Involvement of Nuclear Receptor Co-repressors in the Development of Human Breast Cancers

摘要

All-trans retinoic acids (RA) inhibits proliferation of breast cancer cells. This effect is presumably mediated by the retinoic acid receptors (RAR) . In the absence of RA, the RAR represses basal transcription through interaction with nuclear receptor corepressors such as SMRT (silencing mediator for retinoid and thyroid receptors) or N-CoR (nuclear receptor corepressor) . In this project, we have characterized receptor interaction and transcriptional repression function of SMRT and N-CoR. We have investigated the expression and regulation of SMRT in breast cancer cells. Our data suggest that there are two independent nuclear receptor interacting domains and multiple repression domains on the corepressors. The hormone-binding domain of the receptor is involved in a ligand- independent interaction with the corepressors and it contains a C- terminus AE-2 helix that is essential for ligand-dependent dissociation of the corepressor. We have demonstrated that overexpression of SMRT enhances transcriptional repression of nature RA-responsive promoters. In addition, a novel SMRT isoform termed SMRTe has been isolated. SMRTe is very similar in structure and function to N-CoR. Analysis of SMRTe expression in breast cancer cells suggests that cancerous cells contain higher levels of SMRTe than normal breast cells. Taken together, these results suggest that SMRTe may be involved in regulation of breast cancer cell growth and proliferation.