As described above, estrogen-mediated actions in female reproductive organs should be tightly regulated. The mouse vaginal epithelium cyclically exhibits cell proliferation and differentiation in response to estrogen and provides a unique model for analyzing the tissue homeostasis during estrous cycle. We found that loss-of epithelial ERα in the vagina resulted in aberrant epithelial cell proliferation in the suprabasal cell layers and led to failure of keratinized differentiation. The epithelial ERα integrates estrogen and growth factor signaling and determines epithelial cell fate to squamous differentiation in mouse vagina.

Ligand-independent activation of the nuclear receptors often occurs in cancer tissues. We found that phosphorylated ERα activates the expression of EGF-like growth factors even in the absence of estrogen-stimulation. Then, EGF-like growth factor ligands activate signal transduction of erbB receptors-MAPK pathway, which in turn phosphorylates ERα. This auto-activation loop causes precancerous lesion of mouse vagina. This would be the first evidence for the ligand-independent activation of nuclear receptor in precancerous lesion in vivo.