Comparative Oncogenomics Implicates the Neurofibromin 1 Gene (NF1) as a Breast Cancer Driver

Department of Biomedical Sciences.
Genetics (Impact Factor: 5.96). 07/2012; 192(2):385-96. DOI: 10.1534/genetics.112.142802
Source: PubMed


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.

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    • "NF1 is located on the pericentromeric region of the long arm of chromosome 17 (which interestingly also houses the BRCA1 gene), and regulates the conversion of the active Ras-GTP to inactive Ras-GDP (Figure 4) [6]. About 28% of sporadic breast cancers in humans are missing at least one copy of NF1 gene, either due to deletion or mutation [7]. "
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