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 Thr558, 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.

Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation

“…However, E 4 stimulated breast proliferation with a 100-fold weaker efficacy than E 2 in vitro as well as in vivo. This is consistent with competitive binding studies showing that E 4 exhibits considerably lower affinity than E 2 toward ERa (Martucci & Fishman 1976, Tseng & Gurpide 1976, and with the observation that E 4 was less potent than E 2 to increase breast cancer cell line proliferation and migration (Jozan et al 1981, Giretti et al 2014, Liu et al 2014.…”

“…It was maximal in vitro and in vivo when the dose of E 4 was 100 times higher than that of E 2 . Giretti et al (2014) recently showed that E 4 administration to malignant human breast adenocarcinoma T47-D cells weakly stimulated their cytoskeleton remodeling and migration. However, when E 2 was present, E 4 counteracted the stimulatory actions of E 2 .…”

Moesin is an independent prognostic marker for ER‑positive breast cancer

“…The IHC analysis in the present study demonstrated that the expression level of moesin had no impact on OS time, but indicated a notable association with RFS time in patients with breast cancer. Previous studies (32)(33)(34) indicated that estrogen can facilitate breast cancer progression, identifying moesin as a target of ER in breast cancer cells. For these reasons, the prognostic significance of moesin according to ER status was analyzed.…”

O efeito da prolactina na migração de células de câncer de mama pela remodelação da actina no citoesqueleto

“…A mobilidade celular depende da habilidade da célula em remodelar sua membrana plasmática e formar estruturas como ondulações (ruffles) e pseudópodes, que permitem a adesão a outras proteínas extracelulares e/ou outras células, favorecendo a migração celular (Giretti et al, 2014). Nesse processo, as proteínas que se ligam à actina são solicitadas para realizar a despolimerização e reorganização dos microfilamentos de actina na membrana celular.…”

“…Esta técnica já foi reproduzida por outros investigadores nos tipos de células empregadas em nosso estudo Giretti et al, 2014). Contudo, a grande limitação do estudo é que os resultados são in vitro e nem sempre se repetem in vivo.…”