The silent estrogen receptor--can we make it speak?

Abstract

One of the most common cancers in women world wide, breast cancer is classically an endocrine-dependent cancer. It has been known for over a century that development, progression and metastasis of breast cancer are strongly influenced by hormonal factors. Indeed about two-thirds of breast cancers express the estrogen receptor α (ERα) protein, a key predictor of prognosis and response to endocrine therapy. These cancers are frequently amenable to therapies that target estrogen signaling pathways, including selective estrogen receptor modulators like tamoxifen, selective estrogen receptor downregulators like fulvestrant; and agents that reduce estrogen ligand like aromatase inhibitors and ovarian suppression through luteinizing hormone-releasing hormone (LHRH) agonists. It is likely that these approaches, especially adjuvant tamoxifen, have contributed to the reduction in breast cancer mortality that has been observed in recent years. However, data from clinical studies have suggested that only about 60% of ERα-positive breast cancers respond to hormonal therapy. Further, those tumors that lack expression of ERα and the estrogen-regulated progesterone receptor (PgR) are unresponsive to hormone therapy. Thus the problem of acquired or de novo endocrine resistance is a substantial one. Recent molecular and biological advances have contributed to our understanding about potential underlying mechanisms. Here we will focus especially on silencing the expression of ERα as one such endocrine-resistance mechanism and how it might be exploited clinically.

Figure 1

Therapeutic strategies to block estrogen receptor function: Aromatase inhibitors like letrozole, anastrozole and exemestane inhibit the enzyme leading to decreased E2 levels. Selective ER downregulators (SERDs) like fulvestrant bind to ER and sequester it, thereby inhibiting ER-mediated gene transcripton and disrupting ER nuclear localization through the ubiquitin-proteosomal pathway.

Figure 2

Crosstalk between estrogen receptor-α (ERα) and growth factor signaling: overexpression of growth factors is a proposed cause for suppression of ERα expression. E2 bound ER modulates expression of estrogen response genes like cyclin D while its non-genomic targets include inhibition of nuclear factor-κB (NFκB). Activation of epidermal growth factor receptors like EGFR and HER2 (as a consequence of ERα downregualtion) triggers activation of mitogen activated protein kinases (MAPKs) and NFκB. MAPKs are implicated in repression of ERα expression and in enhanced ERα independent cell proliferation. Red T symbol indicates potential targets for inhibition that may result in ERα re-expression.

Figure 3

Methylation sites and epigenetic complexes identified at the estrogen receptor α promoter: Schematic of the ERα gene (ESR1) on chromosome 6q25.1. CpG dinucleotides located on ERα promoter region from −2000 to +2000 are depicted by green lines. Specific CpG residues demonstrated to be sites of potential CpG methylation are marked by dark blue lines and are situated at the distal (B) and proximal promoters (identified by pink arrows at −1987 and +1 respectively). Yellow boxes designate predicted CpG islands (as defined by www.urogene.org/methprimer) which identify four regions of dense CpG population located at the proximal promoter (nucleotides −280 to +359) and just upstream of the proximal promoter (residing at nucleotides +443 to +1140; +1380 to +1427; and +1463 to +1563). Promoter regions determined to contain specific DNA and histone modifications are marked by numbered black arrows. Epigenetic regulators associated with each specific promoter region include DNA Methyltransferases (red boxes), Methyl-CpG-Binding Proteins (blue boxes), histone modifying enzymes (green boxes) and other transcriptional repressors (purple boxes).