Androgen receptor gene and hormonal therapy failure of prostate cancer.

Androgen receptor (AR) is a nuclear transcription factor that binds male sex steroids and mediates the biological effects of these hormones to the target cells, such as the epithelial cells of the prostate gland, 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 cancer. 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 therapy failure is an important goal. A large number of different molecular mechanisms may be responsible for development of hormone-refractory recurrent tumors. Many of these involve the AR gene and its complex downstream signaling pathways. The role of AR mutations and altered transactivational properties of the receptor have received the most attention as causative factors for progression. However, other mechanisms, such as AR gene amplification and overexpression or increased local bioconversion of androgens, may contribute to the development of progression by mechanisms that involve androgen-dependent cell growth. Here we review the role of the AR gene and its putative downstream effector pathways during human prostate cancer progression and endocrine therapy failure.