Epigenetic regulation of estrogen signaling in breast cancer

Abstract

Estrogen signaling is mediated by ERα and ERβ in hormone dependent, breast cancer (BC). Over the last decade the implication of epigenetic pathways in BC tumorigenesis has emerged: cancer-related epigenetic modifications are implicated in both gene expression regulation, and chromosomal instability. In this review, the epigenetic-mediated estrogen signaling, controlling both ER level and ER-targeted gene expression in BC, are discussed: (1) ER silencing is frequently observed in BC and is often associated with epigenetic regulations while chemical epigenetic modulators restore ER expression and increase response to treatment;(2) ER-targeted gene expression is tightly regulated by co-recruitment of ER and both coactivators/corepressors including HATs, HDACs, HMTs, Dnmts and Polycomb proteins.

Keywords: DNA methylation; breast cancer; epigenetic; estrogen; histones.

Figure 1. Structure and activation of Estrogen Receptor. (A) Schematic representation of ERα domains and their potential interaction with co-activators/co-repressors and ERE. (B) Mechanisms of ERα activation by estrogens. Recruitment of liganded ERα on DNA is mediated directly on ERE or not directly via SP1 or NFKB interaction.

Figure 2. Model of epigenetic inactivation of ESR1. Primary methylation and recruitment of ICBP90 on ERα promoter, provoke histone deacetylation and a large secondary methylation and ERα silencing. Ac, acetylation of histones; white circles symbolize unmethylated CpGs and black circles symbolize methylated CpGs.

Figure 3. Model of ER-mediated epigenetic response in ER target genes. (A) Schematic representation of action of coactivators and corepressors. (B) Direct and indirect interactions of ERα with epigenetic related proteins.