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From in vivo gene targeting of oestrogen receptors to optimization of their modulation in menopause

The ancestral status of oestrogen receptor (ER) in the family of the steroid receptors has probably contributed to the pleiotropic actions of oestrogens, and in particular, that of 17β‐oestradiol (E2). Indeed, in addition to their well‐described role in sexual development and reproduction, they influence most of the physiological processes. The pathophysiological counterpart of these actions includes prevention of osteoporosis, atheroma and type 2 diabetes, and also the promotion of uterus and breast cancer growth. Thus, the major challenge consists in uncoupling some beneficial actions from other deleterious ones, that is, selective ER modulation. Tamoxifen and raloxifene are already used, as they prevent the recurrence of breast cancer and mimic oestrogen action mainly on bone. Both E2 and tamoxifen exhibit a proliferative and, thus, a protumoural action on the endometrium. Activation of ERα and ERβ regulates target gene transcription (genomic action) through two independent activation functions, AF‐1 and AF‐2, but can also elicit rapid membrane‐initiated steroid signals. In the present review, we attempted to summarize recent advances provided by the in vivo molecular ‘dissection’ of ERα, allowing the uncoupling of some of its actions and potentially paving the way to optimized selective ER modulators.