Repression by nuclear hormone receptors (NHRs) plays an important role in development, immune response and cellular function. We review mechanisms of how NHRs act as repressors of gene transcription either by direct contact with basal transcription factors or through recruitment of cofactors and enzymic activities that modulate chromatin accessibility. We describe also the role and biochemical mechanism of the cognate hormone that switches a NHR from a transcriptional silencer into an activator. This includes data from crystal structure, functional receptor domain analyses and the role of co-repressors in chromatin modification and remodelling. Furthermore, the comparison of negative response elements with classical response elements unravels the role of co-repressors in this context. We also describe the inhibition of the nuclear factor kappaB and Jun/Fos pathway by NHRs, as well as the molecular mechanism of anti-hormone therapies. Anti-hormones are commonly used in breast and prostate cancer therapy to inhibit cancer proliferation through repression of the oestrogen or androgen receptor, respectively. Here we provide a comprehensive overview of the various mechanism of NHR repression.

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