Sox2 is an androgen receptor-repressed gene that promotes castration-resistant prostate cancer.

Committee on Cancer Biology, The University of Chicago, Chicago, Illinois, United States of America.
PLoS ONE (Impact Factor: 3.53). 01/2013; 8(1):e53701. DOI: 10.1371/journal.pone.0053701
Source: PubMed

ABSTRACT Despite advances in detection and therapy, castration-resistant prostate cancer continues to be a major clinical problem. The aberrant activity of stem cell pathways, and their regulation by the Androgen Receptor (AR), has the potential to provide insight into novel mechanisms and pathways to prevent and treat advanced, castrate-resistant prostate cancers. To this end, we investigated the role of the embryonic stem cell regulator Sox2 [SRY (sex determining region Y)-box 2] in normal and malignant prostate epithelial cells. In the normal prostate, Sox2 is expressed in a portion of basal epithelial cells. Prostate tumors were either Sox2-positive or Sox2-negative, with the percentage of Sox2-positive tumors increasing with Gleason Score and metastases. In the castration-resistant prostate cancer cell line CWR-R1, endogenous expression of Sox2 was repressed by AR signaling, and AR chromatin-IP shows that AR binds the enhancer element within the Sox2 promoter. Likewise, in normal prostate epithelial cells and human embryonic stem cells, increased AR signaling also decreases Sox2 expression. Resistance to the anti-androgen MDV3100 results in a marked increase in Sox2 expression within three prostate cancer cell lines, and in the castration-sensitive LAPC-4 prostate cancer cell line ectopic expression of Sox2 was sufficient to promote castration-resistant tumor formation. Loss of Sox2 expression in the castration-resistant CWR-R1 prostate cancer cell line inhibited cell growth. Up-regulation of Sox2 was not associated with increased CD133 expression but was associated with increased FGF5 (Fibroblast Growth Factor 5) expression. These data propose a model of elevated Sox2 expression due to loss of AR-mediated repression during castration, and consequent castration-resistance via mechanisms not involving induction of canonical embryonic stem cell pathways.

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    ABSTRACT: The protein Sry has been studied for over twenty years, with much focus on its role in sex determination. Recent evidence suggests that it has multiple functions outside of testis determination. Comparing Sry throughout evolution, from its duplication of copies in a single species (such as in Rattus norvegicus), to its evolution in all of mammals, to how it is homologous to the SOX protein family, has helped to elucidate that the Sry protein has likely evolved to function in other pathways outside testis determination. One of the pathways Sry is suggested to function on is the renin-angiotensin system and thus has a potential to regulate blood pressure. The work with Sry and the Sox proteins was aided by a sequence-to-structure-tofunction approach, which was additionally applied to several other proteins, such as proteins of the renin-angiotensin system, the KRAB domain, SNAIL, and Leptin. These show the potential for such an approach and encourage its usage in more molecular research.
    01/2013, Degree: PhD, Supervisor: Dr Amy Milsted
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    ABSTRACT: The cancer stem cell hypothesis postulates that a single stem-like cancer cell is able to produce all cancer cell types found in a tumor. These cells are also thought to be the causative agents of relapse following therapy. In order to confirm the importance of cancer stem cells in tumor formation and patient prognosis, their role in prostate cancer must be comprehensively studied. This review describes current methods and markers for isolating and characterizing prostate cancer stem cells, including assays for self-renewal, multipotency and resistance to therapy. In particular the advantages and limitations of these approaches are analyzed. The review will also examine novel methods for studying the lineage of cancer stem cells in vivo using transgenic mouse models. These lineage tracing approaches have significant advantages and, if a number of challenges can be addressed, offer great potential for understanding the significance of cancer stem cells in human prostate cancer.
    Stem cell reviews 06/2013; 9(5). DOI:10.1007/s12015-013-9453-4 · 3.21 Impact Factor
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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.British Journal of Cancer advance online publication, 23 July 2013; doi:10.1038/bjc.2013.399
    British Journal of Cancer 07/2013; 109(4). DOI:10.1038/bjc.2013.399 · 4.82 Impact Factor


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