Role of coactivators and corepressors in steroid and nuclear receptor signaling: potential markers of tumor growth and drug sensitivity

Nuclear receptors regulate target gene expression in response to steroid an d thyroid hormones, retinoids, vitamin D and other ligands. These ligand-de pendent transcription factors function by contacting various nuclear cooper ating proteins, called coactivators and corepressors, which mediate local c hromatin remodeling as well as communication with the basal transcriptional apparatus. Nuclear receptors and their coregulatory proteins play a role i n cancer and other diseases, one leading example being the estrogen recepto r pathway in breast cancer. Coregulators are often present in limiting amou nts in cell nuclei and modifications of their level of expression and/or st ructure lead to alterations in nuclear receptor functioning, which may be a s pronounced as a complete inversion of signaling, i.e. from stimulating to repressing certain genes in response to an identical stimulus. In addition , hemizygous knock-out of certain coactivator genes has been demonstrated t o produce cancer-prone phenotypes in mice. Thus, assessment of coactivator and corepressor expression and structure in tumors may turn out to be essen tial to determine the role of nuclear receptors in cancer and to predict pr ognosis and response to therapy.