Androgen-Induced TMPRSS2:ERG Fusion in Nonmalignant Prostate Epithelial Cells

Abstract

Fusion genes play important roles in tumorigenesis. The identification of the high-frequency TMPRSS2 fusion with ERG and other ETS family genes in prostate cancer highlights the importance of fusion genes in solid tumor development and progression. However, the mechanisms leading to these fusions are unclear. We investigated whether androgen, through stimulating its receptor, could promote spatial genome reorganization and contribute to the generation of the TMPRSS2:ERG fusion. We show that treatment with androgen can induce the TMPRSS2:ERG fusion in both malignant and nonmalignant prostate epithelial cells. Although the fusion could be detected in malignant cells following 24-hour treatment, prolonged exposure to androgen was required to detect the fusion transcript in nonmalignant cells. We associated the fusion incidence with genetic factors, including androgen-induced gene proximity, androgen receptor exon1 CAG repeat length and expression of the PIWIL1 gene. This study demonstrates that fusions can be induced prior to malignant transformation and generation of the fusion is associated with both gene proximity and loss of the ability to prevent double-strand breaks. Cancer Res; 70(23); 9544-8. Ó2010 AACR.

Androgen Receptor CAG Repeat Polymorphism and Risk of TMPRSS2:ERG–Positive Prostate Cancer

“…This finding confirms the prior study by Bastus et al (11), who found that mean CAG repeat length was shorter in ERG-positive (mean length = 20 repeats) compared to ERG-negative (mean length = 21 repeats) cancer in a study of 40 prostate cancer patients. Moreover, the results are in line with experimental evidence that heightened AR signaling induces TMPRSS2:ERG formation (10).…”

“…One of the proposed mechanisms of fusion formation is that AR signaling induces spatial proximity, leading to colocalization of the 5′ and 3′ ends of TMPRSS2 and ERG , which may increase the probability of a fusion event occurring. In prostate cancer and noncancer cell lines, TMPRSS2:ERG formation is androgen dose dependent and may be the result of long-term androgen exposure (11). Thus, if shorter CAG repeat length drives increased transactivation of AR and is a proxy for long-term androgen exposure, there may an increased likelihood for the fusion to occur and fusion positive prostate cancer to result.…”

“…Subsequent treatment with gamma irradiation, which causes DNA double-strand breaks, leads to formation of the TMPRSS2:ERG gene fusion, suggesting that heightened AR signaling can facilitate TMPRSS2:ERG formation. Supporting this notion, in a case-only study of 40 men with prostate cancer, Bastus et al found suggestive evidence that the number of CAG repeats is lower in TMPRSS2:ERG positive versus negative prostate cancer (11). …”

Topoisomerase-mediated chromosomal break repair: an emerging player in many games

“…Prolonged androgen treatment induces TMPRSS2-ERG fusion in both malignant and non-malignant prostate epithelial cells, but at remarkably different rates; 24 hours versus 5 months, respectively 129 . In addition, transient androgen treatment did not induce TMPRSS2-ERG fusion in non-malignant prostate epithelial cells 126 .…”

ETS rearrangements in prostate cancer

“…76,77 The androgen receptor and TOP2B are coexpressed in human prostate cancer precursor lesions in which TMPRSS2:ERG rearrangements are known to occur, suggesting a critical role of TOP2B in the recurrent ETS rearrangements. Three recent studies have also shown that androgen signaling promotes TMPRSS2:ERG fusion formation, [78][79][80] in part, by recruiting DNA break-inducing enzymes (e.g., activation of induced cytidine deaminase (AID)) to translocation breakpoint sites. 79 More recently, we demonstrated that rearrangement breakpoints were enriched near open chromatin, androgen receptor and tERG DNA-binding sites in the setting of the ETS gene fusion TMPRSS2:ERG, but inversely correlated with these regions in tumors lacking ETS fusions.…”