Breast cancer oncogenes on the 8p11 amplicon.

8p11 扩增子上的乳腺癌致癌基因。

• 批准号: 7067215
• 负责人: STEPHEN P. ETHIER
• 金额: $ 41.32万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7067215
• 关键词: antisense nucleic acid; breast neoplasm /cancer diagnosis; breast neoplasms; cell line; genetic mapping; genetic markers; genetic screening; human genetic material tag; human tissue; neoplasm /cancer genetics; neoplastic transformation; northern blottings; oncogenes; southern blotting

DESCRIPTION (provided by applicant): Focal amplifications involving chromosome 8p11-p12 occur in approximately 15% of human breast cancers. The fibroblast growth factor receptor 1 (FBFR1) gene has long been considered to be the best candidate oncogene at that locus. Three breast cancer cell lines developed in our lab; SUM-44, SUM-52 and SUM- 225, have overlapping amplicons centered around chromosome 8p11.2. FGFR1 is amplified in two of these cell lines, but is over expressed in only one of them. A second gene that maps to this region, transformation associated coiled-coiled protein 1 (TACC1), has recently been shown to be over expressed in some breast cancer cells and to have transforming activity in NIH3T3 cells. TACC1 is amplified and over expressed in all three of our cell lines. In addition to the FGFR1/TACC1 locus, SUM-52 and SUM-225 cells may each have distinct amplicons that center around 8p12 and 8q11.1 respectively. These regions contain several genes that are highly over expressed. Therefore, the broad aim of this proposal is to examine the prognostic and predictive significance of the 8p11-p12 amplicon in human breast cancer, and to identify genes therein that may be good targets for the development of novel therapeutics. The specific aims of this project are: 1) To complete the fine mapping of the 8p11-p12 amplicon in the SUM-44, SUM-52, and SUM-225 cell lines by Southern blotting using probes for genes known to map to the region of gene amplification in each line, 2) To examine the expression levels of the amplified genes in each cell line by northern blot and RT-PCR, 3) To determine the predictive and/or prognostic significance of amplification of distinct regions of the 8p12-8q11 amplicon, and of specific candidate breast cancer genes, in breast cancer specimens using tissue micro arrays, 4) To test the mechanistic significance of genes found to be amplified and over expressed in the three breast cancer cell lines by transduction of candidate genes into immortalized human mammary epithelial cells, and by antisense techniques to down-regulate over expressed genes in breast cancer cells. Thus, these studies are aimed at defining new and better prognostic and predictive markers for an important subset of breast cancer, and at identifying causally relevant genes the products of which could be good targets for novel therapeutics.

描述（由申请人提供）：约 15% 的人类乳腺癌发生涉及染色体 8p11-p12 的局部扩增。成纤维细胞生长因子受体 1 (FBFR1) 基因长期以来被认为是该位点的最佳候选癌基因。我们实验室开发了三种乳腺癌细胞系； SUM-44、SUM-52 和 SUM-225 具有以染色体 8p11.2 为中心的重叠扩增子。 FGFR1 在其中两种细胞系中扩增，但仅在其中一种细胞系中过度表达。映射到该区域的第二个基因是转化相关卷曲螺旋蛋白 1 (TACC1)，最近显示在一些乳腺癌细胞中过度表达，并在 NIH3T3 细胞中具有转化活性。 TACC1 在我们的所有三种细胞系中均被扩增并过度表达。除了 FGFR1/TACC1 基因座外，SUM-52 和 SUM-225 细胞可能各自具有分别以 8p12 和 8q11.1 为中心的不同扩增子。这些区域包含几个高度过度表达的基因。因此，该提案的主要目标是检查 8p11-p12 扩增子在人类乳腺癌中的预后和预测意义，并鉴定其中可能成为开发新疗法的良好靶点的基因。该项目的具体目标是：1) 通过 Southern 印迹法，使用已知映射到每个细胞系中基因扩增区域的基因探针，完成 SUM-44、SUM-52 和 SUM-225 细胞系中 8p11-p12 扩增子的精细定位，2) 通过 Northern 印迹和 RT-PCR 检查每个细胞系中扩增基因的表达水平，3) 确定预测和/或预后 使用组织微阵列检测乳腺癌样本中 8p12-8q11 扩增子的不同区域和特定候选乳腺癌基因扩增的重要性，4) 通过将候选基因转导至永生化人乳腺上皮细胞中，并通过反义技术下调过度表达，测试在三种乳腺癌细胞系中发现扩增和过度表达的基因的机制意义 乳腺癌细胞中的基因。因此，这些研究旨在为乳腺癌的一个重要子集定义新的、更好的预后和预测标记，并鉴定因果相关的基因，其产物可能是新疗法的良好靶点。