Identifying genomic alterations driving breast cancer is complicated by tumor 
diversity and genetic heterogeneity. Relevant mouse models are powerful for 
untangling this problem because such heterogeneity can be controlled. Inbred 
Chaos3 mice exhibit high levels of genomic instability leading to mammary tumors 
that have tumor gene expression profiles closely resembling mature human mammary 
luminal cell signatures. We genomically characterized mammary adenocarcinomas 
from these mice to identify cancer-causing genomic events that overlap common 
alterations in human breast cancer. Chaos3 tumors underwent recurrent copy 
number alterations (CNAs), particularly deletion of the RAS inhibitor 
Neurofibromin 1 (Nf1) in nearly all cases. These overlap with human CNAs 
including NF1, which is deleted or mutated in 27.7% of all breast carcinomas. 
Chaos3 mammary tumor cells exhibit RAS hyperactivation and increased sensitivity 
to RAS pathway inhibitors. These results indicate that spontaneous NF1 loss can 
drive breast cancer. This should be informative for treatment of the significant 
fraction of patients whose tumors bear NF1 mutations.