Stochastic changes in gene expression promote chaotic dysregulation of homeostasis in clonal breast tumors

Abstract

Cells within tumors vary in phenotype as a result of changes in gene expression caused by a variety of mechanisms, permitting cancers to evolve under selective pressures from immune and other homeostatic processes. Earlier, we traced apparent losses in heterozygosity (LOH) of spontaneous breast tumors from first generation (F1) intercrossed mice to atypical epigenetic modifications in the structure of DNA across the tumor genomes. Here, we describe a parallel pattern of LOH in gene expression, revealed through quantitation of parental alleles across a population of clonal tumors. We found variegated patterns of LOH, based on allelic ratio outliers in hundreds of genes, enriched in regulatory pathways typically co-opted by tumors. The frequency of outliers was correlated with transcriptional repression of a large set of homozygous genes. These findings suggest stochastic losses in gene expression across the genome of tumors generate phenotypic variation among cells, allowing clonal selection during tumor development.