A molecular signature of cell invasion in breast ca

乳腺癌细胞侵袭的分子特征

• 批准号: 6736371
• 负责人: Hyeong-Reh Choi Kim
• 金额: $ 21.84万
• 依托单位: DETROIT R & D, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6736371
• 关键词: bioinformatics; biological signal transduction; breast neoplasms; cell migration; cell proliferation; chromatography; complementary DNA; extracellular matrix; gene expression; genetic markers; guanine nucleotide binding protein; human tissue; laser capture microdissection; mass spectrometry; messenger RNA; metastasis; microarray technology; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic transformation; phosphorylation; polymerase chain reaction; technology /technique development; two dimensional gel electrophoresis

DESCRIPTION (provided by applicant): The long-term objective of this research project is to unveil the molecular signature of tumor cell invasion. Tumor invasion and metastasis are complex processes involving extracellular matrix (ECM) degrading proteinase activity and cell migration through the ECMs. Since mounting evidence suggests that ras expression serves as a marker for tumor aggressiveness of breast cancer, we have investigated ras-mediated signaling pathways critical for human breast epithelial cell invasion. Our study showed that H-ras, but not N-ras, induces migrative and invasive phenotypes involving matrix metalloproteinase (MMP)-2 upregulation, while both Hand N-ras induce cell proliferation and transformation. Since ras is among the most frequently activated signaling molecules in human cancer, we hypothesize that the mRNA expression pattern differentially regulated by H-ras and N-ras reflects a signature representing invasive and migrative capability of cancer cells. To test our hypothesis, during the Phase I study we propose (Aim 1) to further investigate the molecular pathways for the ras-mediated cell migration and invasion; (Aim 2 and 3) to identify mRNA marker candidates of H-ras-mediated breast epithelial cell migration/invasion by microarrays; (Aim 4) to verify clinical relevance of differential mRNA expression profile associated with cell migration and invasion; and (Aim 5) to test feasibility of identifying phosphorylated and/or secreted protein marker candidates. The accomplishment of these aims will help us design diagnostic tools to predict primary tumors with metastatic potential.

描述（由申请人提供）：该研究项目的长期目标是揭示肿瘤细胞浸润的分子特征。肿瘤侵袭和转移是涉及细胞外基质（ECM）降解蛋白酶活性和通过ECM的细胞迁移的复杂过程。由于越来越多的证据表明RAS表达是乳腺癌肿瘤侵袭性的标志物，因此我们研究了RAS介导的信号传导途径对人类乳腺上皮细胞侵袭至关重要。我们的研究表明，H-RAS而非N-RAS诱导涉及基质金属蛋白酶（MMP）-2 -2上调的迁移和侵入性表型，而手动N-RAS均可诱导细胞增殖和转化。由于RAS是人类癌症中最常激活的信号分子之一，因此我们假设由H-RAS和N-RAS差异调节的mRNA表达模式反映了代表癌细胞的侵入性和迁移能力的签名。为了检验我们的假设，在第一阶段研究中，我们提出（目标1），以进一步研究RAS介导的细胞迁移和侵袭的分子途径； （AIM 2和3）确定h-ras介导的乳腺上皮细胞迁移/微阵列的乳房上皮细胞迁移/侵袭的mRNA标记物； （目标4）验证与细胞迁移和侵袭相关的差异mRNA表达谱的临床相关性； （目标5）测试鉴定磷酸化和/或分泌的蛋白质标记候选物的可行性。这些目标的实现将有助于我们设计诊断工具，以预测具有转移性潜力的原发性肿瘤。