A laminin peptide increases breast cancer bone metastasis

层粘连蛋白肽可增加乳腺癌骨转移

基本信息

批准号：
7501968
负责人：
JENNIFER E KOBLINSKI
金额：
$ 15.31万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-28 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7501968
关键词：
Active Sites Address Adhesions Affect Affinity Chromatography Basement membrane Binding Biochemical Biological Biological Models Bone Diseases Breast Cancer Cell Breast Carcinoma Cancer Patient Cell Communication Cell Surface Receptors Cells Cleaved cell Clinical Clinical Treatment Column Chromatography Development Diagnostic Environment Epitopes Event Experimental Models Gene Expression Gene Targeting Genes Glycoproteins Goals Growth Harvest Heparin Binding Homing Human Immunoprecipitation In Vitro Injection of therapeutic agent Knowledge Laminin Lead Malignant Epithelial Cell Mammary Neoplasms Mediating Metastatic Neoplasm to the Bone Modeling Mus Neoplasm Metastasis Organ Pathology Patients Peptides Population Heterogeneity Positioning Attribute Protein Overexpression Proteoglycan RKRLQVQLSIRT RNA Interference Receptor Signaling Research Research Personnel Research Proposals Signal Pathway Signal Transduction Signaling Molecule Site Staging Testing Therapeutic Time Tropism Tumor Burden Universities Work anticancer research base bone bone cell career improved in vivo inhibitor/antagonist innovation interest intraperitoneal knock-down laminin A laminin-1 malignant breast neoplasm matrigel migration neoplastic cell novel diagnostics prevent programs protein expression receptor research study tool tumor

项目摘要

DESCRIPTION (provided by applicant): The career goal of this candidate is to move into a tenure-track position at Northwestern University in the Department of Pathology studying the mechanism of breast cancer metastasis to bone. The long term goal of this research proposal is to elucidate the mechanism(s) for breast cancer metastasis to bone and to identify diagnostic markers to indicate the likelihood of breast cancer bone metastases. Approximately 60-70% of breast cancer patients who have died or are dying of breast cancer have bone metastases. Therefore, resolving the mechanisms of tumor metastasis, in particular, metastasis to bone is a main interest in breast cancer research. Laminin-1, a major basement membrane matrix glycoprotein, enhances adhesion, migration, and metastasis of tumor cells. AG73 (RKRLQVQLSIRT, alpha-1 chain residues 2719- 2731), a peptide found in laminin-1, significantly increases bone metastases of MDA-231 breast carcinoma cells. This proposal will test the central hypothesis that AG73 promotes arrival and/or growth of breast cancer metastasis to bone by binding to a proteoglycan receptor and altering the transcriptional expression of genes that target breast cancer cells to bone. Three specific aims will be addressed to provide a comprehensive assessment of the mechanisms involved in AG73-mediated breast cancer metastasis to bone. Specific aim 1 will determine the metastatic stage (homing versus growth in bone) at which AG73 promotes breast cancer cell metastasis to bone by examining arrival of breast cancer cells to bone and their growth in the bone of mice treated with AG73. Specific aim 2 will identify the receptor for AG73 in breast cancer cells, signaling pathways of AG73, and further downstream effects of AG73 by validating genes that regulate breast cancer metastasis to bone. Specific aim 3 will determine whether AG73 sequence is released in vitro and in vivo by breast cancer cells using biochemical approaches and if this sequence is present in vivo in breast cancer tumors using immunofluorescent approaches on human breast tumors. These results will confirm the biological relevance of the AG73 epitope and provide novel diagnostic tools that may be used to predict the subpopulation of tumors predisposed to bone metastasis. Breast cancer metastasis to bone is a significant clinical problem. Accomplishing the aims described here may lead to better diagnostic and/or therapeutic approaches for breast cancer.

描述（由申请人提供）：该候选人的职业目标是在病理学系西北大学的终身任职状态，研究乳腺癌转移对骨的机制。该研究建议的长期目标是阐明乳腺癌转移到骨骼的机制，并确定诊断标记以表明乳腺癌骨转移的可能性。死亡或死于乳腺癌的乳腺癌患者中，约有60-70％的乳腺癌患有骨转移。因此，解决肿瘤转移的机制，特别是对骨骼的转移是对乳腺癌研究的主要兴趣。 Laminin-1是一个主要地下膜基质糖蛋白，可增强肿瘤细胞的粘附，迁移和转移。 AG73（RKRLQVQLSIRT，Alpha-1链残基2719-2731），一种在层粘连蛋白1中发现的肽，显着增加了MDA-231乳腺癌细胞的骨转移。该提案将检验一个中心假设，即AG73通过与蛋白聚糖受体结合并改变靶向乳腺癌细胞的基因的转录表达来促进乳腺癌转移对骨的到来和/或生长。将解决三个具体目标，以对AG73介导的乳腺癌转移到骨骼中涉及的机制进行全面评估。特定的目标1将通过检查乳腺癌细胞到骨的到来及其在用AG73治疗的小鼠的骨头中的生长来确定AG73促进乳腺癌细胞转移对骨骼的转移阶段（归巢与生长）。特定的目标2将通过验证调节乳腺癌转移对骨骼的基因，鉴定乳腺癌细胞中AG73的受体，AG73的信号通路以及AG73的进一步下游效应。特定的目标3将确定使用生化方法在体外和体内释放AG73序列，并使用人类乳腺肿瘤上的免疫荧光方法在体内存在这种序列。这些结果将证实AG73表位的生物学相关性，并提供新颖的诊断工具，这些工具可用于预测易感骨转移的肿瘤的亚群。乳腺癌向骨骼转移是一个重大的临床问题。在此处描述的目的可能会导致更好的诊断和/或治疗方法用于乳腺癌。