Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras Journal Article

   

Authors:	Podsypanina, K.; Politi, K.; Beverly, L. J.; Varmus, H. E.
Article Title:	Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras
Abstract:	Most, if not all, cancers are composed of cells in which more than one gene has a cancer-promoting mutation. Although recent evidence has shown the benefits of therapies targeting a single mutant protein, little attention has been given to situations in which experimental tumors are induced by multiple cooperating oncogenes. Using combinations of doxycycline-inducible and constitutive Myc and mutant Kras transgenes expressed in mouse mammary glands, we show that tumors induced by the cooperative actions of two oncogenes remain dependent on the activity of a single oncogene. Deinduction of either oncogene individually, or both oncogenes simultaneously, led to partial or complete tumor regression. Prolonged remission followed deinduction of KrasG12D in the context of continued Myc expression, deinduction of a MYC transgene with continued expression of mutant Kras produced modest effects on life extension, whereas simultaneous deinduction of both MYC and KrasG12D transgenes further improved survival. Disease relapse after deinduction of both oncogenes was associated with reactivation of both oncogenic transgenes in all recurrent tumors, often in conjunction with secondary somatic mutations in the tetracycline transactivator transgene, MMTV-rtTA, rendering gene expression doxycycline-independent. These results demonstrate that tumor viability is maintained by each gene in a combination of oncogenes and that targeted approaches will also benefit from combination therapies. © 2008 by The National Academy of Sciences of the USA.
Keywords:	adolescent; cancer survival; survival rate; oncoprotein; gene mutation; human cell; somatic mutation; genetics; mutation; nonhuman; cell proliferation; mouse; animal; metabolism; animals; mice; animal tissue; apoptosis; gene expression; animal experiment; animal model; recurrence; tumor regression; pathology; breast neoplasms; cell transformation, neoplastic; gene activation; cancer regression; cell transformation; tumor recurrence; nucleotide sequence; breast tumor; transgene; recurrent disease; cancer relapse; base sequence; gene induction; oncogene k ras; doxycycline; protein p21; proto-oncogene proteins p21(ras); ras; oncogene myc; mammary gland; mouse mammary tumor virus; transgenes; inducible; oncogene protein p55(v-myc)
Journal Title:	Proceedings of the National Academy of Sciences of the United States of America
Volume:	105
Issue:	13
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Date Published:	2008-04-01
Start Page:	5242
End Page:	5247
Language:	English
DOI:	10.1073/pnas.0801197105
PUBMED:	18356293
PROVIDER:	scopus
PMCID:	PMC2278195
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-42449105650&partnerID=40&md5=f7d6359740bf597685b5c6beaa1d082a
Notes:	--- - "Cited By (since 1996): 19" - "Export Date: 17 November 2011" - "CODEN: PNASA" - "Source: Scopus"

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