• plasminogen pathway
• estrogen
• estetrol
• endothelial cells
• breast cancer

Some of the major unwanted effects associated with the use of estrogen-progestin scheduling include its strong hepatic impact, the increase of thromboembolic events and the higher risk of developing breast cancer.
Steroid hormones have an influence on the cardiovascular system through modifications of the lipid profile and through lipid-independent mechanisms at the vascular level.
Nowadays, there is strong evidence that estradiol metabolites are not merely waste products but may play physiological and pathophysiological roles.
Estetrol (E4) is a natural human estrogen produced exclusively by the human fetal liver during pregnancy. Due to its high oral bioavailability and long plasma half-life, E4 is particularly suitable for therapeutic applications including contraception and menopausal hormone therapy.
The aim of this thesis was to analyses the impact of E4 versus estradiol (E2). First, experiments were conducted to analyses the effect of E4 on the migration and invasion in breast cancer cells. Second, we studied the impact of E4 treatment on endothelial cells functions which are recognized to be dependent on membrane initiated steroid signaling, the activation of endothelial NO synthase and the plasminogen activation pathway.
This work report a dual effect of E4 on the migration and invasion of breast cancer cells, showing that E4 moderately stimulates these processes via cytoskeleton remodeling while antagonizing, at the same time, the effect of E2 thereby reducing the tumor invasiveness elicited by E2.
The results for endothelial cells also highlight that E4 is less potent than E2 and exhibits antagonistic properties towards the activation of the endothelial NO synthase and the plasminogen activation pathway as well as cell migration elicited by E2.
In summary, is tempting to speculate that E4 may represent a compound designed by nature to control the maternal and fetal vascular actions of estrogens during gestation. While the exclusive dual weak estrogenic/anti-estrogenic activity of E4 paves the way for several potential clinical applications, experimental and clinical studies are now needed to confirm the efficacy and the safety of E4.