Copy number aberrations in mouse breast tumors reveal loci and genes important in tumorigenic RTK signaling. Mus musculus

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 utilized microarray comparative genomic hybridization (array CGH) to identify and compare copy number aberrations in 5 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 amongst the various models including recurrent chromosome 11 amplifications and chromosome 4 deletions, respectively syntenic with human 17q21-25 and 1p35-36. 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 2 of the genes, ErbB2 and Grb7. Chromosome 11 amplicons distal to Erbb2 arise in a model (DB) over expressing a mutant variant of PyMT (Y315/322F) unable to activate PI3K. These amplicons are not observed in DB hyperplasias or in tumors over expressing wild type PyMT, and result in over expression of Grb2 and Itgb4. Distal chromosome 4 deletions occur in a significantly higher proportion of Erbb2 than PyMT tumors and encompass 14-3-3 sigma (Sfn), which is expressed at low or undetectable levels in the majority of TM tumors. Our studies highlight loci and genes important in the regulation of tumorigenic RTK signaling in mammary epithelial cells in vivo. Keywords: Comparative Genomic Hybridization Overall design: 110 mouse breast tumor genomic DNA samples were labeled with cy3 and co-hybridized with normal, strain matched mouse spleen genomic DNA labeled with cy5 to DNA microarrays in the presence of excess mouse cot-1 DNA. Results presented are those of a single hybridization.