ANTIESTROGENS - MECHANISMS AND ACTIONS IN TARGET-CELLS

Antiestrogens, acting via the estrogen receptor (ER) evoke conformatio nal changes in the ER and inhibit the effects of estrogens as well as exerting anti-growth factor activities. Although the binding of estrog ens and antiestrogens is mutually competitive, studies with ER mutants indicate that some of the contact sites of estrogens and antiestrogen s are likely different. Some mutations in the hormone-binding domain o f the ER and deletions of C-terminal regions result in ligand discrimi nation mutants, i.e. receptors that are differentially altered in thei r ability to bind and/or mediate the actions of estrogens vs antiestro gens. Studies in a variety of cell lines and with different promoters indicate marked cell context- and promoter-dependence in the actions o f antiestrogens and variant ERs. In several cell systems, estrogens an d protein kinase activators such as cAMP synergize to enhance the tran scriptional activity of the ER in a promoter-specific manner. In addit ion, cAMP changes the agonist/antagonist balance of tamoxifen-like ant iestrogens, increasing their agonistic activity and reducing their eff icacy in reversing estrogen actions. Estrogens, and antiestrogens to a lesser extent, as well as protein kinase activators and growth factor s increase phosphorylation of the ER and/or proteins involved in the E R-specific response pathway. These changes in phosphorylation alter th e biological effectiveness of the ER. Multiple interactions among diff erent cellular signal transduction systems are involved in the regulat ion of cell proliferation and gene expression by estrogens and antiest rogens.