Lookup NU author(s): Dr Stuart Williamson,
Dr Anastasia Hepburn,
Professor Hing Leung,
Professor Craig Robson,
Dr Rakesh Heer
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Background: Evidence increasingly supports that prostate cancer is initiated by the malignant transformation of stem cells (SCs). Furthermore, many SC-signalling pathways are shown to be shared in prostate cancer. Therefore, we planned transcriptome characterisation of adult prostate SCs as a strategy to consider new targets for cancer treatment. Methods: Intuitive pathway analysis was used for putative target discovery in 12 matched selections of human prostate SCs, transiently amplifying cells and terminally differentiated cells. These were pooled into three groups according to the stage of differentiation for mRNA microarray analysis. Targets identified were validated using uncultured primary tissue (n = 12), functional models of prostate cancer and a tissue microarray consisting of benign (n = 42) and malignant prostate (n = 223). Results: A deficiency in class 1 UDP glucuronosyltransferase (UGT) enzymes (UGT1A) was identified in prostate SCs, which are involved in androgen catabolism. Class 1 UGT enzyme expression was also downregulated in cancer SCs and during progression to metastatic castration-resistant prostate cancer (CRPC). Reduction of UGT1A expression in vitro was seen to improve cell survival and increase androgen receptor (AR) activity, as shown by upregulation of prostate-specific antigen expression. Interpretation: Inactivation of intracellular androgen catabolism represents a novel mechanism to maintain AR activity during CRPC.
Author(s): Williamson SC, Mitter R, Hepburn AC, Wilson L, Mantilla A, Leung HY, Robson CN, Heer R
Publication type: Article
Publication status: Published
Journal: British Journal of Cancer
Print publication date: 23/07/2013
ISSN (print): 0007-0920
ISSN (electronic): 1532-1827
Publisher: Nature Publishing Group
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