Abstract
Recurrent fusions of ETS genes are considered driving mutations in a diverse array of cancers, including Ewing's sarcoma, acute myeloid leukemia, and prostate cancer. We investigate the mechanisms by which ETS fusions mediate their effects, and find that the product of the predominant ETS gene fusion, TMPRSS2:ERG, interacts in a DNA-independent manner with the enzyme poly (ADP-ribose) polymerase 1 (PARP1) and the catalytic subunit of DNA protein kinase (DNA-PKcs). ETS gene-mediated transcription and cell invasion require PARP1 and DNA-PKcs expression and activity. Importantly, pharmacological inhibition of PARP1 inhibits ETS-positive, but not ETS-negative, prostate cancer xenograft growth. Finally, overexpression of the TMPRSS2:ERG fusion induces DNA damage, which is potentiated by PARP1 inhibition in a manner similar to that of BRCA1/2 deficiency.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 664-678 |
| Number of pages | 15 |
| Journal | Cancer cell |
| Volume | 19 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 17 2011 |
Funding
We thank F. Alt, D. Ferguson, T. Wilson, R. Mani, and J. R. Prensner for discussions of the data, K. Suleman, A. Ayuningtyas, J. Granger, G. Hao, X. Jiang, X. Jing, B. Laxman, B. Russo, and A. Fullen for their technical support, and A. Kim and K. Giles for critically reading the manuscript. We would also like to thank S.J. Weiss for assistance in performing CAM assays and T. Linsenmayer for providing chicken type IV collagen antibody. We thank D. Cortez for sharing data that ERG was one of the genes nominated in a DNA damage response RNAi screen carried out in Hela cells ( Lovejoy et al., 2009 ). A.M.C. is an American Cancer Society Research Professor. A.M.C. is supported by a Burroughs Welcome Foundation Award in Clinical Translational Research and the Doris Duke Charitable Foundation Clinical Scientist Award. B.A. is supported by a Genentech Foundation Postdoctoral Fellowship and Young Investigator Award from Expedition Inspiration. F.Y.F. is supported by a Physician Research Training Award from the Department of Defense (PC094231). This work was supported in part by the National Institutes of Health (R01CA132874 to A.M.C.), Prostate SPORE P50CA69568 to K.J.P. and A.M.C., and the Early Detection Research Network (UO1 CA113913 to A.M.C.) and the Department of Defense (PC051081 to A.M.C.). We also received support from the Prostate Cancer Foundation (F.Y.F., C.A.M., S.A.T., N.M.N., K.J.P., and A.M.C.). A.M.C. serves on the advisory board of Gen-Probe; and is a coinventor on a patent filed by the University of Michigan covering the diagnostic and therapeutic field of use for ETS fusions in prostate cancer. The diagnostic field of use has been licensed to Gen-Probe, Inc. Gen-Probe did not play a role in the design and conduct of this study, in the collection, analysis, or interpretation of the data, or in the preparation, review, or approval of the article. J.C.B., F.Y.F., and A.M.C. designed the overall project and directed the experimental studies. B.A., N.M.N., and K.J.P. coordinated the xenograft/primary prostate cancer xenograft experiments. J.S., W.Y., and R.M. developed tissue microarrays and carried out pathology evaluation. A.K.Y., Y.L., V.B., J.C.B., K.S.J.E-J., and S.V. carried out proteomics analysis. I.A.A. carried out and analyzed CAM assays. R.J.L. and C.A.M. performed statistical analysis. J.C.B., B.A., Y.L., S.P., H.L., Q.C., J.Y., N.P., X.W., X.C., A.S., J.Y., and S.A.T. performed experimental studies. J.C.B., B.A., M.H., K.J.P., F.Y.F., and A.M.C. interpreted the data. J.C.B, S.A.T., F.Y.F., and A.M.C. wrote the paper.
ASJC Scopus subject areas
- Oncology
- Cancer Research
