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.

Peptidylarginine deiminase 2-catalyzed histone H3 arginine 26 citrullination facilitates estrogen receptor α target gene activation

“…Despite decades of research into mechanisms of 17β-estradiol (E2)-responsive gene transcription, our understanding of this process is far from complete (2). It is generally believed that, upon E2 binding, the nuclear hormone receptor estrogen receptor α (hereafter called ER) undergoes major structural reorganization, associates with estrogen-response elements (ERE) within target gene promoters, and recruits a range of coactivators including histone modification enzymes (3)(4)(5)(6). After deposition, the resulting histone modifications can then modulate target gene activity by affecting local chromatin structure and regulating the accessibility of chromatin to transcription factors (2,5,(7)(8)(9).…”

Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer

“…Dysregulation or aberrant deposition of histone acetylation is a common trait of several malignant tumors and has been a successful target for therapeutic intervention (66,67). Many of the histone residues that are methylated (e.g., H3K4, H3K9, and H3K27) can alternatively be modified by acetylation, generally promoting gene activation and antagonizing gene repression (68)(69)(70)(71)(72)(73)(74). Specifically, H3K4 acetylation may play a role in establishing or maintaining bivalent domains in certain cell types.…”

“…While estradiol has biological roles in both normal proliferation and normal differentiation, providing the cellular plasticity needed for tissue remodeling throughout the reproductive years, unregulated estradiol exposure can result in constitutive activation of metabolic and cell cycle regulatory genes and increases the risk of breast cancer. There is strong clinical and epidemiological data linking estrogen exposure with an increased risk of developing breast cancer (68)(69)(70)(71)(72)(73)(74).…”

Targeting transcription factor corepressors in tumor cells

“…Moreover, tamoxifen combined with HDACi has proven to be beneficial in cases of advanced breast cancer unresponsive to hormonal therapy. Coadministration of HDACi with an aromatase inhibitor is also effective for the treatment of ERa-negative and endocrineresistant breast cancers [17]. Interestingly, ER facilitates breast cancer progression through the transcription of estrogen response element (ERE)-containing target genes and blockade of p53 antiproliferative actions via NCoR1/ SMRT.…”