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Inhibition of Estrogen Receptor -Mediated Transcription by Antiestrogenic 1,1-Dichloro-2,2,3-triarylcyclopropanes

University of Pittsburgh, Departments of Pharmacology, Pharmaceutical Sciences and Chemistry, and the University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

A novel class of pure antiestrogens, 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs), lack estrogenic activity in a mouse uterotrophic assay and inhibit the growth of estrogen-sensitive MCF-7 breast cancer cells (Day et al., 1991). Here, reporter assays were used to evaluate the effects of the DTACs on estrogen receptor (ER)-mediated transcription from either classic estrogen-response elements (EREs) or nonclassic AP-1 elements. Among the DTACs tested, only the compounds with smaller aromatic substituents, BDRM72 and BDRM81, displayed weak agonist activity on EREs. Their activity was less than that observed for the ER partial agonist, 4-hydroxytamoxifen (ZOHT). In competition experiments, the DTACs blocked estradiol-stimulated transcription from an ERE in a dose-dependent manner and were more effective inhibitors than ZOHT. Each of the DTACs was significantly less active than ZOHT or the pure antiestrogen ICI 182,780 (faslodex) in stimulating transcription from nonclassic AP-1 elements in the presence of ER. DTACs did not modulate either basal or TPA (12-O-tetradecanoylphorbol-13-acetate)-stimulated transcription from an AP-1 element in the absence of ER, indicating that they are not nonspecific inhibitors of transcription and that ER is the drug target. Glutathione S-transferase pull-down assays were used to examine whether DTACs alter the interaction between ER and the p160 coactivator, GRIP1. BDRM35, which has the same dimethylaminomethoxy and phenolic moieties as ZOHT, reduced binding by more than 50%. Thus, disruption of p160 coactivator recruitment by ER may represent one mechanism by which DTACs function as antiestrogens. BDRM35 also suppresses estradiol induction of endogenous target genes c-myc and cyclin D1 in MCF-7 breast cancer cells.

Address correspondence to: Mark Nichols, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Suite 2.26a, 5117 Centre Ave., Pittsburgh, PA 15213-1863. E-mail: mnichols{at}pitt.edu

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