Integrated analyses of murine breast cancer models reveal critical parallels with human disease

Jonathan P Rennhack,Muthu Jayatissa,Caralynn Li,Evan Bylett,Martin P Ogrodzinski,Eran R Andrechek,Christina Ross,Briana To,Karol Szczepanek,Yueqi Zhang,Matthew Swiatnicki,William Hanrahan,Caleb Dulak,Kent Hunter,Sophia Y Lunt

doi:10.1038/s41467-019-11236-3

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. Here, we complete whole genome sequencing and transcriptome profiling of two widely used mouse models of breast cancer, MMTV-Neu and MMTV-PyMT. Through integrative in vitro and in vivo studies, we identify 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. In addition to copy number alterations, we observe a propensity of the tumors to modulate tyrosine kinase-mediated signaling through mutation of phosphatases such as PTPRH in the MMTV-PyMT mouse model. Mutation in PTPRH leads to increased phospho-EGFR levels and decreased latency. 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.

Highlights

Mouse models have an essential role in cancer research, yet little is known about how various models resemble human cancer at a genomic level
The resulting genes were filtered through human breast cancer datasets to ensure relevance to human breast cancer and confirmed with in vitro/in vivo experiments (Fig. 1a)
We identified a cohort of MMTV-PyMT tumors that co-cluster with basal tumors as well as a significant portion of MMTV-Neu and MMTV-PyMT tumors, which have transcriptional profiles that are similar to human epidermal growth factor receptor 2 (HER2) + breast cancer

Summary

Introduction

Mouse models have an essential role in cancer research, yet little is known about how various models resemble human cancer at a genomic level. Mutation in PTPRH leads to increased phospho-EGFR levels and decreased latency 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. In Neu tumors, a copy number alteration including collagen type 1 alpha 1 (Col1a1) and chondroadherin (Chad) alters metastatic potential, which is validated through genetic ablation. This data demonstrates that genomic alterations beyond the initiating oncogene need to be considered when choosing a model system for breast cancer

Methods

Results

Conclusion