Estrogen receptor transcription and transactivation Estrogen receptor alpha and estrogen receptor beta: regulation by selective estrogen receptor modulators and importance in breast cancer

Estrogens display intriguing tissue-selective action that is of great biome dical importance in the development of optimal therapeutics for the prevent ion and treatment of breast cancer, for menopausal hormone replacement, and for fertility regulation. Certain compounds that act through the estrogen receptor (ER), now referred to as selective estrogen receptor modulators (S ERMs), can demonstrate remarkable differences in activity in the various es trogen target tissues, functioning as agonists in some tissues but as antag onists in others. Recent advances elucidating the tripartite nature of the biochemical and molecular actions of estrogens provide a good basis for und erstanding these tissue-selective actions. As discussed in this thematic re view, the development of optimal SERMs should now be viewed in the context of two estrogen receptor subtypes, ER alpha and ER beta, that have differin g affinities and responsiveness to various SERMs, and differing tissue dist ribution and effectiveness at various gene regulatory sites. Cellular, bioc hemical, and structural approaches have also shown that the nature of the l igand affects the conformation assumed by the ER-ligand complex, thereby re gulating its state of phosphorylation and the recruitment of different core gulator proteins. Growth factors and protein kinases that control the phosp horylation state of the complex also regulate the bioactivity of the ER. Th ese interactions and changes determine the magnitude of the transcriptional response and the potency of different SERMs. As these critical components are becoming increasingly well defined, they provide a sound basis for the development of novel SERMs with optimal profiles of tissue selectivity as m edical therapeutic agents.