The effect of AR overexpression on androgen signaling in prostate cancer
Urbanucci A., Waltering KK., Mills IG., Visakorpi T.
© 2013 Springer Science+Business Media, LLC. All rights are reserved. Androgen receptor (AR) signaling pathway is required for both development of normal prostate gland and prostate cancer (PC). Patient with advanced disease are usually treated with androgen deprivation therapy. However, this treatment is only palliative, since a castration-resistant PC (CRPC) usually arises within 2-3 years of treatment. The mechanism by which CRPC develops is yet to be fully understood. However, common alteration in CRPC is the overexpression of the AR. Several studies have addressed the molecular changes occurring in AR overexpressing PC cells. The overexpression of AR enhances the binding of the receptor to chromatin in the presence of low concentrations of androgens. Furthermore, under the same conditions, AR overexpression alters also the dynamics of chromatin binding of the receptor and the binding of basic components of the transcriptional machinery. These changes translate into global epigenetic changes, which deserve more attention. Many studies have found that AR activation in CRPC cell models stimulates a different transcriptional program, which may be influenced by cooperative functions of other transcription factors. Thus, not only a single target gene but also a network of genes could be responsible for the disease progression. In fact, functional studies have shown that androgen-regulated genes, which are over-expressed in CRPC, are also likely to be important in PC progression.