Abstract
Genomic rearrangements commonly occur in many types of cancers and often initiate or alter the progression of disease. Here we describe an in vivo mouse model that recapitulates the most frequent rearrangement in prostate cancer, the fusion of the promoter region of TMPRSS2 with the coding region of the transcription factor, ERG. A recombinant bacterial artificial chromosome including an extended TMPRSS2 promoter driving genomic ERG was constructed and used for transgenesis in mice. TMPRSS2-ERG expression was evaluated in tissue sections and FACS-fractionated prostate cell populations. In addition to the anticipated expression in luminal cells, TMPRSS2-ERG was similarly expressed in the Sca-1hi/EpCAM+ basal/progenitor fraction, where expanded numbers of clonogenic self-renewing progenitors were found, as assayed by in vitro sphere formation. These clonogenic cells increased intrinsic self renewal in subsequent generations. In addition, ERG dependent self-renewal and invasion in vitro was demonstrated in prostate cell lines derived from the model. Clinical studies have suggested that the TMPRSS2-ERG translocation occurs early in prostate cancer development. In the model described here, the presence of the TMPRSS2-ERG fusion alone was not transforming but synergized with heterozygous Pten deletion to promote PIN. Taken together, these data suggest that one function of TMPRSS2-ERG is the expansion of self-renewing cells, which may serve as targets for subsequent mutations. Primary prostate epithelial cells demonstrated increased post transcriptional turnover of ERG compared to the TMPRSS2-ERG positive VCaP cell line, originally isolated from a prostate cancer metastasis. Finally, we determined that TMPRSS2-ERG expression occurred in both castration-sensitive and resistant prostate epithelial subpopulations, suggesting the existence of androgen-independent mechanisms of TMPRSS2 expression in prostate epithelium.
Highlights
Prostate adenocarcinoma is believed to develop from early precursor lesions known as prostatic intraepithelial neoplasia (PIN) [1]
Recombineering was used to construct a bacterial artificial chromosome (BAC) that incorporated a 25 Kb human transmembrane protease serine 2 (TMPRSS2) promoter plus exons 1 and 2 adjacent to the human Ets related gene (ERG) genomic region downstream of intron 7/exon 8 (Figure 1A); the exon nomenclature used here is from Owczarek et al, [26]
Transgenic animals were generated in the FVB and C57/BL6 backgrounds, and one line from each background, A5 and H7, respectively, was selected for further investigation. cDNA clones of fusion transcripts derived from transgenic prostates demonstrated the expected sequences and the existence of accurately-spliced transcripts with and without ERG exon 12 (Figure 1B)
Summary
Prostate adenocarcinoma is believed to develop from early precursor lesions known as prostatic intraepithelial neoplasia (PIN) [1]. The lower concordance of ERG positive carcinoma and PIN in tissue microarrays may be in part the consequence of multi-focal tumor heterogeneity [11] It appears that TMPRSS2-ERG fusion can be an initiating or pre-malignant event as implied by the rare observations of TMPRSS2-ERG fusions in low grade lesions including atypia and low grade PIN [10,12]. Taken together, these clinical data support the occurrence of TMPRSS2-ERG translocation as an early event in prostate cancer that is subsequently selected during malignant transformation
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