Duality of estrogen receptor β action in cancer progression

Abstract

The physiological actions of estrogens are primarily mediated by the nuclear hormone receptors estrogen receptor alpha (ERα) and beta (ERβ). Activities of these nuclear steroid hormone receptors in etiology and progression of many hormone-responsive cancers are well-established, yet the specific role of each receptor, and their various expressed isoforms, in estrogen-responsive cancers remains unclear. Recent advances in nuclear receptor profiling, characterization of expressed splice variants, and the availability of new experimental cancer models, has extended the understanding of the complex interplay between the differentially expressed nuclear estrogen receptors. In this review, we discuss proposed roles of ERβ in several subtypes of cancers that lack significant ERα expression and define current understanding of how different ERs collaborate to regulate cellular processes.

Figure 1

Comparative representation of ERβ isoforms. Each receptor is represented by a colored bar with structural domains conserved across the steroid/thyroid super-family of nuclear receptors indicated. Shading in the carboxyl terminus of each ERβ isoform is representative of the predicted differential amino acid sequences in each receptor isoform as a result of alternative splicing. Percentage on ERβ1 highlights the homology shared between each domain of ERα and ERβ1. The amino-terminal A/B regions have a transactivation domain with ligand-independent function and recruits co-activators and co-repressors. The C region contains the DNA-binding domain (DBD), which is needed for binding to specific estrogen response elements (EREs) in estrogen responsive genes. The D region contains several functional domains, including the hinge domain to connect C and E/F. The carboxy-terminal regions E and F contain the ligand-binding domain, which is needed for ligand binding, receptor dimerization, and nuclear translocation. ERβ variants are identical in the first 468 amino acid (AA) sequences, and divergence of AAs are shown after 468 in different colors and representative boxes underneath the variant protein structure.

Figure 2

ERβ activation drives progression of medulloblastoma through cytoprotective and anti-apoptotic mechanisms. Granule cells in the IGL of the healthy mouse cerebellum (a) only weakly express ERβ, leading to a highly structured network of mossy fiber and parallel fiber synapses on Purkinje cell dendrites [A1]. Dysregulation of granule cell mitogenesis results in cerebellar overgrowth, excessive granule cell numbers in the IGL and tumor formation associated with the ML (b). In MB cells (c), ERβ is highly expressed and estrogen drives tumor formation and progression through cytoprotective mechanisms that decrease apoptosis. Addition of anti-estrogens (+ anti-estrogen) block the protective ERβ actions increases apoptosis resulting in decreased tumor size. Abbreviations: ML, molecular layer; PL, Purkinje cell layer; IGL, internal granular layer. Purkinje cell adapted from Cell Image Library CCDB_3687.