Genomic analyses as a guide to target identification and preclinical testing of mouse models of breast cancer

Abstract

Cross-species genomic analyses have proven useful for identifying common genomic alterations that occur in human cancers and mouse models designed to recapitulate human tumor development. High-throughput molecular analyses provide a valuable tool for identifying particular animal models that may represent aspects of specific subtypes of human cancers. Corresponding alterations in gene copy number and expression in tumors from mouse and human suggest that these conserved changes may be mechanistically essential for cancer development and progression, and therefore, they may be critical targets for therapeutic intervention. Using a cross-species analysis approach, mouse models in which the functions of p53, Rb, and BRCA1 have been disrupted demonstrate molecular features of human, triple-negative (ER-, PR-, and ERBB2-), basal-type breast cancer. Using mouse tumor models based on the targeted abrogation of p53 and Rb function, we identified a large, integrated genetic network that correlates to poor outcome in several human epithelial cancers. This gene signature is highly enriched for genes involved in DNA replication and repair, chromosome maintenance, cell cycle regulation, and apoptosis. Current studies are determining whether inactivation of specific members within this signature, using drugs or siRNA, will identify potentially important new targets to inhibit triple-negative, basal-type breast cancer for which no targeted therapies currently exist.

Figure 1

Patient outcome based on categorization of human breast tumors by molecular subtype.

Figure 2

Use of genetically engineered mouse models to identify genetic pathways, drugable targets, and novel targets that are critical for tumor growth and survival. Mouse models are amenable to testing of targeted drug therapies and novel drug combinations, and understanding mechanisms of drug resistance that cannot be easily accomplished in clinical trials.

Figure 3

Intrinsic biological network associated with SV40-T/t-antigen inactivation of p53 and Rb. Individual genetic nodes are highlighted. Genes in red exhibit increased expression; genes in green exhibit decreased expression. Adapted from Deeb et al. 2007.