Androgen receptor coregulators and their role in prostate cancer

Abstract

The limiting factor in the survival of a patient with prostate cancer is the rate of progression to the noncurable androgen-independent (AI) stage of disease. The androgen receptor (AR) is a critical regulator of prostate cancer development and is involved in AI progression. Coregulators are proteins that interact directly with AR to enhance (coactivators) or reduce (corepressors) its transcriptional activity. Currently, over 165 AR coregulators have been discovered. In this chapter, we focus on a subset of the most well-characterized AR coregulators that are associated with prostate cancer. The first part of our review discusses the mechanisms by which classical type I and nonclassical type II AR coactivators/corepressors regulate AR transcriptional activity. The second section focuses on the role of coregulators in prostate cancer, including their expression profile in prostate cancer patients, tumor cell growth effects, and potential as therapeutic targets. In view of their involvement in prostate cancer progression, it is anticipated that further study of AR coregulators will provide more treatment options for increasing survival of patients with AI prostate cancer Prostate cancer is the most commonly diagnosed nonskin cancer in men and the second leading cause of cancer death in North America (Jemal et al. 2004). While frequently curable in its early stages, many patients will present with locally advanced or metastatic disease for which there are currently no curative treatment options (Albertsen et al. 2005). Although androgen deprivation therapies, which block the growth promoting effects of androgens, are often used to treat advanced disease, progression to a lethal state variably referred to as castration-resistant, hormone refractory, castration-recurrent, or AI is the usual outcome, giving rise to a median survival of approximately 19 months (Albertsen et al. 2005; Kent and Hussain 2003; Martel et al. 2003). Some brief survival extensions can sometimes be achieved using current docetaxel-based chemotherapy (Petrylak 2005; Tannock et al. 2004). However, to have any major impact on current survival rates, more effective treatment strategies need to be developed. Because androgens mediate their effect on target cells through their receptor, it is thought that the AR is important in the development of AI disease. While the molecular mechanisms responsible for the development of AI prostate cancer are largely unknown, typically they do not appear to involve loss of AR expression (Taplin and Balk 2004). In over 80% of locally advanced AI prostate cancers, high levels of nuclear AR have been observed (Tilley et al. 1994), and in bone metastases, the amount of AR present is often higher than in primary tumors (Hobisch et al. 1995). There is evidence that in most cases, some form of inappropriate activation of AR is linked to recurrent, AI growth of prostate cancers (Taplin and Balk 2004; Rennie and Nelson 1998). In fact, in vivo knockdown of AR can delay AI progression (Cheng et al. 2006). One can envision a variety of molecular alterations that could lead to continued or amplified AR signaling following surgical or medical castration, such as gain of function AR mutations (Culig et al. 2003; Gaddipati et al. 1994; Marcelli et al. 2000; Newmark et al. 1992; Shi et al. 2002; Taplin et al. 2003) and amplification/overexpression of wild-type AR (Ford et al. 2003; Linja et al. 2001; Visakorpi et al. 1995). However, the available evidence suggests that the most commonly occurring mechanisms for progression to the AI stage are likely to be epigenetic, involving ligand-independent (or ligand-reduced) activation of AR either through convergence of cell signaling pathways and/or altered activity and expression of AR coregulators (Taplin and Balk 2004; Rennie and Nelson 1998; Sadar et al. 1999; Ueda et al. 2002). The latter is the focus of this chapter. Section 1 will describe the various types of AR coregulators that have been identified and Sect. 2 will discuss their role in prostate cancer and how they may provide therapeutic targets. © 2009 Springer-Verlag New York.