FIG. 7. Linking SERM action and receptor conformation. The studies that we have done on the mechanism of tamoxifen resistance have led us to believe that resistance and the ability of tamoxifen to manifest partial agonist activity in some contexts are related. Specifically, as mentioned above, it has been demonstrated that upon binding tamoxifen, ER adopts a conformation that does not allow it to interact with the p160 class of coactivators but with a coactivator whose binding properties resemble that of the 
/ßV peptide. We have shown that this peptide (and presumably the corresponding coactivator) does not interact with the GW5638-activated ER, as the alteration in receptor structure induced by this particular ligand is not compatible with its interaction. Thus, a strong case is made for the treatment of tamoxifen-refractory breast tumors with SERMs/anti-estrogens whose mechanism of action is distinct from tamoxifen.
