Integrated sequence and gene expression analysis of mouse models of breast cancer reveals critical events with human parallels

Abstract

Mouse models have an essential role in cancer research, yet little is known about how various models resemble human cancer at a genomic level. However, the shared genomic alterations in each model and corresponding human cancer are critical for translating findings in mice to the clinic. We have completed whole genome sequencing and transcriptome profiling of two widely used mouse models of breast cancer, MMTV-Neu and MMTV-PyMT. This genomic information was integrated with phenotypic data and CRISPR/Cas9 studies to understand the impact of key events on tumor biology. Despite the engineered initiating transgenic event in these mouse models, they contain similar copy number alterations, single nucleotide variants, and translocation events as human breast cancer. Through integrative in vitro and in vivo studies, we identified copy number alterations in key extracellular matrix proteins including Collagen 1 Type 1 alpha 1 (Col1a1) and Chondroadherin (CHAD) that drive metastasis in these mouse models. Importantly this amplification is also found in 25% of HER2+ human breast cancer and is associated with increased metastasis. In addition to copy number alterations, we observed a propensity of the tumors to modulate tyrosine kinase mediated signaling through mutation of phosphatases. Specifically, we found that 81% of MMTV-PyMT tumors have a mutation in the EGFR regulatory phosphatase, PTPRH. Mutation in PTPRH led to increased phospho-EGFR levels and decreased latency. Moreover, PTPRH mutations increased response to EGFR kinase inhibitors. Analogous PTPRH mutations are present in lung cancer patients and together this data suggests that a previously unidentified population of human lung cancer patients may respond to EGFR targeted therapy. These findings underscore the importance of understanding the complete genomic landscape of a mouse model and illustrate the utility this has in understanding human cancers.3 Introductory paragraphHeterogeneity in human breast cancer is present in genomic events, gene expression, metastatic potential, and treatment response. To assess gene function in tumor biology, studies have used model systems, including genetically engineered mouse models (GEMMs). Recent work characterized the transcriptional landscape of breast cancer GEMMs, with particular attention paid to relationships with human breast cancer 1-3 . However, whether additional genomic events are required for tumor development and progression in these models remains unknown. Here we present whole genome sequencing data of two highly utilized mouse models of breast cancer, MMTV-Neu 4 and MMTV-PyMT 5 . In PyMT tumors we identified a highly conserved mutation in the protein tyrosine phosphatase receptor (Ptprh) resulting in elevated EGFR activity and erlotinib sensitivity. In Neu tumors, a copy number alteration including Collagen Type 1 Alpha 1 (Col1a1) and Chondroadherin (Chad) altered metastatic potential, which was validated through genetic ablation. Together, this data demonstrates that genomic alterations beyond the initia...

Claudin-low-like mouse mammary tumors show distinct transcriptomic patterns uncoupled from genomic drivers

“…This suggests that no specific genomic event determines tumor subtype, and that other etiological models may be more appropriate, such as different cells-of-origin [31] or microenvironmental factors [32]. This finding concurs with recent reports showing that transgenic mouse mammary tumors display histological and transcriptomic phenotypes largely uncoupled from their underlying driver mutations [33,34]. One possible model for MPA/DMBA-induced tumorigenesis is therefore as follows: first, MPA induces a RANK-l mediated mammary gland proliferation [10,13].…”