Microarray Data Mining for Potential Selenium Targets in Chemoprevention of Prostate Cancer.

Supplementation with a nutritional dose of selenium was found to reduce prostate cancer incidence by 50% in a randomized, placebo-controlled cancer prevention trial (1–3). Prostate cancer was actually a secondary endpoint in this study, which was designed originally to evaluate the effect of selenium on non-melanoma skin cancer. We reported previously that a selenium metabolite, in the form of methylseleninic acid or MSA, suppressed the growth of both the androgen-responsive LNCaP and the androgen-refractory PC-3 human prostate cancer cells (4,5). Growth inhibition by MSA was time- and dose-dependent, with an IC50 of ~10μM at 48 hours of treatment. In order to identify the molecular alterations that might be responsible for the growth inhibitory effect of selenium, we profiled gene expression changes in PC-3 cells using the Affymetrix 12K-gene oligonucleotide chip (4,5). Several working hypotheses have been generated from this dataset regarding the mechanisms of selenium action (4,5). In the present study, we completed a similar selenium array analysis in the androgen-responsive LNCaP cells using a 3K custom cDNA array. The smaller array is expected to improve the sensitivity of the assay, although the advantage is compromised by the reduced size of the dataset. Recently, Zhao et al. also performed microarray analysis in MSA-treated LNCaP cells using a high-density cDNA array (6). Our goal was to make use of these three selenium datasets and develop a global data mining strategy to earmark putative prostate cancer genes which are sensitive to selenium intervention. Our approach was to compare the selenium datasets to three recently published prostate cancer microarray datasets generated from human tumor specimen. The first was an Affymetrix oligonucletide array study in 50 normal and 52 prostate cancers reported by Singh et al. (7). The second, described by Welsh et al. (8), was similar to the first with the exception that fewer samples were examined (9 normal and 25 prostate cancers). The third was an analysis of 41 normal and 62 prostate cancers by Lapointe et al. (9) using a 26K-gene cDNA microarray. These three prostate cancer datasets offer a rich source of information of dysregulated genes implicated in prostate carcinogenesis. Androgen receptor (AR) signaling is known to play an important role in promoting prostate cancer progression (10). Consequently disruption of AR signaling is an effective means of prostate cancer management. We newly reported that selenium is capable of decreasing the expression and transactivating activity of AR (4). This novel finding underlies the justification of applying microarray analysis to investigate whether the expression of AR-regulated genes might be counteracted by selenium. Recent events have made this query possible. In separate studies by DePrimo et al. (11) and Nelson et al. (12), LNCaP cells were treated with a synthetic androgen and microarray analyses were then performed to identify genes responsive to androgen stimulation. These two androgen datasets are well suited to serve as a tool to mine the selenium datasets for additional clues. Collectively, the timely publication of a number of prostate cancer and androgen microarrays in the past two years provides an opportunity and sets the stage for the present effort to advance our understanding of selenium chemoprevention of prostate cancer.