Androgens and glucocorticoids are steroid hormones that exert pleiotropic functions in mammals. Androgens has anabolic actions in tissues such as bone and muscle, and are crucial for the development and maintenance of reproductive organs in men. Since androgens stimulate prostatic epithelial cell proliferation and the growth of most prostate cancers, down regulation of androgen signaling is the major therapeutic strategy for advanced disease. Glucocorticoids control energy metabolism and the immune response. Synthetic glucocorticoids are widely used for their potent anti-inflammatory and immunosuppressive activities, and to manage symptoms and mitigate side effects induced by androgen deprivation therapy. However, long-term glucocorticoid treatments induce profound disturbances of intermediate metabolism, resulting in abdominal obesity, insulin resistance, and/or muscle wasting, and might confer prostate cancer anti-androgen resistance.

Androgens and glucocorticoids mainly act via two members of the nuclear receptor superfamily, i.e. the androgen receptor (AR, Nr3c4) and the glucocorticoid receptor (GR, Nr3c1), respectively. To identify the molecular and cellular mechanisms by which these steroid hormones control muscle mass and function, we analyzed mice in which the cognate receptors are selectively ablated in myofibers, and performed extensive phenotypic and genome-wide analyses. Moreover, to provide insights into prostatic tumorigenesis and androgen signaling inhibition resistance, we generated genetically engineered mice that faithfully reproduce tumor progression in patients. The results gained from our recent studies will be presented.

Daniel Metzger is invited by Pascal Maire.