Suppression of murine breast cancer metastasis by selective inhibition of CXCR4 by synthetic polypeptide derived from viral macrophage inflammatory protein II

Abstract

Stromal cell-derived factor-1 and its receptor CXC chemokine receptor-4 (CXCR4) have been implicated in breast cancer metastasis. A significant association between HER2 and CXCR4 expression has been observed in human breast tumor tissues, and overexpression of CXCR4 is essential for HER2-mediated tumor metastasis. Moreover, CXCR4 expression is low in normal breast tissues and high in malignant tumors, suggesting that a blockade of CXCR4 may limit tumor metastasis. The present study investigated the action of a synthetic antagonist 21-mer peptide derived from viral macrophage inflammatory protein II against CXCR4 (NT21MP) in inhibiting metastasis in vitro and in vivo. The results showed that chemotaxis of SKBR3 cells toward SDF-1α was reduced by NT21MP in a dose-dependent manner (P < 0.05). NT21MP inhibited tumor growth at 500 μg/kg and in combination with Herceptin, the anti-HER2 antibody. The in vivo metastatic assay showed that NT21MP significantly inhibited pulmonary metastasis, and the number of metastatic tumor nodes on the surface of the lung was greatly decreased. Compared with the saline-treated control group, PCNA expression was dose-dependently decreased by NT21MP, the percentage of apoptotic cells was increased, and CXCR4 mRNA and protein expression were downregulated. In conclusion, NT21MP inhibits cellular proliferation, promotes apoptosis by downregulating CXCR4 expression, and suppresses the progression of primary and metastatic tumors. CXCR4 may be a useful therapeutic target for breast cancer, and NT21MP may serve as a potential target drug for the treatment of breast cancer metastasis.