Functions of Cyclin D1 in Breast Cancer

Cyclin D1 在乳腺癌中的功能

• 批准号: 6941716
• 负责人: EMMETT Vance SCHMIDT
• 金额: $ 38.6万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6941716
• 关键词: apoptosis; breast neoplasms; cell growth regulation; clinical research; cyclin dependent kinase; cyclins; disease /disorder model; estrogen receptors; gene expression; genetic regulation; genetic regulatory element; genetically modified animals; human genetic material tag; human tissue; laboratory mouse; mammary epithelium; messenger RNA; molecular oncology; mouse mammary tumor virus; neoplasm /cancer genetics; neoplastic transformation; oncogenes; tissue /cell culture

DESCRIPTION (provided by applicant): Cyclin D1 contributes to 15-40% of breast cancers through DNA amplification and overexpression. It is associated with estrogen receptor positive tumors, and predicts both a poor prognosis for ER+ tumors and resistance to anti-estrogen treatments. MMTV-cyclin D1 mice develop ER positive adenocarcinomas whose development is not blocked by inhibition of cyclin dependent kinase 4/6 using an MMTV-p16 transgene. Cyclin D1 is also downstream of multiple mitogenic pathways including erbB2, and its function is required for erbB2 transformation. We propose additional studies of the role of cyclin D1 in breast cancer as both a direct cause of ER positive tumors and as a mediator of erbB2's oncogenic function. Aim 1 will evaluate Cdk 4-independent activities of cvclin D1, including interactions between cyclin D1 and the estrogen receptor, that contribute to breast cancer. MMTV-cyclin D1 will be crossed with MMTV-AIB1 transgenic mice to genetically test the role of cyclin D1/ER interactions. Mutant cyclin D1s incapable of Cdk 4 interactions (mu/KE) and lacking steroid coactivator interactions (mu/LALA) will be expressed in model breast cell lines and using MMTV in transgenic mice to evaluate the role of those activities in D1 oncogenesis. We will determine whether cyclin D1 regulates specific estradiol-regulated genes or directly alters ER coactivator/corepressor promoter binding in breast cancer cells. Aim 2 will evaluate the proposed erbB2 ? cvclin D1 pathway in breast cancer. Expression patterns of erbB2 and cell cycle regulators will be evaluated in invasive breast cancers to confirm our preliminary observation that erbB2 is expressed non-redundantly with p16 and pRb loss. Cell cycle functions of erbB2 will be tested in transgenic models to determine whether cyclin D1 can rescue erbB2-deficiency phenotypes and establish whether erbB2 expression is sufficient to deregulate cell cycle progression without need for additional loss of p16 or gain of cyclin D1. Aim 3 will use microarray analysis of laser capture microdissected hyperplasia and tumors from cyclin D1 and erbB2 transgene-induced tumors to identify genes involved in neoplastic progression from hvperlasia to cancer. Our initial screen has identified six genes whose altered regulation is seen in both human and mouse invasive adenocarcinoma. They are predominately genes involved in cell death regulation and we show several are estradiol regulated. These candidate genes involved in neoplastic progression will be validated by analysis of human cancers, in functional assays, and by assessment of their regulatory controls.

描述（由申请人提供）：细胞周期蛋白D1通过DNA扩增和过表达导致15-40%的乳腺癌。它与雌激素受体阳性肿瘤相关，并预测ER+肿瘤的预后不良和对抗雌激素治疗的抗性。MMTV-cyclin D1小鼠发生ER阳性腺癌，其发展不受使用MMTV-p16转基因抑制细胞周期蛋白依赖性激酶4/6的阻断。细胞周期蛋白D1也是包括erbB 2在内的多种促有丝分裂途径的下游，并且其功能是erbB 2转化所必需的。我们建议进一步研究细胞周期蛋白D1在乳腺癌中的作用，它既是ER阳性肿瘤的直接原因，也是erbB 2致癌功能的介导者。 目的1将评估Cdk 4独立的cvclin D1活性，包括cyclin D1和雌激素受体之间的相互作用，有助于乳腺癌。将MMTV-cyclin D1与MMTV-AIB 1转基因小鼠杂交，以遗传学检测cyclin D1/ER相互作用的作用。不能与Cdk 4相互作用（mu/KE）和缺乏类固醇辅激活因子相互作用（mu/LALA）的突变型细胞周期蛋白D1将在模型乳腺细胞系中表达，并在转基因小鼠中使用MMTV来评估这些活性在D1肿瘤发生中的作用。我们将确定细胞周期蛋白D1是否调节特定的雌二醇调节基因或直接改变乳腺癌细胞中ER辅激活子/辅阻遏子启动子的结合。目标2将评估拟议erbB 2？cvclin D1通路在乳腺癌中的作用erbB 2和细胞周期调节因子的表达模式将在浸润性乳腺癌中进行评估，以证实我们的初步观察结果，即erbB 2表达非冗余，p16和pRb丢失。将在转基因模型中测试erbB 2的细胞周期功能，以确定细胞周期蛋白D1是否可以挽救erbB 2缺陷表型，并确定erbB 2表达是否足以解除细胞周期进程的调控，而不需要额外的p16损失或细胞周期蛋白D1的获得。目的3将使用激光捕获显微切割的增生和来自细胞周期蛋白D1和erbB 2转基因诱导的肿瘤的肿瘤的微阵列分析来鉴定参与从增生到癌症的肿瘤进展的基因。我们的初步筛选已经确定了六个基因，其改变的调节在人类和小鼠侵袭性腺癌中均可见。它们主要是参与细胞死亡调节的基因，我们发现有几个是雌二醇调节的。这些参与肿瘤进展的候选基因将通过对人类癌症的分析、功能测定和对其调控控制的评估来验证。