Genetic changes in the evolution of multidrug resistance for cultured human ovarian cancer cells.

Genetic changes in the evolution of multidrug resistance for cultured human ovarian cancer cells. Research Abstract Details 

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Genetic changes in the evolution of multidrug resistance for cultured human ovarian cancer cells. Abstract Text:

Timon P H Buys,Raj Chari,Eric H L Lee,May Zhang,Calum MacAulay,Stephen Lam,Wan L Lam,Victor Ling,Timon P H Buys,Raj Chari,Eric H L Lee,May Zhang,Calum MacAulay,Stephen Lam,Wan L Lam,Victor Ling,Timon P H Buys,Raj Chari,Eric H L Lee,May Zhang,Calum MacAulay,Stephen Lam,Wan L Lam,Victor Ling,

The multidrug resistant (MDR) phenotype is often attributed to the activity of ATP-binding cassette (ABC) transporters such as P-glycoprotein (ABCB1). Previous work has suggested that modulation of MDR may not necessarily be a single gene trait. To identify factors that contribute to the emergence of MDR, we undertook integrative genomics analysis of the ovarian carcinoma cell line SKOV3 and a series of MDR derivatives of this line (SKVCRs). As resistance increased, comparative analysis of gene expression showed conspicuous activation of a network of genes in addition to ABCB1. Functional annotation and pathway analysis revealed that many of these genes were associated with the extracellular matrix and had previously been implicated in tumor invasion and cell proliferation. Further investigation by whole genome tiling-path array CGH suggested that changes in gene dosage were key to the activation of several of these overexpressed genes. Remarkably, alignment of whole genome profiles for SKVCR lines revealed the emergence and decline of specific segmental DNA alterations. The most prominent alteration was a novel amplicon residing at 16p13 that encompassed the ABC transporter genes ABCC1 and ABCC6. Loss of this amplicon in highly resistant SKVCR lines coincided with the emergence of a different amplicon at 7q21.12, which harbors ABCB1. Integrative analysis suggests that multiple genes are activated during escalation of drug resistance, including a succession of ABC transporter genes and genes that may act synergistically with ABCB1. These results suggest that evolution of the MDR phenotype is a dynamic, multi-genic process in the genomes of cancer cells.

Genetic changes in the evolution of multidrug resistance for cultured human ovarian cancer cells. Publishing Authors By Initials

TP Buys,R Chari,EH Lee,M Zhang,C MacAulay,S Lam,WL Lam,V Ling,TP Buys,R Chari,EH Lee,M Zhang,C MacAulay,S Lam,WL Lam,V Ling,TP Buys,R Chari,EH Lee,M Zhang,C MacAulay,S Lam,WL Lam,V Ling,

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Genetic changes in the evolution of multidrug resistance for cultured human ovarian cancer cells. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Genes, chromosomes & cancer

VOLUME: 46

Page Numbers: 1069-79

Journal Abbreviation: Genes Chromosomes Cancer

ISSN: 1045-2257

DAY: 9

MONTH: Dec

YEAR: 2007

Genetic changes in the evolution of multidrug resistance for cultured human ovarian cancer cells. Information

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LANGUAGE: eng

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Grant and Affiliation Information for Genetic changes in the evolution of multidrug resistance for cultured human ovarian cancer cells.

AFFILIATION: British Columbia Cancer Research Centre, Vancouver, BC, Canada V5Z 1L3. tbuys@bccrc.ca

Country: United States

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MEDLINETA: Genes Chromosomes Cancer

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