Evaluation of NF1 as a Major Breast Cancer Driver

描述（由申请人提供）：每年在美国，大约有25万妇女被诊断为乳腺癌，4万人死于乳腺癌，大多数（约75%）病例似乎是“散发性的”，而不是遗传性的。这集中了努力，以确定共同的自发基因组改变，可能是致癌的基础。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是非常有效的，因为这种异质性是可以控制的。在以前的研究中，我们发现，小鼠携带基因组不稳定性突变“Chaos 3”，复制解旋酶组分Mcm4的等位基因，导致几乎所有的纯合子未经产的女性专门乳腺癌。引人注目的是，几乎所有的Chaos 3乳腺肿瘤都经历了Nf1（神经纤维蛋白1）的缺失。NF1是负调节Ras癌基因的肿瘤抑制因子。最近的基因组研究表明，NF1的自发突变有助于几种人类癌症，尽管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检查显示，>27%的人类乳腺肿瘤具有NF 1的缺失（主要）或突变。结合Chaos 3小鼠乳腺肿瘤中Nf1的复发性丢失，这些数据暗示NF1是重要的乳腺肿瘤抑制因子。我们建议使用小鼠模型来直接测试是否遗传或诱导Nf1缺陷导致乳腺肿瘤。此外，使用Chaos 3乳腺癌和人乳腺癌细胞系在小鼠中进行肿瘤重建实验，我们将确定是否需要NF1损失来维持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，并为治疗开发提供一个强大的模型。

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.