Stochastic Changes in Gene Expression Promote Chaotic Dysregulation of Homeostasis in Clonal Breast Tumors

Much remains unknown about the mechanisms contributing to molecular and cellular diversity in cancer. This diversity enables the evolutionary processes that govern tumor progression and contributes to treatment failures. In a previous study, we described atypical losses of heterozygosity at the DNA level in Her2/neu-driven breast tumors from first generation (F1) intercrossed mice. We now describe similar losses of heterozygosity at the level of gene expression. By quantitating each parental allele for genes expressed across a population of clonal tumors, we found variegated patterns of expression outliers in hundreds of genes, enriched in pathways typically co-opted by tumors. The frequency of outliers was correlated with transcriptional repression of a large set of homozygous genes. These findings reveal the potential for sporadic epigenetic errors that cause dysregulated cellular homeostasis and generate phenotypic variations available for clonal selection. Overall design: Quantitation and characterization of germline-encoded BALB/c versus FVB/J allelic expression in breast tumors from [BALB/c x FVB/J] F1 mice.