Estrogens are involved in a multiplicity of programmed events in target tis
sues e.g.: uterus, breast, and pituitary gland, and hormone-responsive tumo
rs occur at these target sites. We have addressed the possibility that all
of the estrogens do not produce the same conformation of estrogen receptor
ce (ER). A novel assay in vitro was used to activate the transforming growt
h factor a (TGF-alpha) gene in situ in MDA-MB-231 cells stably transfected
with cDNA for D351 ER or D351G ER. Three estrogen types were used: estradio
l, diethylstilbestrol, and a triphenylethylene (TPE) derivative of tamoxife
n without the antiestrogenic side chain. Computer molecular modeling was us
ed to interpret data. A flat estrogen such as estradiol or diethylstilbestr
ol can induce TGF-alpha through a correctly positioned activating function
2 (AF2) and bind SRC-I. The TPE did not activate AF2 but activated the TGF-
alpha gene through AF2b. This was demonstrated because D351 but not D351G E
R activated the TGF-alpha gene with the TPE. We propose two classes of estr
ogens with different ER complexes that may incorporate different coactivato
rs to function. Phytoestrogens and environmental xenoestrogens will fall in
to different classes based on structure and may exhibit selective actions a
nd carcinogenic potential based on different ER conformations.