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Approximately 60-70% of breast cancer patients who have died or are dying of breast cancer have bone metastases. Therefore, resolving the mechanisms of metastasis to bone is of critical importance in breast cancer research. Laminin-1 (α1β1γ1), a major basement membrane matrix glycoprotein, is involved in both normal and neoplastic breast biology, and enhances adhesion, migration, and metastasis of tumor cells. Laminin-1 is cleaved in the tumor environment and peptides of laminin-1 alter the behavior of tumor cells. AG73 (LQVQLSIRT, α-1 chain 2719-2731), is one of these peptides that affects tumor growth and metastasis. MDA-231 breast cancer cells adhere to AG73 and A4G82 (control peptide, TLFLAHGRLVFM, α-4 chain 1514–1525). This adhesion is inhibited by heparin but not EDTA, suggesting these peptides bind to tumor cells through heparin/heparan sulfate proteoglycans but not through integrins. In addition, MDA-231 cells bind to a recombinant globular 4 domain of the laminin-α1 chain, the domain where AG73 is located; however, the cells do not bind to the recombinant globular 4 domain that has a mutated AG73 site (RKR-AAA). AG73, but not A4G82, significantly increases brain and bone metastases of MDA-231 breast carcinoma cells in an intracardiac metastasis model. The tumors in the bone of these mice treated with AG73 were also larger than the control group. These results are intriguing since AG73 and A4G82 both interact with the cells in a similar manner, suggesting that the increased brain and bone metastasis is specific to AG73. Additionally, these results indicate that AG73-mediated increased brain and bone metastasis may be biologically relevant. Gene array analysis is now being used to identify genes which are up- and downreguglated by AG73 in MDA-231 breast cancer cells. The ultimate goal is to identify genes which regulate breast cancer metastasis to bone and brain for potential diagnostic and therapeutic treatments.
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