Searching for the gatekeeper oncogene of prostate cancer

Prostate cancer is a common malignancy that has a heterogeneous etiology and a variable outcome. Nearly all prostatic adenocarcinoma results from androgen-dependent tumor promotion. However, the cause of prostate cancer initiation is not well understood and only a few of the target oncogenes activated during prostate cancer initiation have been identified. Prostate cancer risk is strongly influenced by family history. Several genetic loci have been found to cosegregate with prostate cancer occurrence in high-risk families. Some candidate oncogenes that map to these loci have been implicated by the identification of mutations in high-risk kindreds. However, the roles of the putative oncogene products in the biochemical pathways that mediate carcinogenesis remain obscure and their influence on cancer etiology has yet to be supported by gene targeting experiments in mice. Moreover, the genes that have been implicated in hereditary prostate cancers do not appear to be mutated in sporadic cancers. Karyotypic and loss of heterozygosity analysis of sporadic prostate cancers have identified 8p, 10q, and 17p as the loci most often disrupted. Candidate oncogenes have been identified at each of these regions. Additional genes with pathogenic significance in prostate cancer have been identified by analysis of cDNA microarrays comparing benign and malignant prostate tissue, by differential genetic analysis of benign and malignant prostatic epithelium, and by induction of experimental prostate cancer in genetically engineered mice.