Estrogen receptor enhances endometrial cell motility and invasion via extra-nuclear activation of focal adhesion kinase.

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

March 4-7, FIRENZE, ITALY.

Congreso; 14th World Congress of Gynecological Endocrinology, II Congresso ISGE Italia; 2010

INTERNATIONAL SOCIETY OF GYNECOLOGICAL ENDOCRINOLOGY (ISGE)

While estrogen plays multiple actions in the process of endometrial development and differentiation, its role on endometrial cancer is less understood. We previously showed that estrogen stimulate endometrial cancer cell migration and invasion because of the activation of rapid signaling cascades leading to modifications of the actin cytoskeleton and of cell membrane that are required for cell movement. In this study, we investigate the effects of estrogen on the formation of focal adhesion complexes, that provide anchoring sites for cell attachment to the extracellular matrix during cell movement and invasion. In Ishikawa and endometrial stromal cells, estrogen rapidly enhances focal adhesion kinase (FAK) phosphorylation at Tyr397 and Tyr576 in a time- and concentration-dependent manner. As a result, exposure to estrogen leads to increased formation of focal adhesion complexes within specialized cell membrane protrusions. The cascade of events required for this phenomenon involves estrogen receptor (ER) interaction with the tyrosine kinase c-Src and the phosphatidylinositol-3 kinase pathway. In the presence of estrogen, endometrial cells display enhanced horizontal migration and invasion of three-dimensional matrices, which is reversed by small interfering RNAs abrogating FAK. In conclusion, estrogen promotes endometrial cells movement and invasion by facilitating the formation of focal adhesion complexes via the rapid regulation of FAK. These results provide novel mechanistic views on the effects of estrogen on endometrial cancer progression and may in the future be helpful to develop new strategies for the treatment of endocrine-sensitive endometrial cancers.