Evaluation of NF1 as a Major Breast Cancer Driver

描述（由申请人提供）：在美国，每年约有25万名女性被诊断患有乳腺癌，其中4万人死于乳腺癌。大多数（约75%）的病例似乎是“散发的”，而不是遗传性的。这集中在鉴定可能致癌的常见的自发基因组改变上。这种方法由于患者的遗传异质性和肿瘤类型的多样性而变得复杂。小鼠模型对于解决这个问题非常有用，因为这种异质性是可以控制的。在之前的研究中，我们发现携带基因组不稳定突变“Chaos3”的小鼠，即复制解旋酶成分Mcm4的等位基因，在几乎所有纯合子的无生育雌性中引起专一性乳腺腺癌。引人注目的是，几乎所有的Chaos3乳腺肿瘤都存在Nf1（神经纤维蛋白1）缺失。NF1是一种负调控Ras癌基因的肿瘤抑制因子。最近的基因组研究表明，NF1的自发突变与几种人类癌症有关，但在乳腺癌中的潜在作用尚未确定。值得注意的是，我们对人类乳腺癌基因组数据集的研究显示，大约27%的人类乳腺癌肿瘤存在NF1缺失（主要是）或突变。结合Chaos3小鼠乳腺肿瘤中Nf1的复发性缺失，这些数据提示Nf1是一个重要的乳腺肿瘤抑制因子。我们建议使用小鼠模型直接测试遗传或诱导的Nf1缺陷是否会导致乳腺肿瘤。此外，我们使用Chaos3乳腺和人乳腺癌细胞系在小鼠中进行肿瘤重建实验，我们将确定NF1缺失是否需要维持NF1突变的癌症。总之，这个探索性的R21项目将严格检验NF1是一个重要的乳腺癌易感基因的假设。这一假设的验证将影响nf1突变乳腺癌患者的治疗，并为治疗发展提供一个强有力的模型。

DESCRIPTION (provided by applicant): Annually in the U.S., about 250,000 women are diagnosed with breast cancer, and 40,000 die from it. The majority (~75%) of cases appear to have a "sporadic," rather than an inherited basis. This has concentrated efforts on identifying common spontaneous genomic alterations that may underlie carcinogenesis. This approach is complicated by the genetic heterogeneity of patients and variety of tumor types. Mouse models are powerful for untangling this problem because such heterogeneities can be controlled. In previous studies, we found that mice bearing the genomic instability mutation "Chaos3", an allele of the replicative helicase component Mcm4, caused exclusively mammary adenocarcinomas in nearly all homozygous nulliparous females. Strikingly, nearly all Chaos3 mammary tumors underwent deletions of Nf1 (Neurofibromin 1). NF1 is a tumor suppressor that negatively regulates the Ras oncogene. Recent genomic studies suggest that spontaneous mutation of NF1 contributes to several human cancers, though a potential role in breast cancer hasn't been established. Remarkably, our examination of human breast cancer genome datasets revealed that >27% of human breast tumors have deletions (primarily) or mutations of NF1. Combined with the recurrent loss of Nf1 in Chaos3 mouse mammary tumors, these data implicate NF1 as an important breast tumor suppressor. We propose to use mouse models to test directly whether inherited or induced Nf1 deficiency contributes to mammary tumors. Additionally, using Chaos3 mammary and human breast cancer cell lines for tumor reconstitution experiments in mice, we will determine if NF1 loss is needed for maintenance of NF1-mutated cancers. In sum, this exploratory R21 project will rigorously test the hypothesis that NF1 is a significant breast cancer susceptibility gene. Validation of this hypothesis would impact the treatment of patients with NF1-mutated breast cancers, and provide a powerful model for therapeutic development.