NDLI: Centrosome aberrations in human mammary epithelial cells driven by cooperative interactions between p16INK4a deficiency and telomere-dependent genotoxic stress

Content Provider	PubMed Central
Author	Domínguez, Daniel Feijoo, Purificación Bernal, Aina Ercilla, Amaia Agell, Neus Anna, Genescà Tusell, Laura
Copyright Year	2015
Abstract	Virtually all human cancers display chromosome instability (CIN), a condition in which chromosomes are gained or lost at a high rate. CIN occurs early in cancer development where it may undermine the advance of the neoplastic disease. With the aim of establishing the mechanisms underlying CIN in cancer, we investigated possible links between telomere-dysfunction and centrosome defects, which were seen to coincide in early in breast carcinogenesis using human mammary epithelial cells (HMECs). In this study, we show that TP53 proficient vHMECs cells develop centrosome aberrations when telomere-dysfunction genotoxic stress is produced in the presence of a defective p16INK4a setting and in parallel with an activation of the DNA damage checkpoint response. These aberrations consist of the accumulation of centrosomes in polyploid vHMECs, plus centriole overduplication in both diploid and polyploid cells, thus reflecting that distinct mechanisms underlie the generation of centrosome aberrations in vHMECs. Transduction of vHMEC with hTERT, which rescued the telomere dysfunction phenotype and consequently reduced DNA damage checkpoint activation, led to a progressive reduction of centrosome aberrations with cell culture, both in diploid and in polyploid vHMECs. Radiation-induced DNA damage also raised centrosome aberrations in vHMEC-hTERT. Collectively, our results, using vHMECs define a model where p16INK4a deficiency along with short dysfunctional telomeres cooperatively engenders centrosome abnormalities before p53 function is compromised.
Ending Page	28256
Starting Page	28238
File Format	PDF
ISSN	19492553
e-ISSN	19492553
Journal	Oncotarget
Issue Number	29
Volume Number	6
Language	English
Publisher	Impact Journals LLC
Publisher Date	2015-07-22
Access Restriction	Open
Rights Holder	Impact Journals LLC
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Oncology

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