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

在具有完整免疫系统的大鼠模型中，NF1的缺失会导致激素依赖性乳腺癌发生

基本信息

批准号：
10642882
负责人：
ROBERT A KESTERSON
金额：
$ 53.62万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10642882
关键词：
Acceleration Address Advanced Development Affect Age Alleles Base Pairing Binding Breast Cancer Patient Cell Line Cell Proliferation Cells Clinical Data Data Set Databases Development Disease Drug Targeting Estrogen Antagonists Estrogen Receptors Estrogens Evaluation Female Future Genes Genetic Transcription Genotype Goals Growth Harvest Heterozygote Histology Histopathology Hormone Receptor Hormones Human Human Biology Immune Immune Targeting Immune system Immunotherapy In Vitro Knock-in Knock-out Lead MAP Kinase Gene MEKs Macrophage Maintenance Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Metastatic Neoplasm to the Lung Metastatic breast cancer Modeling Molecular Mutation NF1 gene NF1 mutation Oncogenic Outcome Ovariectomy Partner in relationship Pathogenicity Patients Phenotype Play Population Pre-Clinical Model Pregnancy RAS driven tumor Rattus Receptor Signaling Resistance Role Sampling Signal Transduction Spinal Syndrome Tamoxifen Testing The Cancer Genome Atlas Therapeutic Time Tissues Tumor Cell Line Validation Variant Vertebral column Xenograft Model antagonist biobank cancer biomarkers cancer risk cancer type cell type differential expression genetic corepressor hormonal signals hormone therapy in vivo inhibitor lung lesion malignant breast neoplasm mouse model mutant neoplastic novel novel marker novel therapeutics patient derived xenograft model pre-clinical prognostic prognostic indicator public database response response biomarker synergism targeted treatment therapeutic evaluation therapeutic target therapy resistant transcriptome sequencing treatment response tumor tumor growth tumor initiation tumor microenvironment

项目摘要

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.

NF1的缺失在许多癌症类型中作为致癌驱动因素起着重要作用，可在高达33%的癌症类型中发现NF1缺失