A molecular signature of cell invasion in breast ca

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侵袭的分子特征。肿瘤侵袭和转移是复杂的过程，涉及细胞外基质（ECM）降解蛋白酶活性以及细胞通过ECM迁移。由于越来越多的证据表明 ras 表达可作为乳腺癌肿瘤侵袭性的标志，因此我们研究了 ras 介导的信号通路，这对人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 上调的迁移和侵袭表型，而 Hand N-ras 均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，我们假设H-ras和N-ras差异调节的mRNA表达模式反映了代表癌细胞侵袭和迁移能力的特征。为了检验我们的假设，在 I 期研究中，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）通过微阵列鉴定 H-ras 介导的乳腺上皮细胞迁移/侵袭的 mRNA 标记候选物； （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/或分泌蛋白标记候选物的可行性。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性肿瘤。

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.