THERAPEUTIC TARGETS TO PREVENT BREAST CANCER METASTASIS

描述：(申请人的描述)我们的研究结果与 角质形成细胞生长因子(KGF)和现有文献表明KGF 对乳腺癌细胞的运动有快速而深远的影响。基于 这些结果似乎表明，从乳腺间质组织分泌的KGF可能 作为肿瘤细胞增殖和启动的早期信号 转移。如果这一假设是正确的，基因的治疗性抑制 和/或受KGF调节的蛋白质，应该阻止ER阳性的进展 乳腺癌细胞向转移性表型转化，使肿瘤更 可通过手术、内分泌治疗或其他细胞毒性药物治疗。这个 从文献和我们之前的研究中得出的中心假设是 KGF调控的基因产物诱导人细胞弥散运动 乳腺癌细胞，这可能是转移过程中的早期事件 原发肿瘤细胞。使用cdna表达阵列，我们已经鉴定出一种 一组特定的“候选靶基因”，其上调或下调受 KGF可能与KGF对乳腺癌细胞的作用直接相关。 在这项提议中要检验的假设是特定的基因，受调控的 通过KGF，都参与了调节乳腺癌细胞的运动。 使用反义技术选择性抑制单个候选基因 寡核苷酸，将被用来证明每个基因的参与 KGF产物诱导乳腺癌细胞在培养和小鼠体内的运动 活体包裹体照片。 这项研究的结果应该导致确定重要的新的 乳腺癌细胞进展中的治疗靶点和生物标志物 和转移性发育。这应该会导致新的 可能是非常特异和高效的抑制剂的治疗剂 乳腺癌的进展和转移扩散和/或提供关键的新的 癌症分期和治疗设计的生物标志物。

DESCRIPTION: (Applicant's Description) The results of our studies with Keratinocyte Growth Factor (KGF) and the existing literature indicate that KGF has a rapid and profound influence on breast cancer cell motility. Based on these results, it appears that KGF, secreted from breast stromal tissue, may act as an early signal in tumor cell proliferation and the initiation of metastasis. If this hypothesis is correct, therapeutic inhibition of genes and/or proteins regulated by KGF, should impede the progression of ER-positive breast cancer cells to a metastatic phenotype and make the tumor more manageable by surgery, endocrine therapy or other cytotoxic agents. The central hypothesis, derived from the literature and our previous studies, is that KGF-regulated gene products induce cell scattering motility of human breast cancer cells, which may be an early event in the metastatic progression of primary tumor cells. Using cDNA expression arrays, we have identified a specific group of "Candidate Target Genes", that are up or down regulated by KGF, which may be directly associated with KGF effects on breast cancer cells. The hypothesis to be tested in this proposal is that specific genes, regulated by KGF, are involved in mediating the motility of breast cancer cells. Selective inhibition of individual candidate genes, using antisense oligonucleotides, will be used to demonstrate the involvement of each gene product in KGF induced motility of breast cancer cells in culture and in mouse xenographs in vivo. The results of this study should lead to the identification of important new therapeutic targets and biomarkers involved in breast cancer cell progression and metastatic development. This should result in the development of new therapeutic agents that may be very specific and highly effective inhibitors of breast cancer progression and metastatic spread and/or provide critical new biomarkers for cancer staging and treatment design.