Cholesterol desensitizes the response of endometrial cancer to progestin by attenuating progestin signaling
Menée notamment à l'aide de modèles murins et d'échantillons sériques prélevés sur des patientes atteintes d'un cancer de l'endomètre, cette étude met en évidence un mécanisme par lequel l'accumulation de cholestérol dans les tissus de l'endomètre contribue à la résistance des cellules cancéreuses à la progestérone en atténuant la voie de signalisation de cette dernière
Progestin is the primary fertility-preserving treatment for patients with endometrial cancer (EC) and its precursor lesions, endometrial atypical hyperplasia (EAH); however, a subset of patients exhibits a poor response. In this study, through the analysis of serum lipid differences, we found that progestin-resistant patients with EC/EAH exhibited reduced serum apolipoprotein A-I concentrations and increased cholesterol accumulation in endometrial tissue. Mechanistically, molecular docking simulations and cellular models confirmed that cellular cholesterol interfered with progestin-driven signaling by competing with progestin for binding to progesterone receptor B (PRB), thereby impairing its phosphorylation, nuclear translocation, and downstream gene activation. Substitution of leucine887 with alanine887 in PRB disrupted cholesterol binding but preserved progestin responsiveness. Furthermore, cholesterol-lowering therapy with rosuvastatin calcium restored progestin sensitivity in animal models and in a single-arm, open-label phase 2 clinical trial. Our work shows that cholesterol accumulation contributes to progestin resistance and that combining progestin with statins may enhance therapeutic efficacy in EC.
Science Translational Medicine , résumé, 2025