Estrogen Receptors: Their Actions and Functional Roles in Health and Disease

Abstract

Abstract:Our view of estrogen signalling has undergone a paradigm shift over the recent 10-15 years with the discovery of a second estrogen receptor, ERβ, in 1995 and the finding that estrogens play an important role also in male physiology. Aromatase deficient patients and aromatase knock-out mice have highlighted the importance of estrogens in development and metabolic homeostasis while ER knock-out mice, ERα-/-and ERβ-/-, have shown that both ERs are of physiological importance and that ERα and ERβ have distinct and non-overlapping functions in the body. The uses of ER subtype-selective ligands in various animal models have further substantiated the distinctive physiological roles of ERα and ERβ and shown that they, in many contexts, are antagonistic against one another. Structural studies of the ligand-binding domains of ERα and ERβ have provided in-depth information on ligand recognition, receptor activation, and recruitment of coregulators. The cloning of coregulators and chromatin modulators together with sophisticated methodology to study gene regulation has significantly increased our understanding of cellular and target gene responses to estrogens, SERMs, and ER subtype-selective ligands. This book chapter will review our current understanding of the mechanisms of ERα-and ERβ-dependent estrogen signalling, the role of ERα and ERβ in health and disease, and the potential clinical uses of ERα-and ERβ-selective pharmaceuticals. INTRODUCTION AND HISTORICAL PERSPECTIVEIn the late nineteenth century two scientists made the observation that female sex steroid hormones played an essential role in promoting mammary tumour growth [1,2]. A little more than half a century later the pioneering endocrinologists, Jensen and Jacobsen [3,4], arrived at the conclusion that the biological effects of 17β-estradiol (E2) could be mediated through a specific receptor rather than through enzymatic metabolism of estradiol itself. A few years later the groups of Gorski and Jensen isolated and characterized an estrogen-binding protein from the uterus and proposed a model for its mechanism of action [5][6][7]. For many years this protein and 91

Estrogen Receptors: Therapies Targeted to Receptor Subtypes

“…In more recent years, we have also learned that the effects of E2 can have a very rapid onset, within seconds to minutes. These effects may be mediated by membrane‐localized ERα and ERβ, respectively (after exposure to ligand stimuli), or by membrane receptors that are genetically and structurally unrelated to ERα and ERβ, for example, GPR30 (G‐protein coupled receptor 30) 1 , 2 , 3 , 4 (). The very rapid effects of E2 may include release of intracellular Ca 2+ and activation of calcium‐calmodulin‐dependent kinases or activation of other signal transduction pathways of the mitogen‐activated protein kinase family and phosphoinositide 3‐kinase.…”

“… 1 , 4 , 5 , 6 Each class of ER ligands induces a unique ER conformation, which promotes specific coregulator protein interactions and association of the ER N‐ and C‐terminal transcription activation functions, AF‐1 and AF‐2, respectively. 1 , 7 , 8 …”

“…Other reported mechanisms of ER‐mediated gene transcription are binding to non–estrogen response elements on DNA and tethering to other transcription factors that are already bound to their specific sites on DNA, respectively. 1 …”

Recent insights into the effect of natural and environmental estrogens on mammary development and carcinogenesis

“…Treatment of ovariectomized rats with an ERb-selective agonist (ERB-041) had no significant effects on the mammary tissue, indicating that ERb-selective agonists are non-mammotrophic (Nilsson and Gustafsson, 2011). Female ERb knockout mice (bERKO) were reported to show a normal mammary gland development, while female aERKO mice showed impaired postpartum mammary development despite elevated levels of circulating estradiol (Nilsson and Gustafsson, 2010). However, the role of ERb is still not established because studies focusing on this isoform remain few in comparison to those on ERa.Tissue recombinant techniques conducted in mice concluded that stromal cell ERa expression might be essential for growth stimulation of the ductal mammary epithelium.…”

Hormonal Resistance in Breast Cancer: Evolving Treatment Strategies

“…Effects of estrogen are mediated by not one but two distinct subtypes of estrogen receptors, ER alpha and ER beta [10]. The two receptors have differing affinities and responsiveness to various SERMs, and differing tissue distribution and effectiveness at various gene regulatory sites.…”