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

NF1的缺失在许多癌症类型中扮演着致癌驱动因素的主要角色，并可在高达33%的 所有乳腺癌(BC)。NF1的缺失也是较早患癌症风险增加的一个预后指标， 较差的结果，以及治疗阻力。此外，某些NF1基因类型可能会增加癌症风险， 而其他人则不这么认为。NF1在很大程度上被认为是一种典型的RAS病综合征，原因是 神经纤维蛋白对Ras-MAPK信号转导的影响然而，最近的研究表明，nf1可以结合雌激素。 受体(ER)，并作为转录辅阻遏子。这有助于具体解释BC的一些发现 ER+BC患者。在该模型中，阻断ER信号的NF1的特定变化导致RAS驱动的肿瘤 高达20%的ER+患者对内分泌治疗产生抵抗，因为细胞能够在低水平的E2(和 他莫昔芬)。我们已经建立了NF1缺乏的新型大鼠模型，这些模型具有非常健壮的ER+BC表型， 因此，与其他临床前模型相比，更贴近地概括了临床肿瘤。我们的型号包括 致病患者错义等位基因c.3827G&gt；A，p.R1276Q(敲门或Ki)，与人类脊柱NF1相关 恶性，以及14个碱基对缺失c.3661_3674del，p.P1220fs*1223(基因敲除或KO)模式。 我们模型之间的表型差异表明，变异的物质，以及对肿瘤的限制 KI女性妊娠的发展表明荷尔蒙诱导在肿瘤中起主要作用 发展。大鼠也会出现转移性BC标志物阳性的肺部病变。我们的总体目标是 从组织病理学、RAS信号、激素信号、 免疫成分和靶向药物反应，并将它们与已知的 体细胞或生殖系NF1失活的患者和乳腺癌。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。AIM 1将评估肿瘤的发病、生长、 RAS和雌激素信号随时间变化的组织学和分子特征及其与 人BC肿瘤标本。目的2表征NF1缺陷肿瘤微环境(TME)，鉴定 免疫靶点，并评估使用和不使用RAS靶向治疗的免疫靶向。目标3将 评价激素在肿瘤启动、维持和靶向治疗中的作用。我们会更好地定义 哪种激素(S)同时驱动NF1缺乏的乳腺肿瘤的启动和维持，并利用这一点 在有和没有共同瞄准RAS的情况下针对它们的信息，以显示协同效应。因为HR+BC占 约80%的患者，以及缺乏合适的具有完整免疫系统的哺乳动物模型，我们 相信我们建议的研究具有非常重要的意义，并将大大推动新技术的发展 这种疾病的治疗方法。

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.