Abstract
After castration was shown by Charles Huggins in 1941 to be an effective treatment for advanced prostate cancer, androgenic hormones were assumed to be responsible in some way for disease development.
Nonetheless, the manner in which androgens might contribute to prostatic carcinogenesis has remained elusive over the subsequent seven decades. Androgen levels decline steadily throughout adulthood in men, just as prostate cancers begin to appear (Rohrmann S et al. J Clin Endocrinol Metabol 92:2519-25, 2007). In addition, the action of testosterone, and its metabolite dihydrotestosterone, on prostate epithelial cells in adult men tends to be the promotion of terminal differentiation by activating transcription of target genes, such as PSA and TMPRSS2, which form the secretion elaborated by the prostate for the ejaculate. By driving terminal differentiation of normal prostate cells, androgens seem unlikely to cause neoplastic transformation. However, new insights into the generation of somatic genome rearrangements that create fusion oncogenes in prostate cells have revealed a new mechanism of androgen receptor-associated cancer pathogenesis. The fusion oncogene TMPRSS2-ERG, present in at least half of all prostate cancer cases, may be the most common somatic gene fusion event in all of human cancer (Tomlins SA et al. Science 310:644-8, 2005). We have found that androgen receptor-triggered transcription in prostate cells leads to the recruitment of topoisomerase II-beta (TOP2B) by the receptor to sites of TMPRSS2-ERG genomic breakpoints, promoting TOP2B-mediated DNA double strand breaks and de novo TMPRSS2-ERG fusion transcripts. The results implicate androgens in the creation of TMPRSS2-ERG rearrangements, via a mechanism involving the androgen receptor and TOP2B, and provide new hints as to how prostate cancers might be better prevented.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN05-04.
RSS Feeds