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.
Highlights
One out of eight women develops breast cancer at some stage throughout life [1]
We studied the effects of estetrol on migration and invasion of estrogen receptor (ER)+ breast cancer cells and we related these observations to actin remodeling and to the activation of moesin, characterizing the signaling steps involved in these actions
E4 CONTROLS ER+ BREAST CANCER CELL MIGRATION Estrogen receptor agonists are able to enhance the ability of ER+ breast cancer cells to migrate in the surrounding environment
Summary
One out of eight women develops breast cancer at some stage throughout life [1]. Estrogen promotes breast growth and development at puberty and during the menstrual cycle and pregnancy [2]. In addition to these physiological effects, estrogen plays a major role in the development and progression of breast cancer. I.e., early menarche, late menopause, or postmenopausal hormone therapy, is associated with a greater risk of developing breast cancer [3]. Estrogen promotes breast cancer proliferation and tumor cell motility and invasion through a number of established pathways [4]
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