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Background  In human Estrogen Receptor α (ERα)-positive breast cancers,  5 ′ end dense methylation of the estrogen-regulated  pS2/TFF1  gene correlates with its transcriptional inhibition. However, in some ERα-rich biopsies,  pS2  expression is observed despite the methylation of its TATA-box region. Herein, we investigated the methylation-dependent mechanism of  pS2  regulation.    Methodology/Principal Findings  We observed interplay between Methyl-CpG Binding Domain protein 2 (MBD2) transcriptional repressor and ERα transactivator: (i) the  pS2  gene is poised for transcription upon demethylation limited to the enhancer region containing the estrogen responsive element (ERE); (ii) MBD2-binding sites overlapped with the methylation status of the  pS2  5′ end; (iii) MBD2 depletion elevated  pS2  expression and ectopic expression of ERα partially overcame the inhibitory effect of MBD2 when the ERE is unmethylated. Furthermore, serial chromatin immunoprecipitation assays indicated that MBD2 and ERα could simultaneously occupy the same  pS2  DNA molecule; (iv) concomitant ectopic  ER α expression and MBD2 depletion resulted in synergistic transcriptional stimulation, while the  pS2  promoter remains methylated.    Conclusions/Significance  MBD2 and ERα drive opposite effects on  pS2  expression, which are associated with specific steady state levels of histone H3 acetylation and methylation marks. Thus, epigenetic silencing of  pS2  could be dependent on balance of the relative intracellular concentrations of ERα and MBD2.

A Role for Methyl-CpG Binding Domain Protein 2 in the Modulation of the Estrogen Response of pS2/TFF1 Gene