An S296R mutation in the human androgen receptor causes activation of the receptor by non-androgenic steroids and stronger inhibition by the nuclear receptor corepressor N-coR.

Mutation of the androgen receptor (AR) is believed to contribute to androgen-independent growth of prostate cancer. In the present study, we examined the functional changes associated with the novel somatic mutation S296R in the N-terminal domain of the AR identified from one recurrent prostate cancer sample. The results indicate that the S296R mutation does not differ obviously from the wild-type AR in its ability to bind the synthetic androgen methyltrienolone, or in its transcriptional activity induced by dihydrotestosterone (DHT) in the absence or presence of the overexpression of coactivators (steroid receptor coactivator-1, transcription intermediary factor-2, cAMP response element-binding protein-binding protein and p300). However, S296R was found to differ from wild-type AR in that its transcriptional activity could be activated by high concentrations (1 micromol/L) of 17beta-oestradiol and progesterone and its transactivity induced by DHT was more obviously inhibited by overexpression of the nuclear receptor corepressor N-coR in CV-1 cells. These findings indicate that a point mutation (S296R) in the N-terminal domain of the AR can decrease the ligand specificity of the AR and alter the interaction between S296R and the corepressor N-coR.