Molecular Function of Cyclin D1 in Breast Development and Breast Cancer

Cyclin D1 在乳腺发育和乳腺癌中的分子功能

• 批准号: 7617424
• 负责人: Peter Sicinski
• 金额: $ 32.13万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7617424
• 关键词: Address; Animals; Binding; Biological Assay; Breast; Breast Adenocarcinoma; Breast Cancer Cell; Breast Carcinoma; CCND1 gene; CDK4 gene; Cancer cell line; Cell Cycle; Cell physiology; Complement; Complex; Cyclin D1; Cyclin-Dependent Kinases; Cyclins; Development; Ductal; ERBB2 gene; Epithelial; Female; Goals; Guns; Human; Human Mammary Carcinoma; Hyperplasia; In Vitro; Knock-in Mouse; Knock-out; Knockout Mice; Malignant Neoplasms; Mammary Tumorigenesis; Mammary gland; Mass Spectrum Analysis; Molecular; Mouse Strains; Mus; Neoplasms; Organ; Pathogenesis; Phosphorylation; Phosphotransferases; Play; Pregnancy; Process; Proteins; Puberty; Public Health; Resistance; Role; Staging; Testing; Therapeutic; Transgenic Mice; Tumor-Derived; Work; bcl-1 Genes; cancer cell; carcinogenesis; cell type; design; follow-up; in vivo; malignant breast neoplasm; mammary gland development; mutant; novel; overexpression; ras Oncogene; repaired; tool; transcription factor; tumor; tumor progression; tumorigenic

The goal of this project is to define the molecular function of cyclin D1 in mammary gland development and n breast cancer. Cyclin D1 is a component of the core cell cycle machinery. The best-documented function of cyclin D1 is its ability to bind and to activate the cyclin-dependent kinases CDK4 and CDK6. In addition, cyclin D1 was proposed to play CDK-independent, possibly cell cycle-independent functions by acting as a :o-activa1or or -represser of specific transcription factors. The cyclin D1 gene is amplified in 15-20% of uiman mammary carcinomas, whereas cyclin D1 protein is overexpressedin the majority of human breast cancers. In the past, we used cyclin D1 knockout and knock-in mice to demonstrate the requirement for cyclin D1 function in normal breast development and in breast neoplasia. The exact molecular function of cyclin D1 in these processes is currently unclear. The goal of this proposal is to elucidate the full range of cyclin D1's molecular functions in normal breast development, and in mammary tumorigenesis. To address this issue, we recently generated a novel knock-in strain of mice expressing tandemly-tagged version of cyclin D1. This strain allows us to use sequential immunoaffinity purifications followed by high-sensitivity shot-gun mass spec sequencing to define the full range of cyclin D1 interacting partners in essentially any organ, at any point of development, and at any stage of cancer progression. We have already demonstrated that this general approach is successful, and we will now apply it to analyses of mammary glands and mammary carcinomas. We will combine our analyses with studies of human breast cancers. The combined use of these approaches will allow us to determine the molecular functions of cyclin D1 in normal breast development, and will help to understand how these functions are deranged in breast neoplasia. The Specific Aims are: Aim 1: To study the molecular function of cyclin D1 during mammary development. Aim 2: To study the molecular function of cyclin D1 during mammary neoplasia. RELEVANCE TO PUBLIC HEALTH Cyclin D1 protein is overexpressed in many human cancers, including the majority of breast cancers. Although the key role for cyclin D1 overexpression in pathogenesis of mammary carcinomas is firmly established, the exact molecular function of cyclin D1 in this process remains unclear. The work proposed in this application will address this critical issue. Understanding of cyclin D1's function in neoplasia is essential in order to design rational therapeutic strategies.

该项目的目的是定义细胞周期蛋白D1在乳腺发育中的分子功能和 n乳腺癌。 Cyclin D1是核心细胞周期机械的组成部分。最有记录的功能 Cyclin D1的结合能力和激活细胞周期蛋白依赖性激酶CDK4和CDK6的能力。此外， 提议细胞周期蛋白D1通过充当CDK独立的，可能是细胞周期的函数 ：o -Activa1or或 - 特定转录因子的压缩器。细胞周期蛋白D1基因在15-20％的扩增 Uiman乳腺癌，而细胞周期蛋白D1蛋白过表达人的大多数人乳 癌症。过去，我们使用Cyclin D1敲除和敲门鼠标来证明对 细胞周期蛋白D1在正常乳房发育和乳腺癌中的功能。确切的分子功能 这些过程中的细胞周期蛋白D1目前尚不清楚。该提议的目的是阐明 Cyclin D1在正常乳房发育和乳腺肿瘤发生中的分子功能。解决 这个问题，我们最近产生了一种新颖的敲击菌株，表达了串联标记的版本 细胞周期蛋白D1。这种菌株使我们能够使用顺序的免疫亲和力净化，然后进行高敏性 Shot-Gun质量规格测序以定义Cyclin D1相互作用伙伴的全部范围 器官，在任何发育点，以及癌症进展的任何阶段。我们已经证明了 这种一般方法是成功的，我们现在将其应用于乳腺的分析和 乳腺癌。我们将分析与对人乳腺癌的研究相结合。组合 这些方法的使用将使我们能够确定细胞周期蛋白D1在正常乳房中的分子功能 发展，并将有助于了解这些功能如何在乳腺癌中毁灭。这 具体目的是：目标1：研究乳腺发育过程中细胞周期蛋白D1的分子功能。目标2： 研究乳腺肿瘤期间细胞周期蛋白D1的分子功能。 与公共卫生cyclin D1蛋白有关的相关性在许多人类癌症中都过表达 大多数乳腺癌。尽管细胞周期蛋白D1过表达的关键作用在发病机理中 乳腺瘤牢固确定，在此过程中，细胞周期蛋白D1的确切分子功能仍然存在 不清楚。本应用程序中提出的工作将解决此关键问题。了解Cyclin D1的 为了设计合理的治疗策略，肿瘤中的功能至关重要。