Loss of NF1 drives hormone dependent mammary carcinogenesis in a rat model with intact immune system

NF 1的缺失在许多癌症类型中作为致癌驱动因素发挥着重要作用，并且可以在高达33%的癌症中发现。 乳腺癌（BC）NF 1的缺失也是早期癌症风险增加的预后指标， 结果更差和治疗抗性。此外，某些NF 1基因型可能会增加癌症风险， 而另一些则没有。NF 1在很大程度上被认为是一种典型的Ras病综合征，这是由于NF 1基因失活突变引起的。 神经纤维蛋白影响Ras-MAPK信号传导。然而，最近已经表明NF 1结合雌激素， 受体（ER），并作为转录辅阻遏物。这有助于具体解释BC的一些发现 在ER+ BC患者中。在该模型中，废除ER信号传导的NF 1的特异性变化导致Ras驱动的肿瘤 高达20%的ER+患者对内分泌治疗有抵抗力，因为细胞能够在低水平的E2中生长（以及 他莫昔芬）。我们已经产生了Nf 1缺陷的新型大鼠模型，其具有非常稳健的ER+ BC表型， 因此，与其他临床前模型相比，更接近地再现了临床肿瘤。我们的模型包括 致病性患者错义等位基因c.3827G>A，p.R1276Q（敲入或KI），与人类脊髓NF 1相关 和恶性肿瘤，以及14个碱基对缺失c.3661_3674del，p.P1220fs*1223（敲除或KO）模型。 我们的模型之间的表型差异表明，变异的问题，和肿瘤的限制 KI雌性动物的发育至妊娠表明激素诱导在肿瘤中起主要作用 发展大鼠还出现转移性BC标志物阳性的肺部病变。我们的总体目标是 根据组织病理学、Ras信号传导、激素信号传导， 免疫成分和靶向药物反应，并将它们与已知的 NF 1的体细胞或生殖细胞失活和乳腺癌患者。最终，这将提供更好的 对患者的预后预测和更好的治疗方法。目标1将评估肿瘤的发病，生长， Ras和雌激素信号传导随时间变化的组织学和分子表征，并与 人BC肿瘤样品。目的2将表征Nf 1缺陷的肿瘤微环境（TME）， 免疫靶向，并评估使用和不使用Ras靶向治疗剂的免疫靶向。目标3将 评价激素在肿瘤发生、维持和靶向治疗中的作用。我们将更好地定义 哪种激素驱动Nf 1缺陷的乳腺肿瘤的启动和维持，并利用这种 信息以在有和没有共靶向Ras的情况下靶向它们以显示协同作用。由于HR+ BC占 约80%的患者病例，并且缺乏具有完整免疫系统的适当哺乳动物模型，我们 我相信，我们提出的研究是非常重要的，将大大推动新的发展， 治疗这种疾病。

Loss of NF1 plays a major role as an oncogenic driver in many cancer types and can be found in up to 33% of all breast cancers (BC). Loss of NF1 is also a prognostic indicator for increased cancer risk at an earlier age, poorer outcomes, and therapeutic resistance. In addition, certain NF1 genotypes may increase cancer risks, while others do not. NF1 is largely perceived as a classic Ras-opathy syndrome due to inactivating mutations in neurofibromin affecting Ras-MAPK signaling. However, recently it has been shown that NF1 binds estrogen receptor (ER) and acts as a transcriptional corepressor. This helps explain some of these BC findings specifically in ER+ BC patients. In this model, specific changes to NF1 that abrogate ER signaling lead to Ras driven tumor resistance to endocrine therapy in up to 20% of ER+ patients as cells are able to grow in low levels of E2 (and tamoxifen). We have generated novel rat models deficient for Nf1 that have a very robust ER+ BC phenotype, therefore more closely recapitulating clinical tumors compared to other preclinical models. Our models include a pathogenic patient missense allele c.3827G>A, p.R1276Q (knockin or KI), associated in humans with spinal NF1 and malignancy, as well as a 14 base pair deletion c.3661_3674del, p.P1220fs*1223 (knockout or KO) model. Phenotypic differences between our models indicate that the variant matters, and restriction of tumor development to pregnancy in the KI females indicates hormone induction plays a major role in tumor development. Rats also develop lung lesions positive for metastatic BC markers. Our overall goal is to characterize the phenotype of these rat models in terms of histopathology, Ras signaling, hormone signaling, immune components, and targeted drug response and compare/contrast them with what is known regarding patients with somatic or germline inactivation of NF1 and breast cancer. Ultimately, this will provide better prognostic predictions for patients and better therapeutics for treatment. Aim 1 will evaluate tumor onset, growth, histology, and molecular characterization of Ras and estrogen signaling over time and compare/contrast with human BC tumor samples. Aim 2 will characterize the Nf1 deficient tumor microenvironment (TME), identify immuno-targets, and evaluate immuno-targeting with and without Ras-targeting therapeutics. Aim 3 will evaluate the role of hormones in tumor initiation, maintenance and targeting therapeutics. We will better define which hormone(s) drive both initiation and maintenance of mammary tumors deficient for Nf1 and utilize this information to target them both with and without co-targeting Ras to show synergy. As HR+ BC accounts for ~80% of patient cases, and that appropriate mammalian models with intact immune systems are lacking, we believe that our proposed studies are highly significant and will substantially advance the development of new therapies to this disease.