99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA
Molecular Determinants of Tumor Susceptibility and Progression: Poster Presentations - Proffered Abstracts |
Abstract #4567
TMPRSS2-ERG fusion prostate cancer is a molecularly distinct estrogen-sensitive subclass of aggressive prostate cancer
Sunita Setlur,
Kirsten Mertz,
Yujin Hoshida,
Francesca Demichelis,
Mathieu Lupien,
Sven Perner,
Andrea Sboner,
Yudi Pawitan,
Ove Andren,
Laura Johnson,
Jeff Tang,
Hans-Olov Adami,
Stefano Calza,
Arul Chinnaiyan,
Daniel Rhodes,
Scott Tomlins,
Katja Fall,
Lorelei Mucci,
Philip Kantoff,
Meir Stampfer,
Swen-Olof Andersson,
Eberhard Varenhorst,
Jan-Erik Johansson,
Myles Brown,
Todd Golub and
Mark Rubin
Brigham and Women's Hospital, Harvard Medical School, Boston, MA, The Broad Institute of MIT and Harvard, Cambridge, MA, The Dana-Farber Cancer Institute, Boston, MA, Yale University, New Haven, CT, Karolinska Institutet, Stockholm, Sweden, Orebro University Hospital, Orebro, Sweden, Brigham and Women's Hospital, Boston, MA, Harvard School of Public Health, Boston, MA, University of Michigan Medical School, Ann Arbor, MI, University Hospital Linkoping, Linkoping, Sweden
Introduction:
Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men. A striking recent discovery indicates that 40-70% of men diagnosed with PCa harbor a chromosomal translocation, resulting in the fusion of promoter region of the transmembrane protease, serine 2 (TMPRSS2) gene to the coding region of members of the erythroblast transformation specific (ETS) family of transcription factors, most commonly v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG). TMPRSS2-ERG fusion prostate cancers appear to have a more aggressive natural clinical history and the mechanism by which TMPRSS2-ERG contributes to the pathogenesis of PCa is entirely unknown. In order to understand the molecular mechanism underlying the TMPRSS2-ERG fusion prostate cancer, we carried out expression array profiling using archival tissues from patients with and without TMPRSS2-ERG fusion.
Methods:
Archival formalin-fixed paraffin embedded (FFPE) samples were derived from Swedish Watchful Waiting cohort (SWW) consisting of men with localized PCa (1987-1999, N=354) and US based Physicians Health Study cohort (PHS) including men diagnosed with incidental PCa (1983-2003, N=116). We used cDNA-based microarray technology, cDNA-mediated Annealing, Selection, Ligation and Extension (DASL) and a custom designed array to interrogate 6,144 genes for the expression profiling analysis.
Results:
An 87 gene signature distinguishing TMPRSS-ERG fusion prostate cancer as a molecularly distinct sub-class was identified. This signature, when validated on the PHS cohort resulted in an AUC of 80% (p<0.001). Molecular pathway analysis using various computational approaches showed a strong enrichment of estrogen receptor (ER) signaling pathways. Functional studies using TMPRRS2-ERG positive, androgen independent (NCI-H660) and dependent (VCaP), cell lines showed that estrogen could regulate the fusion transcript. Treatment with an ER
selective agonist, resulted in growth stimulation and increase in transcript production, while the converse was true of the ERβ selective agonist. Knock-down of ERβ expression by siRNA increased TMPRSS2-ERG expression. Chromatin immunoprecipitation showed that ERβ localized to a previously unrecognized site in the TMPRSS2 promoter in NCI-H660 cells thereby confirming direct transcriptional regulation.
Conclusions:
This study resulted in the discovery of a robust gene expression signature distinguishing TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity, regulated by estrogens in addition to androgens. The results highlight the need to test ERβ specific agonists in the treatment of PCa, and raise a cautionary note regarding the use of agents with ER agonist activity. The data also suggest a mechanism by which prostate cancers which are initially androgen-dependent, might develop androgen-independence.
