Endometrial actions of estrogen vs. tamoxifen and raloxifene through differential regulation of the actin cytoskeleton.

M.I. FLAMINI; A.M. SANCHEZ; A.R. GENAZZANI; T. SIMONCINI

10-13 September, Rome, Italy

Congreso; 8th ESG Congress of the European Society of Gynecology.; 2009

European Society of Gynecology

Estrogen and selective estrogen receptor modulators (SERMs) differentially impact endometrial cell function, however, the biological basis of these differences is not established. Deregulated cell adhesion to the extracellular matrix, cell movement and invasion are related to endometrial disorders, such as endometriosis or endometrial cancer. Remodeling of the actin cytoskeleton is required to achieve cell adhesion and movement. Estrogen receptor (ER) regulates actin and cell membrane remodeling through extra-nuclear signaling cascades. In this paper we show that administration of 17- estradiol (E2) and tamoxifen (TAM) to immortalized Ishikawa endometrial cells or to human stromal endometrial cells turns into remodeling of actin fibres and cell membrane. This is linked to rapid phosphorylation on Thr558 of the actin binding protein moesin and turns into enhanced migration and invasion of normal and Ishikawa cells. Raloxifene (RAL) does not result in moesin activation or actin remodeling. When endometrial cells are exposed to E2 in the presence of TAM or RAL, both SERMs interfere with the recruitment of moesin, with the remodeling of the cytoskeleton, and with cell movement and migration induced by E2. The differential actions of E2, TAM and RAL are linked to a distinct modulation of the extra-nuclear signaling of ER to G proteins and to the Rho-associated kinase. These findings increase our understanding of the actions of estrogen and SERMs in endometrial cells and highlight potential molecular targets to interfere with the estrogen-related altered cell adhesion encountered in endometrial disorders.