ANTIESTROGENS ACTIVATE AN ESTROGEN-RECEPTOR MUTANT EXHIBITING ENHANCED BINDING TO THE ESTROGEN RESPONSE ELEMENT

The appearance of constitutively active and antiestrogen resistant est rogen receptor variants has been proposed as one of several factors le ading to the development of antiestrogen resistant breast cancers. We recently described the ER2, estrogen receptor mutant, which exhibits e nhanced binding to the estrogen response element on DNA, and partial c onstitutive (estrogen-independent) ability to activate transcription. In this work we used transient transfections to show that the antiestr ogens trans hydroxytamoxifen and ICI 164,384 are unable to suppress th e constitutive activity of the ER2 mutant. Instead, both antiestrogens were concentration-dependent activators of the ER2 mutant. The ER2 mu tant appears to be the first estrogen receptor mutant to show activati on of a simple estrogen response element-containing promoter using the ''pure'' antiestrogen ICI 164,384. (C) 1994 Academic Press, Inc.