Estrogen Receptors as Molecular Targets of Endocrine Therapy for Glioblastoma

Abstract

Hormonal factors may participate in the development and progression of glioblastoma, the most aggressive primary tumor of the central nervous system. Many studies have been conducted on the possible involvement of estrogen receptors (ERs) in gliomas. Since there is a tendency for a reduced expression of ERs as the degree of malignancy of such tumors increases, it is important to understand the role of these receptors in the progression and treatment of this disease. ERs belong to the family of nuclear receptors, although they can also be in the plasmatic membrane, cytoplasm and mitochondria. They are classified as estrogen receptors alpha and beta (ER⍺ and ERβ), each with different isoforms that have a distinct function in the organism. ERs regulate multiple physiological and pathological processes through the activation of genomic and nongenomic pathways in the cell. Nevertheless, the role of each isoform in the development and progression of glioblastoma is not completely clear. Diverse in vitro and in vivo studies have shown encouraging results for endocrine therapy as a treatment for gliomas. At the same time, many questions have arisen concerning the nature of ERs as well as the mechanism of action of the proposed drugs. Hence, the aim of the current review is to describe the drugs that could possibly be utilized in endocrine therapy for the treatment of high-grade gliomas, analyze their interaction with ERs, and explore the involvement of these drugs and receptors in resistance to standard chemotherapy.

Keywords: drugs; endocrine therapy; estrogen receptors; glioblastoma; resistance to chemotherapy.

Figure 1

Structure of estrogen receptors (ERs), as modified by Jia et al. (2015). ER⍺ and ERβ have the same structural regions (A–F), although the degree of similarity of the domains varies. The A/B amino-terminal region contains the amino-terminal domain and the ligand-independent AF-1 domain. These domains are responsible for the recruitment of coregulators (coactivators and corepressors). The C region is the binding domain of DNA (DBD), while D is known as the hinge region. The latter also encompasses part of the ligand-dependent activation function (AF) domain and the nuclear localization signal. The C-terminus region, comprising E and F, contains the ligand binding domain (LBD) and ligand-dependent AF-2. The main isoforms of ERα are portrayed, with their respective molecular weight. A difference can be appreciated in region F of ERα36, which is caused by the transcription of exon 9. In the case of ERβ, each isoform presents variations in the F domain due to the shuffling of exon 8. Reprinted from ref. [5]. Best Pract Res Clin Endocrinol Metab, 29(4), Jia M.; Dahlman-Wright K.; Gustafsson JÅ. Estrogen receptor alpha and beta in health and disease, pp. 557–568. Copyright 2015, with permission from Elsevier.

Figure 2

Genomic and non-genomic pathways of estrogen receptors (ERs). ERs can act through genomic pathways and nongenomic pathways. The nongenomic pathways may also result in the transcriptional activation of genes. (1) Classic pathway: dimerization of ERs triggered by the binding of E2, followed by nuclear translocation to regulate the transcriptional activity of genes bearing the estrogen response element (ERE). (2) ER activity independent of ERE: the recognition of promoters result from the protein−protein interaction of ERs with other transcription factors (TF). (3) Ligand-independent activity: the binding of growth factors to membrane receptors triggers protein kinase cascades that activate ERs by phosphorylation, promoting their nuclear translocation and recognition of the ERE in target genes. (4) Nongenomic pathway: the binding of the ligand causes mER and GPER1 to initiate signaling pathways, which promote the activation of enzymes and transcriptional factors that can regulate the transcription of diverse genes. ER, estrogen receptors; mER, membrane estrogen receptors; TF, transcription factor; ERE, estrogen response element; non-ERE, other transcription factors distinct from ERE; P, phosphorylated receptor; G, G protein-coupled receptor; GPER, G protein-coupled estrogen receptor; cav, caveolin.