PT  - JOURNAL ARTICLE
AU  - Jonathan P Rennhack
AU  - Matthew Swiatnicki
AU  - Yueqi Zhang
AU  - Caralynn Li
AU  - Evan Bylett
AU  - Christina Ross
AU  - Karol Szczepanek
AU  - William Hanrahan
AU  - Muthu Jayatissa
AU  - Kent Hunter
AU  - Eran R. Andrechek
TI  - Integrated sequence and gene expression analysis of mouse models of breast cancer reveals critical events with human parallels
AID  - 10.1101/375154
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 375154
4099  - http://biorxiv.org/content/early/2018/07/24/375154.short
4100  - http://biorxiv.org/content/early/2018/07/24/375154.full
AB  - 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.