Role of SDF-1alpha and CXCR4 in Metastatic Breast Cancer

摘要

A major clinical manifestation of breast cancer patients is the development of bone metastasis. Several lines of experimental evidence suggested that chemokine receptor CXCR4 and its ligand SDF-1 signaling molecules may play an important role in the bone metastasis of breast cancer via activating NF- B, a key transcription factor. We have previously shown that Indole-3-carbinol (I3C), a natural compound present in vegetables of the genus Brassica can inhibit NF- B in breast cancer cells. Therefore, we hypothesize that I3C may be able to inhibit the bone metastasis of breast cancer by inhibition of NF- B, resulting in inhibition of CXCR4/SDF-1 and other NF- B targeted genes. This is the first time report that we have established an animal model of breast cancer bone metastasis using SCID human (SCID-hu) animal. Using this model, we investigated the effect of I3C on MDA-MB-231 breast cancer cells and experimental MDA-MB-231 bone tumors created by injecting MDA-MB-231 cells into human bone fragments. We found that I3C significantly inhibited MDA-MB-231 bone tumor growth. This correlated well with down regulation of NF- B. We studied the mRNA expression of CXCR4 and SDF-1 and found that 60 M I3C significantly inhibited SDF-1 and CXCR4 expression in MDA- MB-231 cells. Our hypotheses will be tested using MDA-MB-231 human breast cancer cells growing in the SCID-hu model, wherein we can document the expression profile of specific targeted genes could be altered by I3C treatment. By using a novel siRNA technology to silence the SDF-1 and/or CXCR4 genes, we plan to study how SDF-1 /CXCR4 signaling affects the infiltrating growth of MDA-MB-231 cells to the bone in the SCID-hu model, and to delineate whether the effects are exerted via activation of MMPs, uPA and NF- B. The data obtained from our experiments will provide novel pathways that could be exploited for the prevention and/or treatment of breast cancer bone metastasis in the clinic.