Glucocorticoid Receptor Function and Hormone Therapy Resistance
Geffen, J.P. van
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Nuclear receptors (NRs) are a superfamily of transcription factors that can be activated by ligands and thereby regulate the activation of a variety of genes for, amongst others, homeostasis. Nowadays, these NRs represent very important targets for endocrine therapeutic drug development. However, it is known that some patients (eventually) become resistant towards this therapy. An example is glucocorticoid (GC) hormone therapy resistance in asthmatic patients. Hormone therapy resistance harbours a large clinical burden with severe consequences. It is still poorly understood why and how some people develop hormone therapy resistance. In order to predict and/or prevent resistance development by novel therapies, it is of significant relevance to investigate the (possible) cellular and molecular mechanisms underlying the physiology and pathology. Various mechanisms that contribute to GC hormone therapy resistance have already been described in the literature. However, the exact mechanism still remains inconclusive. Therefore, this review describes the current insights to and the currently known mechanisms behind the development of GC hormone therapy resistance in asthmatic patients. In addition, we tried to unravel novel cellular and molecular mechanisms involved. Based on the data reviewed in this thesis, it is hypothesized that the changes and alterations of posttranscriptional modifications of coregulators lead to changes in the actions of glucocorticoid receptors (members of the NR super family) and thereby eventually lead to GC hormone therapy resistance.