title: Effects of Estetrol on Migration and Invasion in T47-D Breast Cancer Cells through the Actin Cytoskeleton.
abstract: Estetrol (E4) is a natural human estrogen present at high concentrations during pregnancy. Due to its high oral bioavailability and long plasma half-life, E4 is particularly suitable for therapeutic applications. E4 acts as a selective estrogen receptor (ER) modulator, exerting estrogenic actions on the endometrium or the central nervous system, while antagonizing the actions of estradiol in the breast. We tested the effects of E4 on its own or in the presence of 17β-estradiol (E2) on T47-D ER+ breast cancer cell migration and invasion of three-dimensional matrices. E4 administration to T47-D cells weakly stimulated migration and invasion. However, E4 decreased the extent of movement and invasion induced by E2. Breast cancer cell movement requires a remodeling of the actin cytoskeleton. During exposure to E4, a weak, concentration-dependent, re-distribution of actin fibers toward the cell membrane was observed. However, when E4 was added to E2, an inhibition of actin remodeling induced by E2 was seen. Estrogens stimulate ER+ breast cancer cell movement through the ezrin-radixin-moesin family of actin regulatory proteins, inducing actin and cell membrane remodeling. E4 was a weak inducer of moesin phosphorylation on Thr(558), which accounts for its functional activation. In co-treatment with E2, E4 blocked the activation of this actin controller in a concentration-related fashion. These effects were obtained through recruitment of estrogen receptor-α. In conclusion, E4 acted as a weak estrogen on breast cancer cell cytoskeleton remodeling and movement. However, when E2 was present, E4 counteracted the stimulatory actions of E2. This contributes to the emerging hypothesis that E4 may be a naturally occurring ER modulator in the breast.
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy.
authors.forename: Maria Silvia
authors.initials: MS
authors.lastname: Giretti
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy.
authors.forename: Maria Magdalena
authors.initials: MM
authors.lastname: Montt Guevara
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cecchi
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mannella
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Palla
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Spina
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy.
authors.forename: Guja
authors.initials: G
authors.lastname: Bernacchi
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Di Bello
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy.
authors.forename: Andrea Riccardo
authors.initials: AR
authors.lastname: Genazzani
authors.affiliation: Department of Obstetrics and Gynecology, University of Modena and Reggio Emilia , Modena , Italy.
authors.forename: Alessandro D
authors.initials: AD
authors.lastname: Genazzani
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Simoncini
keywords: actin cytoskeleton; breast cancer; cancer progression; estetrol; estrogen