Physiological Findings from Transgenic Mouse Models with Altered Levels of Estrogen Receptor Expression

Abstract

The original cloning and descriptions of the estrogen receptor (ER) cDNAs in both the human (Walter et al, 1985) and mouse (White et al, 1987) has greatly contributed to the acceleration of research into the mechanisms of estrogen and ER action. It is now known that the ER, like other steroid hormone receptors, functions as a ligand-inducible trans-acting factor that regulates transcription by binding to specific DNA elements in the vicinity of target gene promoters (reviewed in Tsai and O’Malley, 1994; see Chapter 4 by L. Wei, on steroid hormone action, in this volume). Along with an increased understanding of the mechanisms of ER action has come a greater appreciation for its role in several normal physiological processes. Estradiol has long been thought to play a crucial role in the development and differentiation of the embryonic reproductive system, the development of secondary sexual characteristics, and the control of reproduction and reproductive behavior in animals (Evans, 1988). Clinically, estrogens and the ER have also been implicated in the development of a variety of cancers, especially breast cancer (Auchus and Fuqua, 1994) and endometrial cancer (Fujimoto et al, 1994). Although the effects of estrogen on bone growth and remodeling were thought to be indirect, further investigations have demonstrated the presence of both ER mRNA and protein, and subsequent estrogen responsiveness in bone cells, strongly suggesting a more direct role for estrogen in these processes (Eriksen et al, 1988; Komm et al, 1988; Oursler et al, 1991; Migliaccio et al, 1992; Davis et al, 1994a). Less understood “nonclassical” roles of estrogen action have also come to light, such as an involvement in lipid metabolism (Auchus and Fuqua, 1994) and in proper function of the cardiovascular system (Barrett-Conner and Bush, 1991).