FUNCTIONS OF CYCLIN D1 IN BREAST CANCER

CYCLIN D1 在乳腺癌中的功能

• 批准号: 2009080
• 负责人: EMMETT Vance SCHMIDT
• 金额: $ 20.61万
• 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 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2009080
• 关键词: 3T3 cells; adenocarcinoma; apoptosis; breast neoplasms; cell cycle; cell growth regulation; cell proliferation; cyclins; gene expression; gene targeting; genetic regulation; genetic regulatory element; genetically modified animals; laboratory mouse; mammary epithelium; messenger RNA; molecular cloning; mouse mammary tumor virus; natural gene amplification; neoplasm /cancer genetics; neoplastic transformation; oncogenes; polymerase chain reaction; protein kinase; protein metabolism; protein transport; tissue /cell culture

Physical associations between cyclins, viral oncogenes, and tumor suppressor genes imply a central role for cyclins in growth control. Cyclin D1 was identified as a candidate oncogene in tumor-specific DNA rearrangements. By virtue of DNA amplification, it contributes to 15% of breast cancers. Cyclin D1 protein is overexpressed in an additional 15-20% of breast cancers through unknown mechanisms. To evaluate its oncogenic potential, we overexpressed cyclin D1 in mammary cells in transgenic mice. Overexpression resulted in abnormal mammary proliferation and adenocarcinomas. We propose further studies of cyclin D1's role in breast cancer: AIM 1: Characterization of mechanisms regulating cyclin D1. Cyclin D1 protein is specifically increased in one-third of mammary carcinomas without accompanying increases in mRNA. We will evaluate mechanisms by which this increase in cyclin D1 protein might be regulated using tissue culture models, and we will identify factors regulating cyclin D1 during mammary growth and involution in vivo. AIM 2: Characterization of growth abnormalities in mammary epithelium overexpressing cyclin D1. The functions of cyclin D1 may be more complex than anticipated in vivo since our new preliminary data suggest that cyclin D1 may regulate apoptosis during mammary involution. We will further characterize this new phenotype. We will evaluate interactions between the genes involved in cyclin/cdk 4 complexes that might alter the role of cyclin D1 during mammary involution. By quantifying histologic changes, we will assess the overall function of cyclin D1 in mammary growth and involution. AIM 3: Assessment of second oncogenic events in adenocarcinomas in MMTV-cyclin D1 transcienic mice. Given the prolonged latency period of tumor development in cyclin D1 transgenic mice, the role of "second hits" will be tested by random insertional mutagenesis using mouse mammary tumor virus infections and using differential display of mRNAs expressed at different levels during malignant transformation. Characterization of MMTV insertion sites by inverse PCR and identification of differentially expressed genes during cyclin D1-driven oncogenesis will be used to identify and clone oncogenes that may collaborate with cyclin D1 to cause breast cancer.

细胞周期蛋白、病毒癌基因与肿瘤的物理联系 抑制基因暗示了细胞周期蛋白在生长控制中的核心作用。 细胞周期蛋白D1被认为是肿瘤特异性的候选癌基因 DNA重排。通过DNA扩增，它有助于 到15%的乳腺癌患者。Cyclin D1蛋白在人卵巢癌中的过度表达 另外15%-20%的乳腺癌是通过未知的机制发生的。至 评估其致癌潜力，我们过表达了细胞周期蛋白D1 转基因小鼠的乳腺细胞。过度表达导致 乳腺异常增殖和腺癌。我们建议 细胞周期蛋白D1‘S在乳腺癌中作用的进一步研究：目的1： 细胞周期蛋白D1调控机制的表征。细胞周期蛋白D1 蛋白质在三分之一的乳腺癌中特异性增加 而不伴随mRNA的增加。我们将评估 Cyclin D1蛋白表达增加的机制可能是 使用组织培养模型进行调控，我们将确定影响因素 乳腺生长发育和退化过程中细胞周期蛋白D1的调节。 目标2：乳腺生长异常的特征 上皮细胞过度表达细胞周期蛋白D1。细胞周期蛋白D1的功能可能 在活体内比预期的更复杂，因为我们新的初步 有数据表明，细胞周期蛋白D1可能调节乳腺细胞的凋亡 内卷曲。我们将进一步描述这种新的表型。我们会 评价细胞周期蛋白/细胞周期蛋白4相关基因之间的相互作用 可能改变细胞周期蛋白D1在乳腺过程中作用的复合体 内卷曲。通过量化组织学变化，我们将评估总体 细胞周期蛋白D1在乳腺生长发育和退化中的作用目标3： 年腺癌第二次致癌事件的评估 MMTV-Cyclin D1转基因小鼠。考虑到延长的延迟 细胞周期蛋白D_1转基因小鼠肿瘤发生发展期的作用 “第二次命中”将通过随机插入突变进行测试， 小鼠乳腺肿瘤病毒感染与差异显示技术研究 不同水平的mRNAs在癌变过程中的表达 转型。MMTV插入位点的逆序表征 周期调控基因的聚合酶链式反应及差异表达基因的筛选 将利用d1驱动的致癌作用来鉴定和克隆癌基因 这可能与细胞周期蛋白D1共同导致乳腺癌。