Maintenance of genomic integrity after DNA double strand breaks in the human prostate and seminal vesicle epithelium: the best and the worst

Abstract

Prostate cancer is one of the most frequent cancer types in men, and its incidence is steadily increasing. On the other hand, primary seminal vesicle carcinomas are extremely rare with less than 60 cases reported worldwide. Therefore the difference in cancer incidence has been estimated to be more than a 100,000-fold. This is astonishing, as both tissues share similar epithelial structure and hormonal cues. Clearly, the two epithelia differ substantially in the maintenance of genomic integrity, possibly due to inherent differences in their DNA damage burden and DNA damage signaling. The DNA damage response evoked by DNA double strand breaks may be relevant, as their faulty repair has been implicated in the formation of common genomic rearrangements such as TMPRSS2-ERG fusions during prostate carcinogenesis. Here, we review DNA damaging processes of both tissues with an emphasis on inflammation and androgen signaling. We discuss how benign prostate and seminal vesicle epithelia respond to acute DNA damage, focusing on the canonical DNA double strand break-induced ATM-pathway, p53 and DNA damage induced checkpoints. We propose that the prostate might be more prone to the accumulation of genetic aberrations during epithelial regeneration than seminal vesicles due to a weaker ability to enforce DNA damage checkpoints.

Figure 1

Histology of SVs and the prostate. The glandular structure of SVs and the prostate is visualized in standard paraffin‐embedded tissue sections. The sections were stained with hematoxylin‐eosin (HE) (A) and for basal cytokeratins 5/14 (B) as described in Jäämaa et al. (2010). The epithelium of both tissues consists of two major cell types, basal (B) and secretory (S) cells. Note the discontinuous layer of basal cells in SVs.

Figure 2

TOP2B expression and ERG‐fusions in prostate and SV tissues. Standard paraffin‐embedded SV and prostate tissue sections were stained for topoisomerase 2B (A) expressed mainly in the basal epithelial cells, and ERG (B) as described in Jäämaa et al. (2010). ERG expression in normal prostate and SV tissue is detectable in endothelial cells of small vessels (marked with *) and lymphocytes. Arrows indicate basal (B) and secretory (S) cells. (C) ERG‐fusions can be detected in a fraction of prostate tumors, and not in benign prostate or SVs.

Figure 3

Predisposition factors increasing DNA damage load in the prostate. Prostate and SV epithelia encounter many DNA damaging events of exogenous and endogenous sources, including inflammation, carcinogens, microbes and androgen signaling. Combined with the deficient cell cycle checkpoint responses and multiple replicative cycles of prostate cells predisposes to the accumulation of genomic alterations.

Figure 4

Model of DDR in prostate and seminal vesicle epithelia. After cell damage in SV or prostate epithelium, replication is increased to replace lost epithelial cells. Relaxed cell cycle checkpoints in prostate epithelium allow cells with unsuccessful DSB repair to proliferate, and over time genetic lesions e.g. TMPRSS2‐ERG fusions may start to accumulate. In SV epithelium, only cells with successful DNA damage repair are allowed to complete their replication due to vigilant cell cycle checkpoints, high levels of Wee1A and active p53, and genetic integrity is maintained.