deficiency correlates with estrogen receptor signaling and diminished survival in breast cancer.

The key negative regulatory gene of the RAS pathway, , is mutated or deleted in numerous cancer types and is associated with increased cancer risk and drug resistance. Even though women with neurofibromatosis (germline mutations) have a substantially increased breast cancer risk at a young age and is commonly mutated in sporadic breast cancers, we have a limited understanding of the role of in breast cancer. We utilized CRISPR-Cas9 gene editing to create rat models to evaluate the effect of deficiency on tumorigenesis. The resulting indels induced highly penetrant, aggressive mammary adenocarcinomas that express estrogen receptor (ER) and progesterone receptor (PR). We identified distinct mRNA and protein isoforms that were altered during tumorigenesis. To evaluate in human breast cancer, we analyzed genomic changes in a data set of 2000 clinically annotated breast cancers. We found shallow deletions in 25% of sporadic breast cancers, which correlated with poor clinical outcome. To identify biological networks impacted by deficiency, we constructed gene co-expression networks using weighted gene correlation network analysis (WGCNA) and identified a network connected to (estrogen receptor). Moreover, -deficient cancers correlated with established RAS activation signatures. Estrogen-dependence was verified by estrogen-ablation in rats where rapid tumor regression was observed. Additionally, deficiency correlated with increased estrogen receptor phosphorylation in mammary adenocarcinomas. These results demonstrate a significant role for in both -related breast cancer and sporadic breast cancer, and highlight a potential functional link between neurofibromin and the estrogen receptor.