Role of Autophagy in Breast Cancer

自噬在乳腺癌中的作用

基本信息

批准号：
7917076
负责人：
Vassiliki Karantza
金额：
$ 24.9万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7917076
关键词：
Acinus organ component Address Alleles Apoptosis Apoptotic Autophagocytosis Breast Breast Cancer Cell Buffers Cancer cell line Catabolic Process Cell Death Cell physiology Chromosomal Instability Clinical Cytoplasm DNA DNA Damage DNA Modification Process DNA biosynthesis DNA strand break Databases Defect Disease ERBB2 gene Epithelial Cells Exhibits Gene Amplification Gene Expression Profiling Genes Genome Genomic Instability Homeostasis Human In Vitro Kinetics Lead Life Liver neoplasms Loss of Heterozygosity Lysosomes Malignant neoplasm of prostate Mammary Neoplasms Mammary Tumorigenesis Mammary gland Measures Mentors Messenger RNA Metabolic stress Metabolism Mitosis Molecular Mus N phosphonoacetyl L aspartate Nerve Degeneration Neurons Nutrient Oncogenes Organelles Outcome Ovarian Oxidative Stress Pathway interactions Phase Play Production Proteins RNA Interference Recycling Role Sampling Secondary to Specimen Staging Starvation Stress Testing Therapeutic Tissues Transgenic Mice base c-myc Genes cancer gene expression cell type comparative genomic hybridization coping deprivation functional status in vivo insight malignant breast neoplasm neoplastic cell outcome forecast prevent prognostic recombinase research study response tissue resource treatment response tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Autophagy is a catabolic process involving self-digestion of cellular organelles during starvation as a means of cell survival; however, if it proceeds to completion, autophagy can lead to cell death. The essential autophagy regulator beclinl is monoallelically deleted in breast cancers, but the mechanism of tumor suppression by autophagy is not known. We developed a new mouse model for breast cancer progression and applied it to the study of autophagy in mammary tumorigenesis. We found that autophagy mitigates metabolic stress and protects mammary cancer cells from genome damage and instability, likely thereby limiting tumorigenesis. I now propose to further characterize the role of autophagy in breast cancer. The specific aims of my proposal are: 1) to determine the mechanism by which deficient autophagy promotes genome damage in mouse mammary epithelial cells and to validate the identified mechanism in human breast cancer cell lines and tumors. The hypothesis is that autophagy defects compromise cellular metabolism under starvation resulting in DMA and likely also protein damage. DMA strand breaks and damaged protein accumulation will be compared in wild type and autophagy-deficient cells under metabolic stress in vitro and in tumors in vivo, and their underlying causes will be examined. 2) To determine the role of deficient autophagy in breast cancer progression. The hypothesis is that autophagy defects promote genomic instability and synergize with breast cancer promoting functions to accelerate cancer progression. To test this hypothesis, tumors generated by autophagy-deficient cells will be tested for genomic instability and activation of breast cancer promoting biological pathways. Also, beclinl mice will be crossed with mammary tumor-prone mice and tumorigenesis will be studied. 3) To determine whether deficient autophagy correlates with disease stage, treatment responsiveness and clinical outcome in breast cancer by using human breast cancer databases. The long-term objective of my proposal is to apply the knowledge obtained for the rational design of more efficacious treatments against breast cancer based on the functional status of important biological processes, such as autophagy. Relevance: The results of the proposed studies will provide novel insights into breast cancer pathogenesis and will hopefully contribute to the development of individualized and improved anticancer treatments.

描述（由申请人提供）：自噬是一种分解代谢过程，涉及饥饿期间细胞器的自我消化，作为细胞生存的一种手段；然而，如果它继续完成，自噬会导致细胞死亡。乳腺癌中必需的自噬调节因子 beclinl 被单等位基因缺失，但自噬抑制肿瘤的机制尚不清楚。我们开发了一种新的乳腺癌进展小鼠模型，并将其应用于乳腺肿瘤发生中的自噬研究。我们发现自噬可以减轻代谢应激并保护乳腺癌细胞免受基因组损伤和不稳定，从而可能限制肿瘤发生。我现在建议进一步描述自噬在乳腺癌中的作用。我的提案的具体目标是：1）确定自噬缺陷促进小鼠乳腺上皮细胞基因组损伤的机制，并在人乳腺癌细胞系和肿瘤中验证已确定的机制。假设认为，自噬缺陷会损害饥饿条件下的细胞代谢，导致 DMA 和蛋白质损伤。将在体外和体内肿瘤代谢应激下比较野生型和自噬缺陷细胞的 DMA 链断裂和受损蛋白质积累，并检查其根本原因。 2) 确定自噬缺陷在乳腺癌进展中的作用。该假设认为，自噬缺陷会促进基因组不稳定，并与乳腺癌促进功能协同作用，加速癌症进展。为了检验这一假设，将测试自噬缺陷细胞产生的肿瘤的基因组不稳定性和促进乳腺癌的生物途径的激活。此外，beclinl 小鼠将与乳腺肿瘤易感小鼠杂交，并研究肿瘤发生。 3) 通过使用人类乳腺癌数据库来确定自噬缺陷是否与乳腺癌的疾病阶段、治疗反应性和临床结果相关。我的建议的长期目标是应用所获得的知识，根据重要生物过程（例如自噬）的功能状态，合理设计更有效的乳腺癌治疗方法。相关性：拟议研究的结果将为乳腺癌发病机制提供新的见解，并有望有助于开发个体化和改进的抗癌治疗。