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Series GSE55989 Query DataSets for GSE55989
Status Public on Dec 31, 2015
Title ZEB1 expression prevents DNA replication stress in cancer stem cells and delays chromosomal instability [Agilent]
Organism Homo sapiens
Experiment type Genome variation profiling by array
Summary Aberrant cell proliferation, a hallmark of most cancers, requires the escape from intrinsic antitumour barriers. Primary among these is the DNA damage response (DDR). In both cell culture-models and in early stages of tumorigenesis in vivo, activated oncogenes induce DNA replication stress and DNA double-strand breaks (DSBs), leading to DDR activation and p53-dependent apoptosis and/or senescence. The means by which tumour initiating cells, also termed cancer stem cells (CSCs), circumvent this oncosuppressive response is unknown. Here we demonstrate that the ZEB1 transcription factor provides breast CSCs with the ability to withstand an aberrant mitogenic activity. Its forced expression in human mammary epithelial cells is sufficient to alleviate DNA replicative stress and to decrease the production of reactive oxygen species, an important contributor to DDR and oncogene-induced senescence. Consistently, human breast cancer cells with endogenous ZEB1 expression show two characteristic features: low levels of DSBs and DDR markers, reflecting mitigation of the DNA replication stress, and a low p53 mutation frequency, reflecting a weak selective pressure for inactivation. Using high-throughput sequencing analysis of controlled cellular models, we further demonstrate that ZEB1 delays the onset of structural chromosomal instability (CIN), a known consequence of replicative stress and prevents the emergence of chromosome 8p deletions and 8q amplifications, two prevalent abnormalities in high grade breast cancers. Supporting these findings, ZEB1 expression discriminates human breast tumours by their copy number alterations (CNAs) and chromosome 8 aberrations. We propose that the tumorigenic potential of CSCs relies upon their unique capacity to tolerate oncogenic stimuli through the alleviation of DNA replication stress.
Overall design Immortalized human mammary epithelial cells were infected with retrovirus expressing H-RASV12 with or without a retrovirus expressing ZEB1.
Contributor(s) Morel A, Puisieux A, Combaret V, Lamblot C, Pinatel C, Iacono I, Bréjon S
Citation(s) 28394329
Submission date Mar 18, 2014
Last update date Apr 13, 2017
Contact name Anne Wierinckx
Organization name University Lyon1
Street address 8, av Rockefeller
City Lyon
State/province select a state
ZIP/Postal code 69008
Country France
Platforms (1)
GPL10123 Agilent-022060 SurePrint G3 Human CGH Microarray 4x180K (Feature Number version)
Samples (15)
GSM1349896 HME1 D15
GSM1349897 HME1 D45
GSM1349898 HME1 D90
This SubSeries is part of SuperSeries:
GSE56031 ZEB1 expression prevents DNA replication stress in cancer stem cells and delays chromosomal instability
BioProject PRJNA279696

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE55989_RAW.tar 277.4 Mb (http)(custom) TAR (of TXT)
Processed data included within Sample table
Processed data provided as supplementary file

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