Extra-nuclear signalling of estrogen receptor to breast cancer cytoskeletal remodelling, migration and invasion.
BACKGROUND
Estrogen is an established enhancer of breast cancer development, but less is known on its effect on local progression or metastasis. We studied the effect of estrogen receptor recruitment on actin cytoskeleton remodeling and breast cancer cell movement and invasion. Moreover, we characterized the signaling steps through which these actions are enacted.


RESULTS
In estrogen receptor (ER) positive T47-D breast cancer cells ER activation with 17beta-estradiol induces rapid and dynamic actin cytoskeleton remodeling with the formation of specialized cell membrane structures like ruffles and pseudopodia. These effects depend on the rapid recruitment of the actin-binding protein moesin. Moesin activation by estradiol depends on the interaction of ER alpha with the G protein G alpha(13), 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 G alpha(13)/RhoA/ROCK/moesin cascade is necessary for the cytoskeletal remodeling and for the enhancement of breast cancer cell horizontal migration and invasion of three-dimensional matrices induced by estrogen. In addition, human samples of normal breast tissue, 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
These results provide an original mechanism through which estrogen can facilitate breast cancer local and distant progression, identifying the extra-nuclear G alpha(13)/RhoA/ROCK/moesin signaling cascade as a target of ER alpha in breast cancer cells. This information helps to understand the effects of estrogen on breast cancer metastasis and may provide new targets for therapeutic interventions.
Giretti
Maria Silvia
MS
Department of Reproductive Medicine and Child Development, University of Pisa, Pisa, Italy.
Fu
Xiao-Dong
XD
De Rosa
Giovanni
G
Sarotto
Ivana
I
Baldacci
Chiara
C
Garibaldi
Silvia
S
Mannella
Paolo
P
Biglia
Nicoletta
N
Sismondi
Piero
P
Genazzani
Andrea Riccardo
AR
Simoncini
Tommaso
T
D000199:Actins / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism*; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction
D000199:Actins; D008840:Microfilament Proteins; D011960:Receptors, Estrogen; C071058:moesin