Main advances of team 9
The life expectancy of women has increased from 48 years to more than 80 years in a century. Arrest of the endogenous production of estrogens at menopause (51 years on average) often results in a series of functional disorders (impacting the quality of life) as well as lower proetction of arteries, metabolic and bone. The hormone therapy (HT) of menopause is therefore a relatively new challenge, the benefit / risk ratio of which has been called into question following the Women Health Initiative study in american post-menopausal women.
Over the past 15 years, the research program of our team has been to: 1) understand the protective effects of 17-b estradiol (E2) on the development of atherosclerosis and type II diabetes in animal models, 2) develop unique transgenic mouse models targeting the estrogen receptors (ER). We have thus been able to demonstrate that ERα, and not ERβ, is absolutely necessary for most vasculoprotective and metabolic actions. However, estrogens also have deleterious long-term effects on the uterus and breast (partly via their proliferative effect which increases the risk of cancer), as well as on the thromboembolic risk that they increase.
ERα contains the two independent AF-1 and AF-2 transactivation functions and we dissected for the first time their respective roles for the actions of E2 in vivo (Summary in: From in vivo gene targeting of ERs to optimize their modulation in menopause, J. Pharmacol., 2012, 165: 57-66). Thus, our team has demonstrated that ERα AF-1 is not required for the vasculoprotective actions of E2, whereas it is necessary for its effects on the reproductive organs. We also demonstrated that ERαAF-1 is not necessary for the prevention by E2 of the development of adiposity and insulin resistance in response to a fatty diet. On the other hand, these different beneficial effects are totally dependent on ERα AF-2. This led us to propose a new type of ERα modulation, namely molecules with an activating profile AF2 >> AF1, or favor the activation and/or preferential expression of the 46kD ERα isoform, deficient in AF-1, currently being characterized in the laboratory.
More recently, we have begun to elucidate the role of the ERα fraction localized to the plasma membrane, which induces the "membrane / non-genomic" effects, thanks in particular to the generation of a murine model of which ERα is mutated on the palmitoylation site (C451A-ERα). This is the first model to abolish the membrane / non-genomic / rapid effects of estrogens, demonstrating that they are absolutely necessary for the endothelial effects of E2, and more unexpectedly, also essential for fertility in both males and females. The selective activation of the membrane effects could, in turn, provide endothelial protection.
This approach consisting in the molecular uncoupling in vivo of: i) beneficial effects (vascular, metabolic, bone) and ii) adverse / deleterious effects on reproductive targets (endometrium and mammary gland), but also thromboembolic risk (involving the liver, veins and potentially platelets) is unique to date in the field of steroid receptors. It provides a new insight into the mechanisms responsible for the tissue-specificity of the effects of estrogens and selective modulators of ERa (Selective Estrogen Receptor Modulators, SERMs).
Health Outcomes / Cooperation / partnerships
Our final ambition is to contribute to the optimization of ERα modulation and the revival of menopausal hormone therapy (HT). The murine tools and models we have developed have already enabled us to better understand the mechanisms of action of SERMs currently used against breast cancer (such as tamoxifen). Most importantly, they are currently contributing to the development of two new treatments: 1) A foeto-estrogen, Estetrol (E4), which, remarkably, could be devoid of hepatic effects (in particular on coagulation factors in women), E4 may therefore not increase the risk of thromboembolism. 2) A new approach to HT called Tissue Selective Estrogen Complex (TSEC), combining conjugated estrogens and a SERM (bazedoxifen), which would be the first HT of menopause not increasing the risk of breast cancer. E4 and TSEC are developed respectively by Laboratoires Mithra (Belgium) and Pfizer (USA) with whom we collaborate in order to better define their mechanisms of action, and in particular their respective impacts on thrombotic mechanisms.