Definition of the Molecular Mechanisms Which Distinguish Between Selective Estrogen Receptor Modulators (SERMs) and Full Antiestrogens
Annual summary rept. 1 May 2003-30 Apr 2004
DUKE UNIV MEDICAL CENTER DURHAM NC
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The antiestrogen tamoxifen is the most commonly used endocrine treatment for all stages of breast cancer. Tamoxifen is a SERM Selective Estrogen Receptor Modulator which can act as an estrogen or an antiestrogen depending on the tissues in which it operates. Initially, tamoxifen may have profound effects on the survival and proliferation of breast cancer cells, but progressively, resistance emerges through mechanisms that are only partially understood. Some pure antiestrogens lack cross-resistance with tamoxifen, thus makes them good candidates as second-line therapy for patients who develop tamoxifen resistance and also suggests that the mechanisms underlying the actions of SERMs and pure antagonists are very different. This proposal investigates the possible involvement of different corepressor proteins in mediating the actions of different classes of antiestrogens. To probe the changes in the structure of the estrogen receptor ER upon binding of different antiestrogens, a focused phage displayed peptide library which expresses peptides containing a CoRNR box motif, important for corepressor to bind nuclear receptor, was made. Peptides that differentially interact with ER occupied by different antiestrogens were obtained. These peptides had provided a better understanding of actions of different antiestrogens and the assay which detects the peptide-ER interaction can be used as a sensitive and efficient system to screen for novel antiestrogens. During the course of the project in the last year, we have also used the technology we developed in studying estrogen receptor to examine the interaction of corepressor and retinoic acid receptor RAR and have brought forward more fundamental questions regarding nuclear receptor-corepressor interaction and its implication in breast cancer treatment.
- Medicine and Medical Research