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Mol. Hum. Reprod. Advance Access published online on June 18, 2009
Molecular Human Reproduction, doi:10.1093/molehr/gap045
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© The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Differential actions of estrogen and SERMs in regulation of the actin cytoskeleton of endometrial cells

M.I. Flamini, A.M. Sanchez, L. Goglia, V. Tosi, A.R. Genazzani and T. Simoncini

Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa 56100, Italy

Address correspondences and reprint requests to: Tommaso Simoncini, M.D., Ph.D., Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Via Roma, 57, 56100, Pisa, Italy. Phone: +39.050.553412 Fax: +39.050.553410 E-mail: t.simoncini{at}obgyn.med.unipi.it Web site: http//www.med.unipi.it/mcgel

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 17β-estradiol (E2) and tamoxifen (TAM) to immortalized Ishikawa endometrial cells or to human endometrial stromal cells (ESC) results in remodeling of actin fibres and cell membrane. This is linked to rapid phosphorylation on Thr558 of the actin-binding protein moesin and 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(ROCK). 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.

Key Words: actin cytoskeleton/endometrial cells/estrogen/moesin/SERMs

Submitted on April 23, 2009; resubmitted on May 27, 2009; accepted on June 10, 2009.


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