PPM1D Is a Potential Therapeutic Target in Ovarian Clear Cell Carcinomas

被引：140

作者：

Tan, David S. P. ^{[1
,3
]}

Lambros, Maryou B. K. ^{[1
]}

Rayter, Sydonia ^{[1
]}

Natrajan, Rachael ^{[1
]}

Vatcheva, Radost ^{[1
]}

Gao, Qiong ^{[1
]}

Marchio, Caterina ^{[1
]}

Geyer, Felipe C. ^{[1
]}

Savage, Kay ^{[1
]}

Parry, Suzanne ^{[1
]}

Fenwick, Kerry ^{[1
]}

Tamber, Narinder ^{[1
]}

Mackay, Alan ^{[1
]}

Dexter, Tim ^{[1
]}

Jameson, Charles

McCluggage, W. Glenn ^{[4
]}

Williams, Alistair ^{[5
,6
]}

Graham, Ashley ^{[5
,6
]}

Faratian, Dana ^{[5
,6
]}

El-Bahrawy, Mona ^{[2
]}

Paige, Adam J. ^{[2
]}

Gabra, Hani ^{[2
]}

Gore, Martin E.

Zvelebil, Marketa ^{[1
]}

Lord, Christopher J. ^{[1
]}

Kaye, Stanley B. ^{[3
]}

Ashworth, Alan ^{[1
]}

Reis-Filho, Jorge S. ^{[1
]}

机构：

[1] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England

[2] Univ London Imperial Coll Sci Technol & Med, Ovarian Canc Act Res Ctr, London, England

[3] Royal Marsden Hosp, Inst Canc Res, Med Sect, Surrey, England

[4] Royal Grp Hosp Trust, Dept Pathol, Belfast, Antrim, North Ireland

[5] Univ Edinburgh, Dept Pathol, Edinburgh, Midlothian, Scotland

[6] Univ Edinburgh, Edinburgh Breakthrough Res Ctr, Edinburgh, Midlothian, Scotland

来源：

CLINICAL CANCER RESEARCH | 2009年 / 15卷 / 07期

关键词：

COMPARATIVE GENOMIC HYBRIDIZATION; BREAST-CANCER; ACTIVATING MUTATIONS; AMPLIFICATION; DNA; IDENTIFICATION; EXPRESSION; LINES; GAIN; ADENOCARCINOMAS;

D O I：

10.1158/1078-0432.CCR-08-2403

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: To identify therapeutic targets in ovarian clear cell carcinomas, a chemoresistant and aggressive type of ovarian cancer. Experimental Design: Twelve ovarian clear cell carcinoma cell lines were subjected to tiling path microarray comparative genomic hybridization and genome-wide expression profiling analysis. Regions of high-level amplification were defined and genes whose expression levels were determined by copy number and correlated with gene amplification were identified. The effects of inhibition of PPM1D were assessed using short hairpin RNA constructs and a small-molecule inhibitor (CCT007093). The prevalence of PPM1D amplification and mRNA expression was determined using chromogenic in situ hybridization and quantitative real-time reverse transcription-PCR in a cohort of pure ovarian clear cell carcinomas and on an independent series of unselected epithelial ovarian cancers. Results: Array-based comparative genomic hybridization analysis revealed regions of high-level amplification on 1q32, 1q42, 2q11, 3q24-q26, 5p15,7p21-p22, 11q13.2-q13.4, 11q22,17q21-q22, 17q23.2,19q12-q13, and 20q13.2. Thirty-four genes mapping to these regions displayed expression levels that correlated with copy number gains/amplification. PPM1D had significantly higher levels of mRNA expression in ovarian clear cell carcinoma cell lines harboring gains/amplifications of 17q23.2. PPM1D inhibition revealed that PPM1D expression and phosphatase activity are selectively required for the survival of ovarian clear cell carcinoma cell lines with 17q23.2 amplification, PPM1D amplification was significantly associated with ovarian clear cell carcinoma histology (P = 0.0003) and found in 10% of primary ovarian clear cell carcinomas. PPM1D expression levels were significantly correlated with PPM1D gene amplification in primary ovarian clear cell carcinomas. Conclusion: Our data provide strong circumstantial evidence that PPM1D is a potential therapeutic target for a subgroup of ovarian clear cell carcinomas.

引用

页码：2269 / 2280

页数：12

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