Estrogen Receptors: How Do They Signal and What Are Their Targets

Abstract

During the past decade there has been a substantial advance in our understanding of estrogen signaling both from a clinical as well as a preclinical perspective. Estrogen signaling is a balance between two opposing forces in the form of two distinct receptors (ERα and ERβ) and their splice variants. The prospect that these two pathways can be selectively stimulated or inhibited with subtype-selective drugs constitutes new and promising therapeutic opportunities in clinical areas as diverse as hormone replacement, autoimmune diseases, prostate and breast cancer, and depression. Molecular biological, biochemical, and structural studies have generated information which is invaluable for the development of more selective and effective ER ligands. We have also become aware that ERs do not function by themselves but require a number of coregulatory proteins whose cell-specific expression explains some of the distinct cellular actions of estrogen. Estrogen is an important morphogen, and many of its proliferative effects on the epithelial compartment of glands are mediated by growth factors secreted from the stromal compartment. Thus understanding the cross-talk between growth factor and estrogen signaling is essential for understanding both normal and malignant growth. In this review we focus on several of the interesting recent discoveries concerning estrogen receptors, on estrogen as a morphogen, and on the molecular mechanisms of anti-estrogen signaling.

Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer

“…TAP-ERb effects on E2-induced MCF-7 cell proliferation and cell cycle progression were also investigated and the results, reported in Figures 1c and d, show that cells expressing exogenous ERb grow much slower in response to estrogen than wt or C-TAP-ERa cells, consequent to reduced G1-S transition (Figure 1d). It is worth mentioning that the cell cycle inhibitory effects of ERb are well known (Heldring et al, 2007;Grober et al, 2011, and references therein) and are more evident at relatively higher concentrations of E2 (X10 À10 ), compatible with the lower affinity of this ER subtype for the hormone (compare, for each cell clone, the S þ G2 fraction in hormone-stimulated vs -starved cells). The efficiency of PPT in promoting cell cycle progression (Figure 1d) relates to its ability to promote ERamediated gene transcription (Figure 1b), confirming the direct link between transcriptional activity of this receptor subtype and the mitogenic effects of estrogen (Cicatiello et al, 2010).…”

“…Estrogens have a role in breast cancer (BC) pathogenesis and progression by controlling mammary cell proliferation and key cellular functions via the estrogen receptors (ERa and ERb: Heldring et al, 2007). ERs are members of the nuclear receptors superfamily of ligand-dependent transcription factors that both regulate gene expression controlling the estrogen signal transduction cascade with distinct and even antagonistic roles.…”

Effect of ligand-activated estrogen receptor β on lymphoma growth in vitro and in vivo

“…1 Cellular signaling by estrogens is mediated via the estrogen receptors a and b (ERa and ERb). 2 In human beings, ERa is mainly expressed in reproductive tissues (uterus, ovary), breast, kidney, bone, white adipose tissue and liver, whereas the highest levels of ERb expression is found in the ovary, central nervous system, cardiovascular system, lung, male reproductive organs, prostate, colon, kidney and the immune system. 3,4 With regard to the immune system, previous studies have shown that ERb is the dominant ER expressed in mature leukocytes from peripheral blood, tonsils or spleen of healthy individuals.…”

“…5 Although the main physiologically active estrogen, 17b-estradiol (E 2 ), binds and activates both ERa and ERb, the two ER's exert different biological responses. 2 This means that the ratio of ERa/ERb in any given cell or tissue will determine the response to estrogen. Several studies have suggested that ERa and ERb elicit opposite effects on cell proliferation.…”

Assessment of Estrogenic Activity of Perfluoroalkyl Acids Based on Ligand-induced Conformation State of Human Estrogen Receptor

“…20 Ligand binding induces distinct conformational alteration of the ER ligand binding domain (LBD), and then may trigger gene transcription and disturb the hormone response pathways. 21 It is reported that the specific conformation changes in the ER-LBD are highly dependent on the structure of the ligand. The crystal structure reveals that ER-LBD consists of 12 helixes, which form a three-layered antiparallel α-helical sandwich conformation.…”