Epigenetics of estrogen receptor signaling: role in hormonal cancer progression and therapy

Abstract

Estrogen receptor (ERα) signaling plays a key role in hormonal cancer progression. ERα is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin. Emerging evidence suggests that ERα signaling has the potential to contribute to epigenetic changes. Estrogen stimulation is shown to induce several histone modifications at the ERα target gene promoters including acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes. Deregulation of enzymes involved in the ERα-mediated epigenetic pathway could play a vital role in ERα driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERα driven epigenetic changes. In this review, we summarize current knowledge on mechanisms by which ERα signaling potentiates epigenetic changes in cancer cells via histone modifications.

Figure 1.

Schematic representation of the current understanding of ERα regulation of epigenetic modifications of histones. ERα–mediated transcription involves coordinated interactions of ERα with acetylases and deacetylases, methylases and demethylases. Ligand stimulation uniquely modulates ERα interactions with histone modifying enzymes. In addition, estrogen signaling has the potential to activate extranuclear signaling that activates several kinase cascades that either directly modifies histone tails or indirectly influence functions and/or recruitment of histone modifying enzymes. Deregulation of ERα-mediated epigenetic signaling will have implications in hormonal tumor progression and therapy resistance.