The key element in control of growth of benign and malignant prostate is the androgen receptor (AR). It belongs to the superfamily of nuclear receptors, which transmit extracellular hormonal signals to the nucleus. The AR regulates the expression of genes required for male sexual development and maintenance of function of accessory sexual organs. The structure of the AR is similar to that of other steroid receptors; it consists of highly conserved DNA- and ligand-binding domains, which are separated by a hinge region. The length of the N-terminal AR region varies because of differences in polymorphic polyglycine and polyglutamine repeats (1). African-American (AA), population with the highest prostate cancer (PCA) risk, has a reduced number of N-terminal polyglycine repeats. Increased PCA risk in these individuals may thus occur because of high AR activity.

Detection of PCA has considerably improved in the last decade due to introduction of screening programs. PCA in early stages could be cured by radical surgery or radiotherapy. However, it should be emphasized that many PCAs remain latent during patients' life time. They are frequently detected on autopsy in patients who died from other illnesses. At present, little is known about prognostic factors that will help to discriminate between potentially indolent and aggressive tumours.

Non-organ confined PCAs require endocrine therapy, which is palliative. Orchiectomy is still a golden standard in assessment of survival; however, there are also alternative approaches, such as chemical castration [use of luteinizing hormone-releasing hormone (LHRL) analogues] and anti-androgens. Nonsteroidal anti-androgens are widely used in PCA treatment to block initial increase in testosterone levels during treatment with LHRL agonists, or as a mono-therapy. Hydroxyflutamide and bicalutamide are nonsteroidal compounds that bind to the AR with a low affinity and prevent acquisition of a transcriptionally active conformation ofthe AR. Bicalutamide prevents interactions between the N- and C-terminal of the AR (2). In the last decade, it became clear that anti-androgens frequently exhibit agonistic properties in PCA because ofchanges in expression and activity of the AR.

This chapter will focus on the following issues essential to understand the role of the AR in PCA:

a) AR regulation in PCA models and tissue specimens.

b) Impact of AR mutations on PCA progression.

c) AR interaction with signaling pathways of cytokines and growth factors.

d) Inappropriate expression and function of AR cofactors

In addition, a summary of the current knowledge on IL-6 expression and signaling in human PCA, and a discussion ofpossible novel experimental therapies on the basis of these findings are described.

Was this article helpful?

0 0

Post a comment