Caracterología 31 

Changes in the androgen receptor can lead to cancer initiation or progression in a number of ways. For example, increased AR expression is commonplace in castrate resistant disease, making these cancers more sensitive to lower available androgen levels in the androgen-depleted treatment state (Bubendorf et al, 1999). The AR has also been shown to be mutated in up to 50% of prostate cancers, leading to increased ligand affinity or indiscriminate activation by various ligands (Bostwick et al, 2004). Cross talk between the AR and other pathways can lead to AR activation and permit ongoing AR mediated

29 transcription (Culig et al, 1994). Knockdown of AR in an in-vivo mouse model of implanted tumours showed that significant inhibition of tumour growth, PSA decline and tumour regression is possible using shRNA to the AR (Snoek et al, 2009)

TMPRSS2

One of the most well-known gene fusions in prostate cancer is the fusion of the 5’ untranslated end of the TMPRSS2 gene (21q22.2) to members of the ETS family of oncogenic transcription factors (Tomlins et al, 2005). In the original work the investigators discovered the gene fusion in 23 of 29 prostate cancer samples. It was found that the androgen responsive elements of TMPRSS2 facilitate the overexpression of ETS proteins. The most common variant of this fusion appears to be between TMPRSS2 and ERG (21q22.3), in roughly 50% of patients (Kumar-Sinha et al, 2008). The TMPRSS2 gene is specific to the prostate and expressed in both benign and malignant tissue, and is induced by androgens. The presence of this gene fusion has been found to be associated with a much higher risk of death in men treated with watchful waiting (Demichelis et al, 2007). Currently the diagnosis of TMPRSS2:ETS gene fusions has not translated into any meaningful change in clinical practice, despite its potential as a diagnostic and therapeutic target.

PTEN

The phosphatase and tensin homolog, PTEN, has been widely implicated in cancer pathogenesis. It is mutated in a large number of cancer types at high frequency. The protein product dephosphorylates phospho-inositide substrates and negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and acts as a tumour suppressor by also negatively regulating the AKT/PKB pathway. In prostate cancer it has been shown to induce cancer in mice when deleted (Wang et al, 2003), and loss of PTEN function is associated with a higher Gleason score and androgen independent tumours (Rubin et al, 2000).

30 Glutathione-S-Transferase (GST)

GST is responsible for inactivating reactive oxygen species, and the expression of GSTP1 is absent in approximately 70% of PIN lesions and in virtually all cases of prostate cancer (Nelson et al, 2003).

CDKN1B/p27

CDKN1B is part of the CIP/KIP family of cyclin-dependent kinase inhibitors and regulates progression of the cell cycle from G1 to S phase. It has been shown that loss of CDKN1B may accelerate tumourigenesis by allowing cells to progress unchecked through the cell cycle. Mice lacking CDKN1B develop prostate hyperplasia, and mice lacking both CDKN1B and PTEN develop prostate cancer in a significant proportion of animals, with lower levels of CDKN1B protein being associated with more aggressive carcinoma (Cordon- Cardo et al, 1998). Human studies have demonstrated loss of heterozygosity in 50% of patients with metastatic disease (Kibel et al, 2000). Loss of CDKN1B in radical prostatectomy specimens has also been linked to a higher risk of disease recurrence (Guo et al, 1997).

E-cadherin

E-cadherin is located on 16q22.1 and encodes a transmembrane glycoprotein important in mediating calcium-dependent intercellular adhesion and cell signalling (Takeichi, 1991). E-cadherin expression is reduced or lost in a large proportion of prostate cancers, especially in poorly differentiated tumours and expression of the protein correlates inversely with tumour grade, stage, metastasis, recurrence and survival (Bussemakers et al, 1992; Umbas et al, 1994; Umbas et al, 1992). E-cadherin is typically lost during the epithelial to mesenchymal transition (EMT), discussed later in this chapter. It is therefore functional as a tumour suppressor in this respect, as cells gain an invasive phenotype during the process of EMT. E-Cadherin levels appear to be regulated by both oestrogen and androgens in LNCaP cells, with both steroids causing increased E-cadherin expression (Carruba et al, 1995). However, when compared to other markers such as TP53, bcl-2 and CD44, E-cadherin performed less well than TP53 and Gleason score in predicting relapse of disease after radical prostatectomy(Brewster et al, 1999). Interestingly , E-cadherin has been detected in bone metastases of prostate cancer (Bryden et al, 1999), which may reflect re-expression of this

31 protein in the metastatic lesion, or the fact that loss of the protein is not necessary for metastasis.

1.4.5 Prostate cancer susceptibility loci identified through Genome-wide association studies (GWAS)

Data from a number of international GWAS in prostate cancer, in particular the PRACTICAL Consortium, have yielded some important new candidate alleles conferring familial risk for prostate cancer (Kote-Jarai et al, 2011; Schumacher et al, 2011). The top candidates include rs10187424 on 2p11, rs7584330 on 2q37, rs6763931 on 3q23, rs2242652 on 5p15, rs10936632 on 3q26 and rs10875943 on 12q13. One of these , rs2242652 showed an association with PSA level in the direction consistent with its association for prostate cancer risk. Only one SNP, rs5919432, has shown an association for a higher per-allele OR for Gleason score ≥ 8 disease. Many of these loci have been shown to lie within plausible causative genes, including TERT, ZBTB38 (encoding a zinc finger transcriptional repressor which binds methylated DNA), FGF10 (often overexpressed in breast cancers), CCHCR1 (upregulated in skin cancer and associated with EGFR expression and also promoting steroidogenesis by interacting with the steroidogenic acute regulator protein (StAR)). Overall, more than 40 susceptibility loci for prostate cancer have been identified, accounting for 23% of familial risk for prostate cancer (Kote-Jarai et al, 2011), with the top 10% of the population at highest risk holding a 2.4-fold greater risk than the average population for developing prostate cancer.

1.5 THE CLINICAL COURSE AND CONTEMPORARY TREATMENT OPTIONS