Evaluation of HSPD1 (Heat Shock Protein, 60) as a theranostic target for breast cancer

我们实验室使用了一种新的消减噬菌体展示技术来鉴定噬菌体 能特异性和选择性结合上皮细胞向间充质细胞过渡的配体 (EMT)乳腺癌细胞。我们挑选了几个具有亲和力的噬菌体并对其进行了鉴定 转移到EMT细胞。与外源多肽序列CLGLRGSLC结合的噬菌体之一 对EMT乳腺癌和EMT成纤维细胞具有更强的亲和力和特异性。我们 确定HSPD1(热休克蛋白，60Kda)为可能的结合伙伴 CLGLRGSLC噬菌体。随后的研究，包括生物信息学数据集分析， 惰性与侵袭性乳腺癌细胞的免疫印迹 对原发和转移性乳腺癌组织的分析显示表达增加 HSPD1在乳腺癌进展过程中的表达及其与生存期的关系 病人。这初步产生了一种新的假设，即HSPD1可能在 HSPD1结合肽在乳腺癌转移过程中的作用 还建议使用基于选择性的新型成像和治疗药物 有约束力的。我们推测，HSPD1是一种新的癌基因，可以作为临床上的 乳腺癌转移的相关标记物和可利用的理想受体 用于将肿瘤靶向药物输送到转移部位。遵循具体目标将是 追查： A)确定HSPD1的表达是否与转移的疾病相关。 B)确定HSPD1在乳腺癌发生和发展中的致癌作用 进展体外和体内试验， C)将致力于开发模拟多肽的靶向系统，以抑制转移 与HSPD1结合的噬菌体多肽与促凋亡部分D(KLAKLAK)2融合。

Our laboratory has used a novel subtractive phage display technique to identify phage ligands that can specifically and selectively bind to epithelial to mesenchymal transitioned (EMT) breast cancer cells. We selected and characterized several phages that had affinity to EMT cells. One of the phages with the foreign peptide sequence CLGLRGSLC bound with greater affinity and specificity to EMT breast cancer and EMT fibroblasts cells. We identified HSPD1 (heat shock protein, 60Kda) as a putative binding partner to CLGLRGSLC phage. Subsequent studies, including bioinformatics dataset analysis, immunoblotting of indolent vs aggressive breast cancer cells, immunohistochemical analysis of primary and metastatic breast cancer tissues showed increased expression of HSPD1 during disease progression and correlates with survival of breast cancer patients. This preliminary engenders the novel hypothesis that HSPD1 might play a role in metastatic progression of breast cancer and the discovery of HSPD1-binding peptide also suggests the use of novel imaging and therapeutic agents based on the selective binding. We hypothesize that HSPD1 is a novel oncogene that can serve as a clinically relevant marker for breast cancer metastasis and an ideal receptor that can be utilized for tumor-targeted drug delivery to metastatic sites. Following specific aims will be pursued: a) to determine if HSPD1 expression correlates with metastatic disease. b) to determine the oncogenic role of HSPD1 in breast cancer development and progression invitro and invivo, c) will aim to develop peptidomimetic targeting system to suppress metastasis based on HSPD1-binding phage peptide fused to proapoptotic moiety D(KLAKLAK)2.