title: TMPRSS2- driven ERG expression in vivo increases self-renewal and maintains expression in a castration resistant subpopulation.
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-1(hi)/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.
authors.affiliation: Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Orla M
authors.initials: OM
authors.lastname: Casey
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.forename: Paul G
authors.initials: PG
authors.lastname: Hynes
authors.forename: Wassim G
authors.initials: WG
authors.lastname: Abou-Kheir
authors.forename: Philip L
authors.initials: PL
authors.lastname: Martin
authors.forename: Heather S
authors.initials: HS
authors.lastname: Tillman
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Petrovics
authors.forename: Hibah O
authors.initials: HO
authors.lastname: Awwad
authors.forename: Yvona
authors.initials: Y
authors.lastname: Ward
authors.forename: Ross
authors.initials: R
authors.lastname: Lake
authors.forename: Luhua
authors.initials: L
authors.lastname: Zhang
authors.forename: Kathleen
authors.initials: K
authors.lastname: Kelly
mesh_terms: D000728:Androgens / Q000502:physiology; D000818:Animals; D049109:Cell Proliferation; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D004848:Epithelium / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D009919:Orchiectomy; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012697:Serine Endopeptidases / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D000071230:Transcriptional Regulator ERG; D014407:Tumor Cells, Cultured
chemical_list: D000728:Androgens; C072312:ERG protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human