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.
Highlights
Relapse of malignant prostate cancer after hormone therapy is a significant clinical problem and new strategies are needed to prevent and treat castration-resistant prostate cancers
Analyses of pre-malignant prostatic intra-epithelial neoplasia (PIN) lesions documented a mixed basal and luminal epithelial cell staining (Figure 1C). These tumor data are consistent with the observation made by Jia et al using a different Sox2 antibody showing that expression correlates with Gleason Grade [23]
Our data contrasts with this report, as we observe strong basal-epithelial staining in non-malignant tissues, as well as uniform strong Sox2 expression in a small percentage of tumors, rather than a graded increase in staining intensity [23]
Summary
Relapse of malignant prostate cancer after hormone therapy is a significant clinical problem and new strategies are needed to prevent and treat castration-resistant prostate cancers. There is inevitable disease progression due to the growth of castrateresistant prostate cancer cells. There are a series of mechanisms for the development of castration-resistant prostate cancer (CRPC), most of which center on the Androgen Receptor (AR) [2]. Inhibiting intracellular AR signaling within prostate cancer cells has been a major focus of prostate cancer research, resulting in a variety of chemical inhibitors targeting AR signaling which are used in the clinic [3]. While all of these inhibitors produce an initial therapeutic response, this is commonly followed by relapse and disease progression
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