The Multifaceted Mechanisms of Estradiol and Estrogen Receptor Signaling*

The steroid hormone 17 -estradiol (E2) 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 E2 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 DNAand 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 E2 and the multitude of synthetic ER ligands. This minireview will discuss the recent progress toward our understanding of the molecular mechanisms of estrogen signaling, focusing on the following four pathways: 1) classical ligand-dependent; 2) ligand-independent; 3) DNA binding-independent; and 4) cell-surface (nongenomic) signaling (Fig. 1). Insights into these cellular/molecular mechanisms and the role of each ER subtype as revealed by ER-null animal models will be incorporated. A discussion of the mechanisms of action of several relevant selective ER modulator (SERM) ligands and their activities through the different ER signaling pathways will follow.