A molecular signature of cell invasion in breast ca

描述(申请人提供)：本研究项目的长期目标是揭示肿瘤细胞侵袭的分子特征。肿瘤的侵袭和转移是一个复杂的过程，涉及细胞外基质(ECM)降解蛋白水解酶活性和细胞通过ECM的迁移。由于越来越多的证据表明ras的表达是乳腺癌肿瘤侵袭性的标志，我们研究了ras介导的信号通路对人类乳腺上皮细胞侵袭至关重要。我们的研究表明，H-ras，而不是N-ras，可诱导涉及基质金属蛋白酶-2上调的迁移和侵袭性表型，而两种N-ras均可诱导细胞增殖和转化。由于ras是人类癌症中最频繁激活的信号分子之一，我们推测H-ras和N-ras差异调控的mRNA表达模式反映了癌细胞侵袭和迁移能力的特征。为了验证我们的假设，在第一阶段研究中，我们建议(目标1)进一步研究ras介导的细胞迁移和侵袭的分子途径；(目标2和3)通过微阵列识别H-ras介导的乳腺上皮细胞迁移/侵袭的mRNA标记候选；(目的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；以及(目的5)测试鉴定磷酸化和/或分泌型蛋白标记候选的可行性。这些目标的实现将帮助我们设计诊断工具来预测具有转移潜力的原发肿瘤。

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.