Insights from Genomic Sequencing of Preclinical Breast Cancer Models Establish Human Parallels to Increase Therapeutic Applicability.

Abstract

The study of breast cancer is complicated by the heterogeneity inherent within the disease. Numerous models have been developed to study the initiation, progression, and treatment of breast cancer. These include carcinogen induced mouse models, genetically engineered mouse models, and patient derived xenografts. The relevance of these mouse models to humans must be precisely defined for appropriate understanding of disease mechanisms to derive intervening treatments. Sequencing projects such as The Cancer Genome Atlas Project (TCGA) and Catalogue Of Somatic Mutations In Cancer (COSMIC) were pivotal developments in understanding driving events in human cancers. These studies have revealed that in addition to activation of strong oncogenes, or loss of tumor suppressors, that secondary events are necessary for tumor development and progression. These techniques should also be applied to mouse models of human breast cancer. For all the available models studied and reviewed here, whole genome sequencing (WGS) in conjunction with gene expression analysis has revealed conserved events between human and mouse model systems. This identification of conserved, critical events driving breast cancer has led to novel targets based on breast cancer subtype, ultimately resulting in new therapeutic opportunities. The combination of sequencing and choice of the appropriate mouse model can provide a powerful tool in developing appropriate pre-clinical models of breast cancer.