(Diversity supplement to R01CA188096) Targeting autophagaphy in hereditary breast cancer

（R01CA188096 的多样性补充）针对遗传性乳腺癌的自噬

基本信息

批准号：
9392413
负责人：
Eileen P. White
金额：
$ 5.77万
依托单位：
RBHS -CANCER INSTITUTE OF NEW JERSEY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9392413
关键词：
Allografting Autophagocytosis BRCA1 Mutation BRCA1 gene BRCA2 Mutation BRCA2 gene Binding Breast Cancer Prevention Breast Epithelial Cells Cell Cycle Checkpoint Cell Survival Cells DNA Damage DNA Double Strand Break DNA Repair Defect Development Disease Double Strand Break Repair Epigenetic Process Family General Population Genes Genetic screening method Hereditary Breast Carcinoma Impairment In Situ In Vitro Inherited Isogenic transplantation Knock-out Knockout Mice Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Measures Mediating Metabolism Methylation Mitochondria Molecular Molecular Genetics Mus Mutation Nucleotides Null Lymphocytes Nutrient Ovarian Oxidative Stress Pancreas Pathway interactions Pharmaceutical Preparations Pharmacology Platinum Play Prevention Prevention approach Process Prostate Proteins Recording of previous events Recycling Refuse Disposal Resistance development Risk Role Seminal Susceptibility Gene TP53 gene Technology Testing Tumor Suppressor Proteins United States Xenograft Model base biological adaptation to stress cancer prevention cancer therapy clinical phenotype design homologous recombination in vivo inhibition of autophagy inhibitor/antagonist innovation insight killings knock-down malignant breast neoplasm metabolomics mouse model mutant mutation carrier neoplastic cell novel pre-clinical prevent promoter public health relevance repaired response stem tumor tumor initiation tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Hereditary breast cancers stem from inherited mutations in "susceptibility" genes such as BRCA1, BRCA2 and PALB2, which encode large tumor suppressor proteins that play essential roles in homologous recombination (HR)-mediated DNA double strand break repair and cell cycle checkpoint response. Moreover, these proteins also function in oxidative stress response. As a result of seminal discoveries of the role of the BRCA/PALB2 proteins in DNA repair, the repair defect of the deficient tumor cells is now being targeted using platinum drugs and PARP inhibitors. However, the mutant cells tend to develop resistance to both types of drugs. Thus, for both prevention and better treatment of the cancers, it is imperative to find new avenues to selectively kill the mutant cells, preferably ones that taret different pathways. Using our Palb2 conditional knockout mouse model, we have identified autophagy as a protective mechanism for Palb2-deficient cells during breast cancer development. Our results suggest that, in the face of DNA damage and oxidative stress elicited by PALB2 loss, autophagy opposes a p53-mediated barrier to facilitate tumorigenesis. Based on the similarities between the molecular functions and clinical phenotypes of BRCA1/2 and PALB2, we hypothesize that autophagy inhibition may prevent the development and impede the progression of both PALB2- and BRCA-associated hereditary breast cancers. In this proposal, we will use conditional knockout and inducible knockdown mouse models to test the hypothesis, and deploy a combination of in vivo, ex vivo and in vitro analyses and metabolomics to identify the molecular mechanisms by which autophagy promotes the development of cancers associated with HR deficiency and oxidative stress. In Aim 1, we will define the role of autophagy in mammary epithelial cell fate following PALB2 and BRCA1/2 loss. In Aim 2, we will define the role of autophagy in Palb2- and Brca1/2- associated mammary tumor development and explore the potential of autophagy inhibition for prevention and treatment. In Aim3, we will investigate the mechanisms of autophagy-mediated promotion of Palb2- and Brca1/2-associated mammary tumorigenesis.

描述（由适用提供）：遗传性乳腺癌源于“易感性”基因中的遗传突变，例如BRCA1，BRCA2和PALB2，它们编码了大型肿瘤抑制蛋白，这些蛋白在同源重组（HR）介导的DNA DNA双链破裂修复和细胞周期检查点响应中起着重要作用。此外，这些蛋白质也在氧化应激反应中起作用。由于第二次发现BRCA/PALB2蛋白在DNA修复中的作用，现在使用铂药和PARP抑制剂将缺陷肿瘤细胞的修复缺陷靶向。但是，突变细胞倾向于对两种类型的药物产生抗性。对于预防和更好地治疗癌症，必须找到新的途径以选择性地杀死突变细胞，而宁愿击败不同途径的途径。使用我们的PALB2条件敲除小鼠模型，我们将自噬是在乳腺癌发育过程中PALB2缺陷细胞的保护机制。我们的结果表明，面对DNA损伤和PALB2损失引起的氧化应激，自噬反对p53介导的支持肿瘤发生的障碍。基于BRCA1/2和PALB2的分子函数和临床表型之间的相似性，我们假设自噬抑制可能会阻止发展并阻碍PALB2-和BRCA相关的遗传性乳腺癌的发展。在该提案中，我们将使用条件敲除和诱导的敲低小鼠模型来测试假设，并在体内，体内和体外分析和体外分析和代谢组学的组合中鉴定自噬通过自体促进与HR缺乏症和氧化应激相关的发育的分子机制。在AIM 1中，我们将定义自噬在PALB2和BRCA1/2损失后自噬在乳腺上皮细胞脂肪中的作用。在AIM 2中，我们将定义自噬在PALB2-和BRCA1/2相关的乳腺肿瘤发展中的作用，并探索自噬抑制对预防和治疗的潜力。在AIM3中，我们将研究自噬介导的PALB2-和BRCA1/2相关乳腺肿瘤的促进的机制。