Androgen Receptor Mutations in High-Grade Prostate Cancer before Hormonal Therapy

Androgen action is mediated through androgen receptor (AR), which appears to undergo structural and functional alterations during prostate cancer (CaP) progression. AR mutations have been infrequently reported in CaP before hormonal therapy, but in untreated, advanced tumors AR mutations are suggested to be more common. To investigate the frequency of AR mutations in aggressive CaP before hormonal therapy, we have analyzed AR coding region for aberrations in 21 paraffin-embedded prostate carcinoma samples (14 primary tumors, 7 metastases) of poor histologic differentiation. Single-stranded conformational polymorphism and sequencing analyses revealed AR missense mutations in 29% (4/14) of the primary tumors and in one (14%) metastasis. Mutations resided in the transactivation domain and in the hinge region. One of the hinge region mutants, Ser646Phe, that was identified in a patient with short endocrine therapy response, exhibited a markedly increased transcriptional activity on single androgen response element-containing promoters. In conclusion, AR mutations are frequent in high-grade CaP before initiation of hormonal therapy, and these mutations may play a role in poor therapy response and emergence of hormone-refractory CaP in some cases. (Lab Invest 2003, 83:1709-1713).