative human breast cancer cells. Treatment of thes e cells with trichostatin A, a specific histone deacetylase inhibitor, led to dose- and time-dependent re-expression of ER mRNA as detected by reverse transcription-PCR without alteration in ER alpha CpG island methylation. T richostatin A-induced ER re-expression was associated with increased sensit ivity to DNase I at the ER locus in MDA-MB-231 cells. These data implicate inactive chromatin mediated by histone deacetylation as a critical componen t of ER gene silencing in human breast cancer cells. Therefore, histone dea cetylation may be a potential target for therapeutic intervention in the tr eatment of a subset of ER-negative breast cancers.