Overall objective of this project is to understand the endocrinology of hormonal responses in women (e.g., the estrogen response) in order to facilitate the development of clinical therapies directed toward the problems of contraception, pregnancy loss, and fertility. Despite the fact that the estrogen response is central to reproduction, little is known about the ability of other nuclear hormone receptors to influence estrogen receptor function. Recent work has therefore focused on factors modulating the estrogen response in estrogen responsive tissues. Advances in the current period include: 1) Definition of the role of the retinoid X receptor (RXRbeta) in the estrogen response. Cotransfection studies have shown that overexpression of RXR leads to inhibition of estrogen- dependent gene activation. Further, this inhibition is specific for gene activation caused by the estrogen receptor, since inhibition was only observed in estrogen receptor negative cells following introduction of the estrogen receptor. The inhibition was specific for the estrogen response since glucocorticoid-mediated gene activation was not impaired; 2) Demonstration that the RXR receptor was present in estrogen responsive cells in conjunction with an auxiliary factor that bound to estrogen responsive DNA elements; and 3) Demonstration that RXR and thyroid receptor (TR) heterodimers also bound to estrogen responsive DNA sequences and impaired gene activation by the estrogen receptor. We plan to examine the role of other receptors (known to interact with RXR) to determine whether those receptors may play a role in the modulation of estrogen responsive genes as well. In addition, we plan to study the endogenous auxiliary factor which contributes to binding of estrogen responsive DNA sequences by RXR.
