Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal Journal Article

   

Authors:	Sotillo, R.; Schvartzman, J. M.; Socci, N. D.; Benezra, R.
Article Title:	Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal
Abstract:	Inhibition of an initiating oncogene often leads to extensive tumour cell death, a phenomenon known as oncogene addiction. This has led to the search for compounds that specifically target and inhibit oncogenes as anticancer agents. However, there has been no systematic exploration of whether chromosomal instability generated as a result of deregulation of the mitotic checkpoint pathway, a frequent characteristic of solid tumours, has any effect on oncogene addiction. Here we show that induction of chromosome instability by overexpression of the mitotic checkpoint gene Mad2 in mice does not affect the regression of Kras-driven lung tumours when Kras is inhibited. However, tumours that experience transient Mad2 overexpression and consequent chromosome instability recur at markedly elevated rates. The recurrent tumours are highly aneuploid and have varied activation of pro-proliferative pathways. Thus, early chromosomal instability may be responsible for tumour relapse after seemingly effective anticancer treatments. © 2010 Macmillan Publishers Limited. All rights reserved.
Keywords:	cancer chemotherapy; controlled study; protein expression; unclassified drug; nonhuman; mitosis; chromosome; mouse; animals; cell cycle proteins; mice; animal tissue; gene; mus; gene overexpression; enzyme inhibition; neoplasm recurrence, local; lung neoplasms; animal experiment; animal model; enzyme activation; mice, transgenic; oncogenes; lung tumor; oncogene; tumor recurrence; cancer relapse; chromosomal instability; gene inactivation; rodent; gene induction; tumor; doxycycline; proto-oncogene proteins p21(ras); aneuploidy; disease treatment; enzyme; protein mad2; protein kras; respiratory disease
Journal Title:	Nature
Volume:	464
Issue:	7287
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2010-03-18
Start Page:	436
End Page:	440
Language:	English
DOI:	10.1038/nature08803
PUBMED:	20173739
PROVIDER:	scopus
PMCID:	PMC2841716
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-77949773695&partnerID=40&md5=ead19fcc99a2a6898c4a1210101bd0f3
Notes:	--- - "Cited By (since 1996): 7" - "Export Date: 20 April 2011" - "CODEN: NATUA" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/5150