Estrogen receptor signalling: bases for drug actions.

Abstract

Estrogen receptors (ERalpha and ERbeta) mediate the effects of 17beta-estradiol (E2) and account for E2 role on growth, development, and homeostasis maintenance in different tissues and organs. ERalpha and ERbeta function as ligand-dependent transcription factors which directly bind to specific estrogen responsive element (ERE) present into DNA and, in turn, regulate the transcription of E2-sensitive genes. In addition, ERalpha and ERbeta, without direct binding to DNA, regulate transcription indirectly by binding to other transcription factors activating or inactivating the transcription of E2-dependent-ERE-devoid genes. Along with these two E2 mechanisms, it has been recently uncovered that a third signalling pathway, involving cytoplasmic proteins and rapid membrane-initiated responses, serves largely for mitogenic E2-induced effects. The commitment of ERbeta in these rapid E2-induced effects is openly debated. This review will focus and summarize the latest findings regarding the multiple E2 molecular mechanisms and underlines the development of our understanding of anti-cancer drugs acting as ER signalling modulators.