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Characterisations of human prostate stem cells reveal deficiency in class I UGT enzymes as a novel mechanism for castration-resistant prostate cancer

Lookup NU author(s): Dr Stuart Williamson, Dr Anastasia Hepburn, Laura Wilson, Professor Hing Leung, Professor Craig Robson, Dr Rakesh Heer

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Abstract

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.


Publication metadata

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

Year: 2013

Volume: 109

Issue: 4

Pages: 950-956

Print publication date: 23/07/2013

ISSN (print): 0007-0920

ISSN (electronic): 1532-1827

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/bjc.2013.399

DOI: 10.1038/bjc.2013.399


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