A laminin peptide increases breast cancer bone metastasis

描述（由申请人提供）：该候选人的职业目标是进入西北大学病理学系的终身职位，研究乳腺癌骨转移的机制。本研究提案的长期目标是阐明乳腺癌骨转移的机制，并确定诊断标志物，以指示乳腺癌骨转移的可能性。大约60 - 70%死于或即将死于乳腺癌的乳腺癌患者患有骨转移。因此，解决肿瘤转移，特别是骨转移的机制是乳腺癌研究的主要兴趣。层粘连蛋白-1是一种主要的基底膜基质糖蛋白，可增强肿瘤细胞的粘附、迁移和转移。AG73（RKRLQVQLSIRT，α-1链残基2719 - 2731），一种在层粘连蛋白-1中发现的肽，显著增加MDA-231乳腺癌细胞的骨转移。该提案将测试中心假设，即AG73通过与蛋白聚糖受体结合并改变靶向乳腺癌细胞至骨的基因的转录表达来促进乳腺癌转移至骨的到达和/或生长。三个具体的目标将被解决，以提供一个全面的评估AG73介导的乳腺癌骨转移的机制。具体目标1将通过检查乳腺癌细胞到达骨和它们在用AG73处理的小鼠的骨中的生长来确定AG73促进乳腺癌细胞转移到骨的转移阶段（归巢与在骨中的生长）。具体目标2将通过验证调节乳腺癌骨转移的基因来鉴定乳腺癌细胞中AG73的受体、AG73的信号传导通路以及AG73的进一步下游效应。具体目标3将使用生物化学方法确定AG73序列是否由乳腺癌细胞在体外和体内释放，以及使用对人乳腺肿瘤的免疫荧光方法确定该序列是否存在于乳腺癌肿瘤中。这些结果将证实AG73表位的生物学相关性，并提供新的诊断工具，可用于预测易发生骨转移的肿瘤亚群。乳腺癌骨转移是一个重要的临床问题。实现本文所述的目标可能会导致更好的诊断和/或治疗乳腺癌的方法。

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.