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.
The goal of this proposal is to contribute to the study and complex mechanism of breast cancer dissemination and metastasis via studying the role of heat shock protein, 60 Kda, mitochondrial (HSPD1) in breast cancer progression and identifying it as a receptor for targeted drug delivery. The important outcome of this study HSPD1 can serve as a clinically relevant marker for breast cancer metastasis and might provide useful information to clinicians for the improvement of early diagnostic/prognostic evaluation and management of patients with breast cancer.
