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Targeting Cell Cycle Machinery in Breast Cancer

靶向乳腺癌细胞周期机制

基本信息

批准号：
8633711
负责人：
Peter Sicinski
金额：
$ 30.78万
依托单位：
WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8633711
关键词：
Acute Animals Apoptosis Automobile Driving Binding Breast Breast Cancer Cell Breast Carcinoma CDC2 Protein Kinase CDK4 gene Cancer cell line Cell Aging Cell Cycle Cell Cycle Proteins Cell Line Cell Nucleus Cell Proliferation Cell Survival Collection Complex Cyclin A Cyclin D1 Cyclin E Cyclin-Dependent Kinase Inhibitor 2A Cyclin-Dependent Kinases Cyclins DNA Damage Data Development ERBB2 gene Funding Gene Expression Genes Genetic Goals Health Human Human Mammary Carcinoma In Vitro Individual Knock-in Mouse Laboratories Lead Lesion Maintenance Malignant Neoplasms Mammalian Cell Molecular Mouse Mammary Tumor Virus Mus Oncogenic Pathway interactions Phosphotransferases Physiology Play Proteins Proteomics Resistance Resistance development Substrate Specificity Testing Therapeutic Woman Work Xenograft procedure base cancer cell cancer type carcinogenesis cell type in vivo inhibitor/antagonist knockout gene malignant breast neoplasm mouse model neoplastic cell novel therapeutics overexpression purvalanol A research study response senescence transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor progression

项目摘要

The overall goal of this proposal is to test whether targeting individual cell cycle proteins represents a highly selective therapeutic strategy in different types of human breast cancer. The proliferation of mammalian cells is driven by the core cell cycle machinery operating in cell nucleus. The key components of this machinery are proteins called cyclins, which bind, activate and provide substrate specificity to their associated cyclin-dependent kinases (CDKs). These cyclin-CDK complexes phosphorylate cellular proteins, thereby driving cell proliferation. Mouse gene knockout experiments demonstrated that individual cyclins and CDKs are dispensable for development and for normal proliferation of the majority of cell types. In contrast, these proteins are essential for the initiation and for maintenance of specific cancer types, depending on the genetic lesion they carry. Relevant for this application, our laboratory recently demonstrated that an ubiquitous, global shutdown of cyclin 01 in mice bearing MMTV-Erb82 (HER2) driven breast cancers blocked tumor cell proliferation and triggered tumor cell senescence, without having any obvious impact on animals' physiology. Importantly, administration of an inhibitor of CDK4 and CDK6 (PD 0332991) to tumor bearing animals had the same effect, namely it caused senescence of Erb82-driven breast cancer cells. These observations suggest that inhibition of CDK4/6 kinase activity may represent a very effective therapeutic strategy in women with HER2-positive (HER2+) breast cancers. In the work proposed in Aim 1, we will extend our analyses to human HER2+ breast cancers. We will take advantage of a very large collection of human breast cancer cell lines (including several HER2+) assembled by Dr. Polyak. We will also use xenografts of primary HER2+ breast cancers, to test the effect of CDK4/6 inhibition on human mammary carcinomas. Lastly, we will elucidate how human HER2+ breast cancer cells develop resistance to CDK4/6 inhibition. In Aim 2, we will extend our approach to triple-negative breast cancers, where very few therapeutic options are available. We will test our hypothesis that this specific cancer type depends of cyclin E-CDK1 and/or A-CDK1 kinase. The Specific Aims are: Aim 1. To determine the response of human Erb82-positive (HER2+) breast cancers to cyclin D-CDK4/6 inhibition; Aim 2. To study the requirement for CDK1 function in triple-negative breast cancers

这项提议的总体目标是测试针对单个细胞周期蛋白是否代表了不同类型的人类乳腺癌的高度选择性治疗策略。哺乳动物细胞的增殖是由细胞核内的核心细胞周期机制驱动的。这种机制的关键组成部分是被称为细胞周期蛋白的蛋白质，它结合、激活并为其相关的细胞周期蛋白依赖性激酶（CDKs）提供底物特异性。这些细胞周期蛋白- cdk复合物使细胞蛋白磷酸化，从而驱动细胞增殖。