Unknown,Transcriptomics,Genomics,Proteomics

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Copy number analysis of OVCAR-3 and CDK2 resistant sublines

ABSTRACT: Cyclin E1 (CCNE1) is amplified in various tumor types including high-grade serous ovarian cancer where it is associated with poor clinical outcome. We have demonstrate that suppression of the Cyclin E1 partner kinase, CDK2, induces apoptosis in a CCNE1 amplicon-dependent manner. Little is known of mechanisms of resistance to CDK inhibitors. We therefore generated OVCAR-3 sublines with reduced sensitivity to CDK2 inhibitors and profiled by SNP copy number microarrays. Arrayed samples included parental OVCAR-3 cells and five independently derived sublines resistant to PHA-533533 (OVCAR3-533533-R1, -R3, -R5, -R6, -R7). The resistant cell lines were arrayed after drug selection (P5).

ORGANISM(S): Homo sapiens

SUBMITTER: Dariush Etemadmoghadam

PROVIDER: E-GEOD-48920 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Resistance to CDK2 inhibitors is associated with selection of polyploid cells in CCNE1-amplified ovarian cancer.

Etemadmoghadam Dariush D Au-Yeung George G Wall Meaghan M Mitchell Chris C Kansara Maya M Loehrer Elizabeth E Batzios Crisoula C George Joshy J Ftouni Sarah S Weir Barbara A BA Carter Scott S Gresshoff Irma I Mileshkin Linda L Rischin Danny D Hahn William C WC Waring Paul M PM Getz Gad G Cullinane Carleen C Campbell Lynda J LJ Bowtell David D DD

Clinical cancer research : an official journal of the American Association for Cancer Research 20130904 21

<h4>Purpose</h4>Amplification of cyclin E1 (CCNE1) is associated with poor outcome in breast, lung, and other solid cancers, and is the most prominent structural variant associated with primary treatment failure in high-grade serous ovarian cancer (HGSC). We have previously shown that CCNE1-amplified tumors show amplicon-dependent sensitivity to CCNE1 suppression. Here, we explore targeting CDK2 as a novel therapeutic strategy in CCNE1-amplified cancers and mechanisms of resistance.<h4>Experimen ...[more]

PMID: 24004674

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Project description:Background & Aims: The CCNE1 locus, which encodes cyclin E1, is amplified in many types of cancer cells and is activated in hepatocellular carcinomas (HCCs) from patients infected with hepatitis B virus or adeno-associated virus type 2, due to integration of the virus nearby. We investigated cell cycle and oncogenic effects of cyclin E1 overexpression in tissues of mice. Methods: We generated mice with doxycycline-inducible expression of Ccne1 (Ccne1T mice) and activated overexpression of cyclin E1 from age 3 weeks onwards. At 14 months of age, livers were collected from mice that overexpress cyclin E1 and non-transgenic mice (controls) and analyzed for tumor burden and by histology. Mouse embryonic fibroblasts (MEFs) and hepatocytes from Ccne1T and control mice were analyzed to determine the extent to which cyclin E1 overexpression perturbs S-phase entry, DNA replication, and numbers and structures of chromosomes. Tissues from 4-month-old Ccne1T and control mice (at that age were free of tumors) were analyzed for chromosome alterations, to investigate the mechanisms by which cyclin E1 predisposes hepatocytes to transformation. Results: Ccne1T mice developed more hepatocellular adenomas and HCCs than control mice. Tumors developed only in livers of Ccne1T mice, despite high levels of cyclin E1 in other tissues. Ccne1T MEFs had defects that promoted chromosome missegregation and aneuploidy, including incomplete replication of DNA, centrosome amplification, and formation of non-perpendicular mitotic spindles. Whereas Ccne1T mice accumulated near-diploid aneuploid cells in multiple tissues and organs, polyploidization was observed only in hepatocytes, with losses and gains of whole chromosomes, DNA damage, and oxidative stress. Conclusions: Livers, but not other tissues of mice with inducible overexpression of cyclin E1, develop tumors. More hepatocytes from the cyclin E-overexpressing mice were polyploid than from control mice, and had losses or gains of whole chromosomes, DNA damage, and oxidative stress – all of these have been observed in human HCC cells. The increased risk of HCC in patients with hepatitis B virus or adeno-associated virus type 2 infection might involve activation of cyclin E1 and its effects on chromosomes and genomes of liver cells.

Dataset Information

Copy number analysis of OVCAR-3 and CDK2 resistant sublines

Publications

Resistance to CDK2 inhibitors is associated with selection of polyploid cells in CCNE1-amplified ovarian cancer.

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