Nuclear receptor conformation, coregulators, and tamoxifen-resistant breast cancer

The development of tamoxifen resistance and consequent disease progression are common occurrences in breast cancers, often despite the continuing expr ession of estrogen receptors (ER). Tamoxifen is a mixed antagonist, having both agonist and antagonist properties. We have suggested that the developm ent of tamoxifen resistance is associated with an increase in its agonist-l ike properties, resulting in loss of antagonist effects or even inappropria te tumor stimulation. Nuclear receptor function is influenced by a family o f transcriptional coregulators, that either enhance or suppress transcripti onal activity. Using a mixed antagonist-biased two-hybrid screening strateg y, we identified two such proteins: the human homolog of the nuclear recept or corepressor, N-CoR, and a novel coactivator, L7/SPA (Switch Protein for Antagonists). In transcriptional studies, N-CoR suppressed the agonist prop erties of tamoxifen and RU486, and L7/SPA increased agonist effects. We spe culated that the relative levels of these coactivators and corepressors may determine the balance of agonist and antagonist properties of mixed antago nists, such as tamoxifen. Using quantitative RT-PCR, we, therefore, measure d the levels of transcripts encoding these coregulators, as well as the cor epressor SMRT, and the coactivator SRC-I, in a small cohort of tamoxifen-re sistant and sensitive breast tumors. The results suggest that tumor sensiti vity to mixed antagonists may be governed by a complex set of transcription factors, which we are only now beginning to understand. (C) 2000 Elsevier Science Inc. All rights reserved.