Androgen Responsive Clusterin Expression in the Developing and Regenerating Mouse Prostate
Open AccessAndrogen-deprivation is an effective first line of treatment for prostate cancer, yet new approaches for treatment are needed, as many prostate cancers will ultimately develop resistance. Because much of prostate organogenesis occurs when androgen levels are low, we hypothesized that both androgen receptor (AR)-dependent and AR-independent progenitor cells may exist in the developing prostate. To understand the heterogeneity of prostate epithelial cells at a molecular level, we analyzed single cell RNA sequencing (scRNA-seq) data from developing mouse prostates at postnatal day 0, week(s) -1, -4,-6, and adult prostates at 10 weeks. At each of these timepoints, we identified a population of luminal epithelial cells that expressed Clusterin, which encodes a chaperone protein that has previously been implicated in prostate cancer and is reported to have anti-apoptotic effects.Since Clusterin is expressed in cells responsible for intestinal epithelial regeneration following injury, we assessed whether Clusterin may also have similar functions during androgen-mediated regeneration in the mouse prostate. Mice were castrated to induce prostate regression and then implanted with testosterone pumps. We assessed Clusterin expression during prostate regeneration by conducting immunofluorescence (IF) staining. We also assessed AR expression in Clusterin-expressing cells by conducting co-staining using antibodies for Clusterin and AR. In developing prostates from 4-week-old mice and in regenerating prostates, we detected Clusterin expression in a small number of luminal cells, many of which expressed high levels of AR, and were enriched at the tips of prostate tufts. The number of Clusterin-expressing cells increased as regeneration progressed, suggesting a response to hormones in these cells. Our findings suggest that Clusterin is a marker for AR-responsive progenitor cells in the normal prostate, and are consistent with previous research that has shown that AR is a transcriptional activator of Clusterin. These findings warrant further studies on the inhibition of Clusterin as a treatment for castration-resistant prostate cancers that continue to be dependent on AR signaling.
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