Abstract
The key negative regulatory gene of the RAS pathway, NF1, is mutated or deleted in numerous cancer types and is associated with increased cancer risk and drug resistance. Even though women with neurofibromatosis (germline NF1 mutations) have a substantially increased breast cancer risk at a young age and NF1 is commonly mutated in sporadic breast cancers, we have a limited understanding of the role of NF1 in breast cancer. We utilized CRISPR–Cas9 gene editing to create Nf1 rat models to evaluate the effect of Nf1 deficiency on tumorigenesis. The resulting Nf1 indels induced highly penetrant, aggressive mammary adenocarcinomas that express estrogen receptor (ER) and progesterone receptor (PR). We identified distinct Nf1 mRNA and protein isoforms that were altered during tumorigenesis. To evaluate NF1 in human breast cancer, we analyzed genomic changes in a data set of 2000 clinically annotated breast cancers. We found NF1 shallow deletions in 25% of sporadic breast cancers, which correlated with poor clinical outcome. To identify biological networks impacted by NF1 deficiency, we constructed gene co-expression networks using weighted gene correlation network analysis (WGCNA) and identified a network connected to ESR1 (estrogen receptor). Moreover, NF1-deficient cancers correlated with established RAS activation signatures. Estrogen-dependence was verified by estrogen-ablation in Nf1 rats where rapid tumor regression was observed. Additionally, Nf1 deficiency correlated with increased estrogen receptor phosphorylation in mammary adenocarcinomas. These results demonstrate a significant role for NF1 in both NF1-related breast cancer and sporadic breast cancer, and highlight a potential functional link between neurofibromin and the estrogen receptor.
Highlights
Deregulated RAS signaling promotes several “hallmarks of cancer”, such as sustained proliferation, invasion, metastasis, and angiogenesis.[1]
Even though KRAS is mutated in only 4% of sporadic breast cancers (HRAS = 1%; NRAS = 2%),[2] the RAS/ERK pathway is hyperactivated in approximately 50% of breast cancers.[3,4,5]
Nf1 premature stop indels result in more aggressive initiation and tumor progression To evaluate how in-frame versus premature Nf1 indels affect disease burden and survival, we examined the overall survival of G1 heterozygous females
Summary
Deregulated RAS signaling promotes several “hallmarks of cancer”, such as sustained proliferation, invasion, metastasis, and angiogenesis.[1]. To investigate the effects of both the Nf1 in-frame (referred to as IF) and premature stop (referred to as PS) indels, we bred four founder rats (2 male and 2 female) that carried a mix of indels that NF1 shallow deletions are present in 25% of sporadic breast cancers and correlated with poor clinical outcome.[33] To identify biological networks impacted by NF1 deficiency, we constructed gene co-expression networks using weighted gene correlation network analysis (WGCNA) and identified co-expression networks.
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