Copy number aberrations in mouse breast tumors reveal loci and genes important in tumorigenic receptor tyrosine kinase signaling.
Receptor tyrosine kinase (RTK) signaling plays a key role in the development of breast cancer. Defining the genes and pathways in the RTK signaling network that are important regulators of tumorigenesis in vivo will unveil potential candidates for targeted therapeutics. To this end, we used microarray comparative genomic hybridization to identify and compare copy number aberrations in five mouse models of breast cancer induced by wild-type and mutated forms of oncogenic ErbB2 or the polyomavirus middle T antigen (PyMT). We observed distinct genomic alterations among the various models, including recurrent chromosome 11 amplifications and chromosome 4 deletions, syntenic with human 17q21-25 and 1p35-36, respectively. Expression of oncogenic Erbb2 (NeuNT) under control of the endogenous Erbb2 promoter results in frequent (85%) amplification at the Erbb2 locus with striking structural similarity to the human amplicon, resulting in overexpression of at least two of the genes, Erbb2 and Grb7. Chromosome 11 amplicons distal to Erbb2 arise in a model (DB) overexpressing a mutant variant of PyMT (Y315/322F) unable to activate phosphatidylinositol 3-kinase. These amplicons are not observed in DB hyperplasias or in tumors overexpressing wild-type PyMT and result in overexpression of Grb2 and Itgb4. Distal chromosome 4 deletions occur in a significantly higher proportion of Erbb2 than PyMT tumors and encompass 14-3-3sigma (Stratifin), which is expressed at low or undetectable levels in the majority of NeuNT tumors. Our studies highlight loci and genes important in the regulation of tumorigenic RTK signaling in mammary epithelial cells in vivo.
Hodgson
J Graeme
JG
Department of Laboratory Medicine and Comprehensive Cancer Center, University of California-San Francisco, San Francisco, California 94143, USA. ghodgson@cc.ucsf.edu
Malek
Tiffany
T
Bornstein
Sophia
S
Hariono
Sujatmi
S
Ginzinger
David G
DG
Muller
William J
WJ
Gray
Joe W
JW
D048948:14-3-3 Proteins / Q000235:genetics; D000818:Animals; D017353:Gene Deletion; D018628:Gene Dosage; D006801:Humans; D019656:Loss of Heterozygosity; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics*; D051379:Mice; D009693:Nucleic Acid Hybridization; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction
D048948:14-3-3 Proteins; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C499130:Sfn protein, mouse