The Multifaceted Mechanisms of Estradiol and Estrogen Receptor Signaling

Abstract

The steroid hormone 17␤-estradiol (E 2 ) is a key regulator of growth, differentiation, and function in a wide array of target tissues, including the male and female reproductive tracts, mammary gland, and skeletal and cardiovascular systems. The predominant biological effects of E 2 are mediated through two distinct intracellular receptors, ER␣ 1 and ER␤, each encoded by unique genes (1) but possessing the hallmark modular structure of functional domains characteristic of the steroid/thyroid hormone superfamily of nuclear receptors (introduced in the Minireview Prologue (54)). Certain functional domains of the ER␣ and ER␤ exhibit a high degree of homology, namely the DNA-and ligand-binding domains, at 97 and 60%, respectively, whereas considerable divergence is apparent in the N terminus (18% homology). Hence, ER␣ and ER␤ interact with identical DNA response elements and exhibit a similar binding affinity profile for an array of endogenous, synthetic, and naturally occurring estrogens when assayed in vitro (2). In vitro studies also suggest the two receptors may play redundant roles in estrogen signaling; however, tissue localization studies have revealed distinct expression patterns for each receptor that suggest otherwise. Whereas ER␣ is the predominant subtype expressed in the breast, uterus, cervix, vagina, and several additional target organs, ER␤ exhibits a more limited expression pattern and is primarily detected in the ovary, prostate, testis, spleen, lung, hypothalamus, and thymus (3). Regional expression differences of the two receptors have been identified in the brain (4). Further evidence of distinct biological functions for the ERs is revealed by the contrasting phenotypes observed in the individual lines of ER knockout mice, the ␣ERKO and ␤ERKO, which exhibit phenotypes that generally mirror the respective ER expression patterns (5). The most striking phenotypes in the female ␣ERKO mice include estrogen insensitivity (leading to hypoplasia) in the reproductive tract, hypergonadotropic hypergonadism, lack of pubertal mammary gland development, and excess adipose tissue, whereas in the male, testicular degeneration and epididymal dysfunction are major factors (5). These phenotypes combined with severe deficits in sexual behavior result in complete infertility in both sexes of the ␣ERKO. In contrast, ␤ERKO males are fertile and to date show no obvious phenotypes; however, ␤ERKO females exhibit inefficient ovarian function and subfertility. Interestingly, compound knockout mice (␣␤ERKO) exhibit phenotypes that most heavily resemble those of the ␣ERKO, with the exception of the ovarian phenotype, characterized by progressive germ cell loss accompanied by redifferentiation of the surrounding somatic cells, suggesting a requisite role for both ER forms in this tissue (6, 7).With the cloning of the first ER cDNA 15 years ago has come an immense appreciation of the complex molecular mechanisms underlying the diverse physiological actions of E 2 and the multitude of synthetic ER ligands. This minireview wi...

Estrogen regulates iron homeostasis through governing hepatic hepcidin expression via an estrogen response element

“…In the absence of estrogen, ERs could be activated by growth factors and bind directly to ERE, which is ligand-independent pathway. There are also ERE-independent pathway and cell membrane signaling pathway (Hall et al, 2001). The consensus sequence of ERE is composed of palindromic half-sites intervened by three nucleotides (5′-GGTCAnnn-TGACC-3′).…”

Evolution of adrenal and sex steroid action in vertebrates: a ligand‐based mechanism for complexity

“…Examples are insulin-like growth factor, epidermal growth factor, and transforming growth factor-beta, which act by binding to receptors on the cell membrane, and c-Fos and c-Jun, transcription factors that bind to AP-1 sites [9][10][11]25]. Cross-talk between these proteins and the five steroid receptors increases the combinatorial complexity for regulation of development in vertebrates.…”

“…1) [5][6][7][8], which is a ligand-based based mechanism for regulating the interactions between networks of transcription factors [9][10][11], as well as directly regulating the transcription of specific genes. Receptors for these steroids have not been found in invertebrates.…”

Antiestrogens: structure-activity relationships and use in breast cancer treatment

“…AEs are steroids or steroid mimics that compete with endogenous estrogens (Fig. 1A) for binding to ERs and modify their activity as ligand-dependent transcriptional regulators (Hall et al . 2001, Ascenzi et al .…”