Epigenetic Reactivation of Estrogen Receptor: Promising Tools for Restoring Response to Endocrine Therapy

Abstract

Breast tumors expressing estrogen receptor alpha (ER) respond well to therapeutic strategies using SERMs (selective estrogen receptor modulators) such as tamoxifen. However, about thirty percent of invasive breast cancers are hormone independent because they lack ER expression due to hypermethylation of ER promoter. Treatment of ER-negative breast cancer cells with demethylating agents and histone deacetylase inhibitors leads to expression of ER mRNA and functional protein. Additionally, growth factor signaling pathways have also been implicated in ER silencing in ER-negative tumor phenotype. Recently, important role of components of ubiquitin-proteasome pathway has been shown in mediating downregulation of ER. In this article, we will review various mechanisms underlying the silencing of ER in ER negative tumor phenotype and discuss diverse strategies to combat it. Ongoing studies may provide the mechanistic insight to design therapeutic strategies directed towards epigenetic and non-epigenetic mechanisms in the prevention or treatment of ER-negative breast cancer.

Conflict of interest statement

Conflicts of Interest

No potential conflicts of interest to disclose.

Figures

Figure 1. Schematic representation of the two human estrogen receptors, ERα and ERβ

Both receptors contain five functional domains (A-E) as other members of the nuclear hormone receptor superfamily and an additional F domain at C terminal. Functional domains include, the DNA-binding domain (DBD), the Ligand-binding domain (LBD), the ligand-independent activation function AF-1, ligand-dependent activation function AF-2. The percentage identity between the two receptors is indicated.

Figure 2. Genomic classical and non-classical actions of ER

In classical genomic mode of action, estrogen (E2) binds estrogen receptor (ER), induces dimerization of the receptors, nuclear translocation and recruitment to estrogen response element (ERE) in the promoter region of the target genes. Coactivators such as AIB1, CBP/p300, PCAF are recruited to the transcription complex followed by gene transcription. In non-classical mode of action, estrogen bound ER gets recruited to other transcription factors such as Jun/Fos to activate transcription.

Figure 3. Nongenomic ER activity. Estrogen activates ER in or near membrane

Membrane ER binds to growth factors signaling elements and activates key molecules of growth factor signaling which can further activate ER and its coregulators to enhance nuclear effects.

Figure 4. Differential recruitment of coregulatory complexes to the promoter region of un/hypomethylatedvshypermethylated ER

ER promoter is un/hypomethylated in ER-positive breast cancer cells with acetylated histones and binding of coactivator complexes. In contrast, ER promoter is hypermethylated in ER-negative breast cancer cells with deacetylated histones and binding of various methyl-binding proteins (MBD1, MBD2 and MeCP2) and DNA methyltransferases (DNMT1 and DNMT3b).

Figure 5. Reactivation of ER in ER-negative breast cancer cells

ER-negative cells can be treated with a combination of DNMT and HDAC inhibitors resulting in demethylation and release of the repression complex consisting of various methyl-binding proteins and DNA methyltransferases. Demethylation and release of repression complex paves the way for histone acetylation and coactivator binding resulting in ER reexpression in ER-negative breast cancer cells.

Figure 6. Sensitizing ER-negative breast cancer cells to endocrine therapy

ER can be reactivated in ER-negative breast cancer cells using a combination of therapies. Reactivated ER can be targeted with tamoxifen. Tamoxifen bound reactivated ER recruits compressor complexes resulting in modulation of ER-responsive gene expression.