The human estrogen receptor has transcriptional activator and repressor functions in the absence of ligand.

Most studies on the cloned human estrogen receptor (hER) have been conducted with a mutant receptor in which Gly400 is changed to Val. Here we describe two novel regulatory functions of wild-type hER that are hormone independent: (i) a constitutive activator function and (ii) a repressor activity. Mutations in the hormone-binding domain, including the Val400 mutation, impair both of these functions. In addition, DNA binding is strongly reduced in the mutant receptors. The hormone-binding domain of the hER thus controls DNA binding (and thereby the repressor function) of the hER as well as its constitutive activator function. Moreover, we find that the antiestrogen tamoxifen restores the constitutive activator function, the DNA binding, and the repressor function of the Val400 mutant, but has no effect on the constitutive activator function or DNA binding of the wild-type hER.