title: Deletion of Interstitial Genes between TMPRSS2 and ERG Promotes Prostate Cancer Progression.
abstract: TMPRSS2-ERG gene fusions that occur frequently in human prostate cancers can be generated either through insertional chromosomal rearrangement or by intrachromosomal deletion. Genetically, a key difference between these two mechanisms is that the latter results in deletion of a ∼3-Mb interstitial region containing genes with unexplored roles in prostate cancer. In this study, we characterized two mouse models recapitulating TMPRSS2-ERG insertion or deletion events in the background of prostate-specific PTEN deficiency. We found that only the mice that lacked the interstitial region developed prostate adenocarcinomas marked by poor differentiation and epithelial-to-mesenchymal transition. Mechanistic investigations identified several interstitial genes, including Ets2 and Bace2, whose reduced expression correlated in the gene homologs in human prostate cancer with biochemical relapse and lethal disease. Accordingly, PTEN-deficient mice with prostate-specific knockout of Ets2 exhibited marked progression of prostate adenocarcinomas that was partly attributed to activation of MAPK signaling. Collectively, our findings established that Ets2 is a tumor suppressor gene in prostate cancer, and its loss along with other genes within the TMPRSS2-ERG interstitial region contributes to disease progression. Cancer Res; 76(7); 1869-81. ©2016 AACR.
authors.affiliation: Division of Genetics, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Linn
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Penney
authors.affiliation: Rodent Histopathology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
authors.affiliation: Division of Genetics, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts. zli4@rics.bwh.harvard.edu.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D018450:Disease Progression; D004596:Electroretinography / Q000295:instrumentation / Q000379:methods*; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism
chemical_list: D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human