The AF-1 Activation Function of Estrogen Receptor α Is Necessary and Sufficient for Uterine Epithelial Cell Proliferation In Vivo

Estrogen receptor-beta (ER alpha) regulates gene transcription through the 2 activation functions (AFs) AF-1 and AF-2. The crucial role of ER alpha AF-2 was previously demonstrated for endometrial proliferative action of 17 beta-estradiol (E2). Here, we investigated the role of ER alpha AF-1 in the regulation of gene transcription and cell proliferation in the uterus. We show that acute treatment with E2 or tamoxifen, which selectively activates ER alpha AF-1, similarly regulate the expression of a uterine set of estrogen-dependent genes as well as epithelial cell proliferation in the uterus of wild-type mice. These effects were abrogated in mice lacking ER alpha AF-1 (ER alpha AF-1(0)). Four weeks of E2 treatment led to uterine hypertrophy and sustained luminal epithelial and stromal cell proliferation in wild-type mice, but not in ER alpha AF-1(0) mice. However, ER alpha AF-1(0) mice still presented a moderate uterine hypertrophy essentially due to a stromal edema, potentially due to the persistence of Vegf-a induction. Epithelial apoptosis is largely decreased in these ER alpha AF-1(0) uteri, and response to progesteroneis also altered. Finally, E2-induced proliferation of an ER alpha-positive epithelial cancer cell line was also inhibited by overexpression of an inducible ER alpha isoform lacking AF-1. Altogether, these data highlight the crucial role of ER alpha AF-1 in the E2-induced proliferative response in vitro and in vivo. Because ER alpha AF-1 was previously reported to be dispensable for several E2 extrareproductive protective effects, an optimal ER alpha modulation could be obtained using molecules activating ER alpha with a minimal ER alpha AF-1 action.