EXTRA-NUCLEAR SIGNALING OF ESTROGEN RECEPTOR TO BREAST CANCER CYTOSKELETAL REMODELING, MIGRATION AND INVASION

Background: Estrogens are established enhancers of breast cancer development and progression, but less is known on the effects on migration and metastasis. We studied the actions of estrogens on actin cytoskeleton and cell movement and invasion in breast cancer cells. Moreover, we characterized the signaling steps through which these actions are enacted Methodology/Principal Findings: In estrogen receptor (ER) positive T47-D breast cancer cells 17â-estradiol induces rapid and dynamic actin cytoskeleton remodeling with a loss of stress fibers and the formation of the specialized membrane structures like membrane ruffles, pseudopodia and lamellipodia. These effects depend on the rapid activation of the actin-binding protein moesin. Moesin activation by estradiol is related to the interaction of ERá with the G protein Gá13, which results in the recruitment of the small GTPase RhoA and in the subsequent activation of its downstream effector Rho-associated kinase-2 (ROCK-2). ROCK-2 is responsible for moesin phosphorylation. The recruitment of the Gá13/RhoA/ROCK/moesin cascade is necessary for the enhancement of breast cancer cell horizontal migration and invasion of three-dimensional matrices by estrogen. In addition, human samples of normal breast tissue, benign fibroadenomas and invasive ductal carcinomas show that the expression of wild-type moesin as well as of its active form is deranged in cancers, with increased protein amounts and a loss of association with the cell membrane. Conclusions/Significance: These results provide an original mechanism through which estrogen can alter the progression of breast cancer, identifying the nongenomic Gá13/RhoA/ROCK/moesin signaling cascade as a target of ERá in breast cancer cells. This information helps to understand the effects of estrogens on breast cancer metastasis and they may provide new targets for therapeutic interventions.