Selective activation of the glucocorticoid receptor by steroid antagonistsin human breast cancer and osteosarcoma cells

Steroid hormones regulate the transcription of numerous genes via high affi nity receptors that act in concert with chromatin remodeling complexes, coa ctivators and corepressors, We have compared the activities of a variety of glucocorticoid receptor (GR) antagonists in breast cancer and osteosarcoma cell lines engineered to stably maintain the mouse mammary tumor virus pro moter. In both cell types, GR activation by dexamethasone occurs via the di sruption of mouse mammary tumor virus chromatin structure and the recruitme nt of receptor coactivator proteins. However, when challenged with a variet y of antagonists the GR displays differential ability to activate transcrip tion within the two cell types. For the breast cancer cells, the antagonist s fail to activate the promoter and do not promote the association of the G R with either remodeling or coactivator proteins. In contrast, in osteosarc oma cells, the antiglucocorticoids, RU486 and RU43044, exhibit partial agon ist activity. The capacity of these antagonists to stimulate transcription in the osteosarcoma cells is reflected in the ability of the RU486-bound re ceptor to remodel chromatin and associate with chromatin-remodeling protein s. Similarly, the observation that the RU486-bound receptor does not fully activate transcription is consistent with its inability to recruit receptor coactivator proteins.