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

• Published in: Steroids Vol. 65; no. 10; pp. 579 - 584
• Main Authors: Graham, J.Dinny, Bain, David L, Richer, Jennifer K, Jackson, Twila A, Tung, Lin, Horwitz, Kathryn B
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 01.10.2000; Elsevier Science
• Subjects: Antineoplastic agents; Biological and medical sciences; Breast neoplasms; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Chemotherapy; Drug Resistance; Estrogen receptors; Female; Humans; Medical sciences; Nuclear Proteins - genetics; Nuclear Proteins - pharmacology; Nuclear Receptor Co-Repressor 1; Pharmacology. Drug treatments; Progesterone; Receptors, Estrogen - chemistry; Receptors, Estrogen - genetics; Repressor Proteins - genetics; Repressor Proteins - pharmacology; Steroid receptors; Tamoxifen; Tamoxifen - pharmacology; Transcription Factors - genetics; Transcription Factors - pharmacology; Transcriptional coregulators; Transcriptional coregulators; Estrogen receptors; Breast neoplasms; Progesterone; Tamoxifen; Steroid receptors; Antineoplastic agent; Nuclear receptor; Transcription; Estrogen; Malignant tumor; Ovarian hormone; Tamoxifene; Mammary gland diseases; Sensitivity resistance; Mammary gland; Sex steroid hormone; Mechanism of action; Non steroid compound
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/S0039-128X(00)00116-1

The development of tamoxifen resistance and consequent disease progression are common occurrences in breast cancers, often despite the continuing expression of estrogen receptors (ER). Tamoxifen is a mixed antagonist, having both agonist and antagonist properties. We have suggested that the development of tamoxifen resistance is associated with an increase in its agonist-like properties, resulting in loss of antagonist effects or even inappropriate tumor stimulation. Nuclear receptor function is influenced by a family of transcriptional coregulators, that either enhance or suppress transcriptional activity. Using a mixed antagonist-biased two-hybrid screening strategy, we identified two such proteins: the human homolog of the nuclear receptor corepressor, N-CoR, and a novel coactivator, L7/SPA (Switch Protein for Antagonists). In transcriptional studies, N-CoR suppressed the agonist properties of tamoxifen and RU486, and L7/SPA increased agonist effects. We speculated that the relative levels of these coactivators and corepressors may determine the balance of agonist and antagonist properties of mixed antagonists, such as tamoxifen. Using quantitative RT-PCR, we, therefore, measured the levels of transcripts encoding these coregulators, as well as the corepressor SMRT, and the coactivator SRC-1, in a small cohort of tamoxifen-resistant and sensitive breast tumors. The results suggest that tumor sensitivity to mixed antagonists may be governed by a complex set of transcription factors, which we are only now beginning to understand.