Etude des mécanismes d'activation des récepteurs aux oestrogènes par l'estétrol et/ou la progestérone dans le sein normal et tumoral

Estetrol (E4) is a natural estrogen we recently characterized as a Selective Estrogen Receptor Modulator (SERM) with agonistic and antagonistic activities depending on target cells. We have also evidenced the functional importance of mixed estrogenic/anti-estrogenic activities of E4 in normal breast development and cancer. Recent molecular studies, indicating that progesterone receptor (PGR) functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, have revolutionized our mechanistic insights of steroid receptor activities in malignant breast.
E4 is a promising candidate for hormone replacement therapy (HRT) at menopause. However, the impact of the combined use of E4 and progesterone on normal breast physiology and on breast cancer development has not been evaluated yet. To fill this gap, we will evaluate the impact of treatments of E4 and/or progesterone on mammary gland development and breast cancer risk as well as on established breast cancer cells. We will unravel the molecular mechanisms driving the dual estrogenic/anti-estrogenic feature of E4 alone or combined to progesterone by evaluating the putative contribution of the extranuclear ERα, of GPER and by studying the modulation of ER/PGR interactions. This study will be conducted thanks to international collaborations (INSERM Toulouse, Reims, CNRS Rennes, Curie Institute Paris) we established through the EU SEPTIME project we coordinate. Through this project, we will bring new insights to the intriguing dual estrogenic/anti-estrogenic activity of E4. We will bring rational data about the putative safety of HRT combining E4 and progesterone. The development of an animal model assessing the effect of HRT on breast cancer risk in menopaused mice will also provide a useful tool to evaluate the effect of new HRT candidates on breast cancer risk. Moreover, the potential anti-tumor synergism of E4 and progesterone would contribute to the evolution of breast cancer treatment.