PROGESTERONE RECEPTOR ENHANCES BREAST CANCER CELL MOTILITY AND INVASION VIA EXTRA-NUCLEAR ACTIVATION OF FOCAL ADHESION KINASE

XIAO-DONG FU; LORENZO GOGLIA; ANGEL MATIAS SANCHEZ; MARINA FLAMINI; MARIA S. GIRETTI; VERONICA TOSI; ANDREA R. GENAZZANI; TOMMASO SIMONCINI

ENDOCRINE - RELATED CANCER

BIOSCIENTIFICA LTD

Año: 2010 vol. 17 p. 431 - 443

1351-0088

While progesterone plays multiple actions in the process of breast development and differentiation, its role on breast cancer is less understood. We previously showed that progestins stimulate breast 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 progesterone on the formation of focal adhesion complexes, that provide anchoring sites for cell attachment to the extracellular matrix during cell movement and invasion. In T47-D breast cancer cells, progesterone rapidly enhances focal adhesion kinase (FAK) phosphorylation at Tyr397 in a time- and concentration-dependent manner. As a result, exposure to progesterone leads to increased formation of focal adhesion complexes within specialized cell membrane protrusions. The cascade of events required for this phenomenon involves progesterone receptor (PR) interaction with the tyrosine kinase c-Src, which activates the phosphatidylinositol-3 kinase/Akt pathway and the small GTPase RhoA/Rho-associated kinase (ROCK-2) complex. In the presence of progesterone, T47-D breast cancer cells display enhanced horizontal migration and invasion of three-dimensional matrices, which is reversed by small interfering RNAs abrogating FAK. In conclusion, progesterone promotes breast cancer cell 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 progesterone on breast cancer progression and may in the future be helpful to develop new strategies for the treatment of endocrine-sensitive breast cancers.role on breast cancer is less understood. We previously showed that progestins stimulate breast 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 progesterone on the formation of focal adhesion complexes, that provide anchoring sites for cell attachment to the extracellular matrix during cell movement and invasion. In T47-D breast cancer cells, progesterone rapidly enhances focal adhesion kinase (FAK) phosphorylation at Tyr397 in a time- and concentration-dependent manner. As a result, exposure to progesterone leads to increased formation of focal adhesion complexes within specialized cell membrane protrusions. The cascade of events required for this phenomenon involves progesterone receptor (PR) interaction with the tyrosine kinase c-Src, which activates the phosphatidylinositol-3 kinase/Akt pathway and the small GTPase RhoA/Rho-associated kinase (ROCK-2) complex. In the presence of progesterone, T47-D breast cancer cells display enhanced horizontal migration and invasion of three-dimensional matrices, which is reversed by small interfering RNAs abrogating FAK. In conclusion, progesterone promotes breast cancer cell 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 progesterone on breast cancer progression and may in the future be helpful to develop new strategies for the treatment of endocrine-sensitive breast cancers.