Molecular biology of prostate cancer Sample Clauses

Molecular biology of prostate cancer. Since the sixties, it has been understood that prostate cancer growth is dependent on steroid hormones termed androgens, such as testosterone, and its major metabolite dihydrotestosterone. This is evident by the regression of prostate tumours in animals deprived of androgen (Xxxxxxxx and Xxxxx, 2002a). Androgens signal through the androgen receptor, a large intracellular hormone-activated transcription factor. Androgen receptor signalling regulates the growth and development of the prostate and maintains prostate homeostasis (Xxxxxxxx and Xxxxx, 2002b). Both stromal and epithelial compartments rely on androgen signalling; stromal tissues respond to androgen signalling to modulate epithelial growth, survival and differentiation in a paracrine manner (Xxxxx et al., 2004), while epithelial tissues respond to androgen signalling to regulate production of secreted proteins (Xx et al., 2009). It is now accepted that prostate tumours commonly result from outgrowth of PIN legions, and are frequently characterised by disruption of a number of key signalling pathways. Studies have shown that 40% of primary prostate tumours, and 70% of metastatic cases have genomic aberrations in the PI3K/Akt pathway. A significant proportion of these feature the loss or mutation of phosphatase and tensin homologue (PTEN), a tumour suppressor protein which limits AKT activation (El Sheikh et al., 2008, Xxxx et al., 2010). Indeed, homozygous PTEN deletion is sufficient to induce progressive, metastasising tumours in mice (Xxxx et al., 2003). Another genetic abnormality associated with large numbers of prostate cancers are chromosomal translocations between coding regions of ETS (E26 transformation specific) family transcription factors (typically ERG, and less commonly ETV1), and the promoter of the androgen responsive gene TMPRSS2 (Xxxxxxx et al., 2005). Indeed, two recent studies have proposed that this genetic lesion is sufficient to induce PIN in otherwise healthy prostate epithelia, and can contribute to progression of neoplasias to invasive cancers (Xxxxxx et al., 2009, Xxxxxxx et al., 2007). A number of studies have indicated that this gene rearrangement may be induced as a direct result of AR signalling (Xxx et al., 2009). As well as ETS recombinations and PTEN mutations, more generic oncogenic alterations are also found in prostate cancer. For example, c-MYC overexpression is frequently observed (Xxxxxx et al., 2010), and as with most cancer types p53 and pRb are frequently m...