Do Estrogen Receptor beta Polymorphisms Play A Role in the Pharmacogenetics of Estrogen Signaling?

Abstract

Estrogen hormones play critical roles in the regulation of many tissue functions. The effects of estrogens are primarily mediated by the estrogen receptors (ER) alpha and beta. ERs are ligand-activated transcription factors that regulate a complex array of genomic events that orchestrate cellular growth, differentiation and death. Although many factors contribute to their etiology, estrogens are thought to be the primary agents for the development and/or progression of target tissue malignancies. Many of the current modalities for the treatment of estrogen target tissue malignancies are based on agents with diverse pharmacology that alter or prevent ER functions by acting as estrogen competitors. Although these compounds have been successfully used in clinical settings, the efficacy of treatment shows variability. An increasing body of evidence implicates ERalpha polymorphisms as one of the contributory factors for differential responses to estrogen competitors. This review aims to highlight the recent findings on polymorphisms of the lately identified ERbeta in order to provide a functional perspective with potential pharmacogenomic implications.

Fig. (1)

Genomic organization of the ERβ gene. Exons encoding the ERβ protein are indicated with black boxes. Exon M is indicated as a solid gray bar. The mRNA of the ERβ is schematized with the untranslated 5’ and 3’ regions together with encoding exons whose boundaries in the ERβ protein are shown with broken lines. Solid bars indicate functional features of the domains. In the ERβ protein, A/B indicates the amino-terminus. The A/B domain of ERβ impairs the ability of the receptor to interact with ERE. C is the DNA binding domain responsible for binding to ERE sequences. D region represents the hinge domain and contains a nuclear localization signal. The multifunctional carboxyl-terminus E and F domains are responsible for the ligand binding, dimerization and co-regulatory protein interactions, consequently for the ligand-dependent transactivation function of the receptor.

Fig. (2)

A model for E2-ERβ action. ERβ is localized at the perimemebrane/cytoplasm, but is primarily located in the nucleus. The binding of 17β-estradiol (E2), as the main circulating estrogen hormone, to ERβ induces conformational changes in the receptor that facilitate protein-protein interactions. The perimembrane/cytoplasmic E2-ERβ complex interacts with effector proteins (EP) to initiate signal transduction cascades that result in the activation of various kinases (K). Kinases then modulate the activities of transcription factors (TF) bound to cognate response elements (RE) to mediate transcription. Upon binding to E2 the nuclear ERβ interacts with estrogen responsive elements (EREs) on DNA, and recruits co-regulatory proteins to alter the expression of the estrogen responsive genes (the ERE-dependent E2-ERβ signaling pathway). The nuclear E2-ERβ also regulates the expression of the responsive gene transcription by functional interactions with transcription factors bound to cognate response elements (the ERE-independent E2-ERβ signaling pathway). Activated kinases could also influence the activity of the E2-ERβ complex through post-translational modifications of the complex or associated co-regulatory proteins. The expression of the responsive genes results in the cellular responses.

Fig. (3)

Locations of polymorphisms in the ERβ gene reviewed in the text.

Fig. (4)

Schematics of ERβ isoforms with potential importance in E2 signaling. The T→G transition (*) leads to the replacement of valine with a glycine residue at position 320 resulting in the synthesis of ERβV320G. The exon 3 deleted (Δ) ERβ isoform (ERβΔ3) lacks the critical residues in the DBD for interaction with ERE. Due to exon 4 skipping, ERβΔ4 lacks the D domain critical for the nuclear localization of the receptor. Deletion of exon 5 or exon 6 results in a frame shift mutation causing premature termination of translation. This generates carboxyl-terminally truncated ERβΔ5 or ERβΔ6 lacking the LBD functions of the parent receptor. Designation of ERβ2-5 indicates various ERβ isoforms generated by the differential splicing of exon 8. A common divergence at amino acid 469, together with the novel amino acid stretches at various lengths, is indicated. In ERβ2, a novel 26 amino acid stretch replaces the last 61 amino acids of the parent ERβ of 530 amino acid in length. ERβ3 is generated by the replacement of the last 61 amino acid region with a novel 44 amino acid peptide, leading to a 510 amino acid long protein. The last 61 amino acid stretch of ERβ is replaced by novel 12 and 3 amino acid lengths in ERβ4 and ERβ5 isoforms, respectively.