Molecular mechanism of a cross-talk between oestrogen and growth factor signalling pathways

Oestrogen (E-2) plays significant roles in variety of biological events such as the development and maintenance of female reproductive organs, bone and lipid metabolisms, More recently, from study of knock-out mice deficient in oestrogen receptor (ER) alpha and ER beta it turned out that normal spermatogenesis requires the E-2 actions. Furthermore, this female steroid hormone is also well known to be deeply involved in many pathophysiological events such as osteoporosis and cancer development in female reproductive organs, It is particularly well known that most breast cancer is dependent on E-2 in its development. Such E-2 actions are thought to be mediated through two subtypes of ERs. Growth factors have been shown to synergize in this E-2 signalling pathway, although the actual molecular mechanism largely remains unknown. Recently, we found that the MAP kinase activated by growth factors phosphorylates the Ser(118) residue of the human ER alpha A/B domain and this phosphorylation potentiates the N-terminal transactivation function (AF-1) of human ER alpha, indicating the possible molecular mechanism of a novel cross-talk between E-2 and growth factor signalling pathways, More recently, we have identified a coactivator associating with the hER alpha AF-1 in a MAPK-mediated phosphorylation-dependent manner. In this review, the molecular mechanism of this cross-talk is discussed in terms of the transactivation function of ERs, and their coactivators.