Development of acquired antihormone resistance exposes a vulnerability in breast cancer: estrogen-induced apoptosis. Triphenylethylenes (TPEs), which are structurally similar to 4-hydroxytamoxifen (4OHT), were used for mechanistic studies of estrogen-induced apoptosis. These TPEs all stimulate growth in MCF-7 cells, but unlike the planar estrogens they block estrogen-induced apoptosis in the long-term estrogen-deprived MCF7:5C cells. To define the conformation of the TPE:estrogen receptor (ER) complex, we employed a previously validated assay using the induction of transforming growth factor α (TGFα) mRNA in situ in MDA-MB 231 cells stably transfected with wild-type ER (MC2) or D351G ER mutant (JM6). The assays discriminate ligand fit in the ER based on the extremes of published crystallography of planar estrogens or TPE antiestrogens. We classified the conformation of planar estrogens or angular TPE complexes as "estrogen-like" or "antiestrogen-like" complexes, respectively. The TPE:ER complexes did not readily recruit the coactivator steroid receptor coactivator-3 (SRC3) or ER to the PS2 promoter in MCF-7 and MCF7:5C cells, and molecular modeling showed that they prefer to bind to the ER in an antagonistic fashion, i.e., helix 12 not sealing the ligand binding domain (LBD) effectively, and therefore reduce critical SRC3 binding. The fully activated ER complex with helix 12 sealing the LBD is suggested to be the appropriate trigger to initiate rapid estrogen-induced apoptosis.