Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
Genetics. 2012 Oct;192(2):385-96. doi: 10.1534/genetics.112.142802. Epub 2012 Jul 30.
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.
鉴定导致乳腺癌的基因组改变很复杂，因为肿瘤具有多样性和遗传异质性。相关的小鼠模型在解决这个问题上非常有力，因为这种异质性是可以控制的。近交系 Chaos3 小鼠表现出高水平的基因组不稳定性，导致乳腺肿瘤的肿瘤基因表达谱与成熟的人类乳腺腔细胞特征非常相似。我们对这些小鼠的乳腺腺癌进行了基因组特征分析，以确定与人类乳腺癌常见改变重叠的致癌基因组事件。Chaos3 肿瘤经历了反复的拷贝数改变（CNAs），特别是几乎所有情况下 Ras 抑制剂神经纤维瘤 1（Nf1）的缺失。这些与人类的 CNA 重叠，包括 NF1，其在所有乳腺癌中缺失或突变的比例为 27.7%。Chaos3 乳腺肿瘤细胞表现出 Ras 过度激活和对 Ras 通路抑制剂的敏感性增加。这些结果表明，自发性 NF1 缺失可导致乳腺癌。这对于治疗那些肿瘤带有 NF1 突变的大量患者应该具有重要意义。
