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. ? ? ?
