Studies with pharmacological agents established the potential of the ER to be activated in the absence of estrogen. The subsequent demonstration that several naturally occurring substances, including the neurotransmitter dopamine and growth factors (see below), could stimulate ER transcriptional activity in transient transfection experiments firmly established the ability of the ER to respond to biologically relevant, ligand-independent signaling pathways. The transcriptional activity of the ER can be stimulated in cells treated with EGF, although to a lesser extent than in cells treated with physiological concentrations of estradiol.
Furthermore, the ability of EGF to stimulate gene expression requires the presence of both the ER and an estrogen response element in the promoter region of the synthetic target gene. Taken together with the ability of the pure antiestrogen ICI 164 384 to block EGF activation of gene expression, these data confirm that EGF signaling pathway(s) can cross-talk with the ER and modulate the activity of this transcription factor. Neutralizing antibodies to the EGF receptor block ER-dependent gene expression stimulated by EGF and indicate that this growth factor must act through its plasma membrane receptor to communicate with the ER. Another mitogen, TGFa, which also binds and activates the EGF receptor, stimulates ER transcriptional activity in a similar fashion.