Estrogen receptors and human disease

Abstract

Estrogens influence many physiological processes in mammals, including but not limited to reproduction, cardiovascular health, bone integrity, cognition, and behavior. Given this widespread role for estrogen in human physiology, it is not surprising that estrogen is also implicated in the development or progression of numerous diseases, which include but are not limited to various types of cancer (breast, ovarian, colorectal, prostate, endometrial), osteoporosis, neurodegenerative diseases, cardiovascular disease, insulin resistance, lupus erythematosus, endometriosis, and obesity. In many of these diseases, estrogen mediates its effects through the estrogen receptor (ER), which serves as the basis for many therapeutic interventions. This Review will describe diseases in which estrogen, through the ER, plays a role in the development or severity of disease.

Figure 1

Models of estrogen action. In the “classical” pathway of estrogen action (i), estrogen or other selective estrogen receptor modulators (SERMs) bind to the estrogen receptor (ER), a ligand-activated transcription factor that regulates transcription of target genes in the nucleus by binding to estrogen response element (ERE) regulatory sequences in target genes and recruiting coregulatory proteins (CoRegs) such as coactivators. Rapid or “nongenomic” effects of estrogen may also occur through the ER located in or adjacent to the plasma membrane (ii), which may require the presence of “adaptor” proteins, which target the ER to the membrane. Activation of the membrane ER leads to a rapid change in cellular signaling molecules and stimulation of kinase activity, which in turn may affect transcription. Lastly, other non-ER membrane-associated estrogen-binding proteins (EBPs) may also trigger an intracellular response (iii).

Figure 2

Exon structure, primary transcript, and common mRNA splice variants of the ER. (A) The most common splice variants of ERα are expressed in multiple tissues and arise from deletions of internal exons, resulting in truncated proteins lacking segments of the DNA-binding domain (DBD) or hormone-binding (ligand-binding) domain (LBD) of the receptor. Most variant isoforms possess little transcriptional activity, with the exception of ER&Dgr;E5, which binds DNA but lacks most of the LBD, resulting in low levels of constitutive activity in some cell lines. ER&Dgr;E2 lacks the DBD and the dimerization domain, while ER&Dgr;E3 lacks part of the DBD. ER&Dgr;E4, which lacks part of the LBD, does not bind DNA or hormone, and ER&Dgr;E6 is missing part of the LBD and dimerization domain. ER&Dgr;E7 lacks the activation function 2 (AF2) domain and part of the LBD. ER&Dgr;E3, ER&Dgr;E5, and ER&Dgr;E7 variants have demonstrated a dominant-negative effect on transcriptional activity mediated by wild-type ER. Adapted with permission from Molecular Endocrinology (S33). (B) Mammalian ERβ variants identified in humans (h), rats (r), mice (m), cows (b), sheep (o), and pigs (p). As described for ERα, wild-type ERβ (ERβ1) possesses both a DBD (C domain) and an LBD (E domain). ERβ2 codes for a variant that contains an additional 18 amino acids in the LBD, while ERβ1-δ3 lacks exon 3 and therefore part of the DBD. ERβ2-δ3 contains both of these variations. ERβ1-δ5 lacks exon 5, and in ERβ_CX, the C-terminal 61 amino acids are replaced by a unique sequence of 26 amino acids. ERβ4 is truncated at both the N and the C termini. In humans, variants lacking exon 2, exon 4, exon 6, and exon 7 also exist. Adapted from ref. S34.

Figure 3

Differential ER structure and coactivator recruitment by ER agonists, antagonists, and SERMs. Upon binding ER ligands such as estradiol or SERMs, the receptor undergoes a conformational change, allowing the ER to exist in a spectrum of conformations from active to inactive depending on the nature of the bound ligand. This conformation, in turn, regulates the recruitment of specific transcriptional coregulatory proteins and the resulting transcriptional apparatus. Coactivators such as SRC1 bind to the active (agonist-bound) form of the receptor and activate transcription, while corepressors interact with the antagonist-bound receptor, inhibiting transcription. Depending on the cellular and promoter context, both unique and overlapping sets of genes may be regulated by various ligands. Adapted with permission from The American Journal of Cardiology (S35).