Deciphering the molecular signaling of estrogenic treatments and their analogues on the human endometrium for safer hormonal treatments

Estrogens are largely used for menopause indication and some of their analogues, the selective estrogen receptor modulators (SERM) are developed for endocrine therapy of breast cancer. Since the endometrium is a highly estrogen-sensitive organ, it is also the main side target of these treatments. Menopause hormone treatment (MHT) based on estrogen-only preparations are associated to an increased risk of endometrial cancers that is prevented by the addition of a progestogen. Nevertheless, formulations based on estrogen and progestogen increase the risk of breast cancer. Beside this, the SERM tamoxifen exhibits antagonist activity on breast cancer cells, but agonist properties on endometrium. Therefore, a better understanding of the estrogen receptor signaling occurring upon treatments with estrogen or their analogues in stromal and epithelial cells of the human endometrium, is thus crucial to develop a new safer generation of MHT or endocrine therapies. To achieve this goal, we have developed 3D organoids and patient-derived xenograft (PDX) from human endometrium samples to characterize at the transcriptomic and the histological levels the impact of various estrogenic treatments on both epithelial and stromal cells. Our results emphasized that depending on the nature of the estrogen used, the transcriptional activity of stromal and epithelial cells of the endometrium is differentially modulated. These results will provide important resources for understanding how different estrogens affect endometrial health and function. This will contribute to pave the way for the development of new safer hormonal treatments.