ANDROGEN RECEPTOR GENE AND HORMONAL-THERAPY FAILURE OF PROSTATE-CANCER

Androgen receptor (AR) is a nuclear transcription factor that binds ma le sex steroids and mediates the biological effects of these hormones to the target cells, such as the epithelial cells of the prostate glan d, by activating transcription of androgen-dependent genes. Withdrawal of androgens or the peripheral blockade of androgen action remain the critical therapeutic options for the treatment of advanced prostate c ancer. However, after initial regression, many prostate cancers become hormone refractory and progress further with eventual fatal outcome, Understanding the mechanisms of tumor progression and endocrine therap y failure is an important goal, A large number of different molecular mechanisms may be responsible for development of hormone-refractory re current tumors, Many of these involve the AR gene and its complex down stream signaling pathways, The role of AR mutations and altered transa ctivational properties of the receptor have received the most attentio n as causative factors for progression. However, other mechanisms, suc h as AR gene amplification and overexpression or increased local bioco nversion of androgens, may contribute to the development of progressio n by mechanisms that involve androgen-dependent cell growth. Here we r eview the role of the AR gene and its putative downstream effector pat hways during human prostate cancer progression and endocrine therapy f ailure.