Mechanistic Rationale for Inhibition of Poly(ADP-Ribose) Polymerase in ETS Gene Fusion-Positive Prostate Cancer

被引：352

作者：

Brenner, J. Chad ^{[1
,2
,3
]}

Ateeq, Bushra ^{[1
,2
]}

Li, Yong ^{[1
,2
]}

Yocum, Anastasia K. ^{[1
,2
,8
]}

Cao, Qi ^{[1
,2
]}

Asangani, Irfan A. ^{[1
]}

Patel, Sonam ^{[1
]}

Wang, Xiaoju ^{[1
,2
]}

Liang, Hallie ^{[1
]}

Yu, Jindan ^{[1
,2
,7
]}

Palanisamy, Nallasivam ^{[1
,2
,9
]}

Siddiqui, Javed ^{[1
,2
,7
]}

Yan, Wei ^{[1
,2
]}

Cao, Xuhong ^{[1
,4
]}

Mehra, Rohit ^{[1
,2
]}

Sabolch, Aaron ^{[5
]}

Basrur, Venkatesha ^{[1
,2
]}

Lonigro, Robert J. ^{[1
,2
]}

Yang, Jun ^{[10
,11
]}

Tomlins, Scott A. ^{[1
,2
]}

Maher, Christopher A. ^{[1
,2
,6
]}

Elenitoba-Johnson, Kojo S. J. ^{[2
]}

Hussain, Maha ^{[7
,8
,9
]}

Navone, Nora M. ^{[10
,11
]}

Pienta, Kenneth J. ^{[1
,3
,7
,8
,9
]}

Varambally, Sooryanarayana ^{[1
,2
,8
]}

Feng, Felix Y. ^{[1
,5
,9
]}

Chinnaiyan, Arul M. ^{[1
,2
,3
,4
,8
,9
]}

机构：

[1] Univ Michigan, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Program Cellular & Mol Biol, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA

[6] Univ Michigan, Ctr Computat Med & Biol, Ann Arbor, MI 48109 USA

[7] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA

[8] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA

[9] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA

[11] Univ Texas MD Anderson Canc Ctr, David H Koch Ctr Appl Res Genitourinary Canc, Houston, TX 77030 USA

来源：

CANCER CELL | 2011年 / 19卷 / 05期

基金：

美国国家卫生研究院;

关键词：

EWINGS-SARCOMA TRANSLOCATION; DNA-LIGASE IV; TRANSCRIPTION FACTORS; TMPRSS2-ERG FUSION; ANDROGEN RECEPTOR; EWS GENE; EXPRESSION; TUMORS; PROGRESSION; ERG;

D O I：

10.1016/j.ccr.2011.04.010

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：664 / 678

页数：15

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