Androgen Regulated Genes in Human Prostate Xenografts in Mice: Relation to BPH and Prostate Cancer

Abstract

Benign prostatic hyperplasia (BPH) and prostate carcinoma (CaP) are linked to aging and the presence of androgens, suggesting that androgen regulated genes play a major role in these common diseases. Androgen regulation of prostate growth and development depends on the presence of intact epithelial-stromal interactions. Further, the prostatic stroma is implicated in BPH. This suggests that epithelial cell lines are inadequate to identify androgen regulated genes that could contribute to BPH and CaP and which could serve as potential clinical biomarkers. In this study, we used a human prostate xenograft model to define a profile of genes regulated in vivo by androgens, with an emphasis on identifying candidate biomarkers. Benign transition zone (TZ) human prostate tissue from radical prostatectomies was grafted to the sub-renal capsule site of intact or castrated male immunodeficient mice, followed by the removal or addition of androgens, respectively. Microarray analysis of RNA from these tissues was used to identify genes that were; 1) highly expressed in prostate, 2) had significant expression changes in response to androgens, and, 3) encode extracellular proteins. A total of 95 genes meeting these criteria were selected for analysis and validation of expression in patient prostate tissues using quantitative real-time PCR. Expression levels of these genes were measured in pooled RNAs from human prostate tissues with varying severity of BPH pathologic changes and CaP of varying Gleason score. A number of androgen regulated genes were identified. Additionally, a subset of these genes were over-expressed in RNA from clinical BPH tissues, and the levels of many were found to correlate with disease status. Our results demonstrate the feasibility, and some of the problems, of using a mouse xenograft model to characterize the androgen regulated expression profiles of intact human prostate tissues.

ERG rearrangement is present in a subset of transition zone prostatic tumors

“…19,20 Hyperplastic growth of the prostate transition zone associated with clinical benign prostatic hyperplasia may be the result of the abnormal expression of key androgen-responsive genes, which lead to an imbalance between cell division and death. 44 Genes regulated by androgenic hormones are of critical importance for the normal physiological function of the human prostate gland, and they contribute to the development and progression of prostate carcinoma.…”

Cyclic GMP signaling in rat urinary bladder, prostate, and epididymis: tissue-specific changes with aging and in response to Leydig cell depletion

“…Considering the pronounced androgen dependency of prostate tissue (Love et al 2009), it was of interest to investigate the expression of cGMP pathway proteins in this tissue under conditions of androgen ablation.…”

“…PRKG1 was localized to stromal areas of the transition zone (Kedia et al 2008) but is not immunohistochemically detectable in epithelial cells (D Mü ller, A K Mukhopadhyay, M S Davidoff & R Middendorff, unpublished results). Thus, PRKG1 is expressed in those areas where androgens are thought to regulate prostate stem cell homeostasis and to maintain a growthquiescent adult prostate gland (Love et al 2009). As advanced age is the most important risk factor for the development of benign prostatic hyperplasia and prostate cancer (Sampson et al 2007), the identified agerelated increase in PRKG1 may have pathophysiological significance.…”

“…Age-related alterations in cGMP pathways of functional significance have also been observed in vascular (Stice et al 2009) and penile (Sampson et al 2007) tissues. The molecular basis for the frequent development of benign prostatic hyperplasia, prostate cancer, and bladder dysfunctions in older men remains poorly understood (Love et al 2009, Goldstein et al 2010, Wang 2010). To facilitate detection of possible age-related changes within the cGMP signaling system, the expression of cGMP pathway proteins in bladders, prostates, and epididymides derived from either young adult (3 months old) or old (23-24 months) Wistar rats was compared.…”

Meta-analysis of Gene Expression Data Identifies Causal Genes for Prostate Cancer

“…The PMEPA1 gene has been shown to suppress the androgen receptor (AR) and TGF-β signaling pathway and is abnormally expressed in prostate tumors (Liu et al, 2011). Besides, PTGDS and PTGER2 have been reported as AR-regulated or involved in prostate cancer (Love et al, 2009).…”