Therapeutic intervention of experimental breast cancer bone metastasis by indole-3-carbinol in SCID-human mouse model

Several lines of experimental evidence have suggested that chemokine receptor CXCR4, a metastasis-promoting molecule, may play important roles in breast cancer bone metastasis. There is emerging evidence linking CXCR4 to matrix metalloproteinases (MMP) as well as their regulator nuclear factor-κB (NF-κB), a key transcription factor, which is known to activate metastasis-promoting molecules for many types of malignancies, including breast cancer. A recent study also showed that promoter region of CXCR4 has several NF-κB-binding sites, suggesting that there may be a cross-talk between CXCR4 and NF-κB. We have shown previously that indole-3-carbinol (I3C), a natural compound present in vegetables of the genus Brassica , can inhibit NF-κB in breast cancer cells. However, there are no reports in the literature showing any effect of I3C on CXCR4 expression in vitro and in vivo . We therefore examined whether I3C could inhibit bone metastasis of breast cancer by inhibiting CXCR4 and MMP-9 expression mediated via the inhibition of the NF-κB signaling pathway. Here, we have modified the severe combined immunodeficient (SCID)-human mouse model of experimental bone metastasis for use with the MDA-MB-231 breast cancer cell line. In this animal model, we found that I3C significantly inhibited MDA-MB-231 bone tumor growth, and our results were correlated with the down-regulation of NF-κB. Moreover, we found that I3C significantly inhibited the expression of multiple genes involved in the control of metastasis and invasion in vitro and in vivo , especially the expression of CXCR4 and MMP-9 along with pro-MMP-9, with concomitant decrease in Bcl-2 and increase in the proapoptotic protein Bax. From these results, we conclude that the CXCR4/NF-κB pathway is critical during I3C-induced inhibition of experimental breast cancer bone metastasis. These results also suggest that I3C could be a promising agent for the prevention and/or treatment of breast cancer bone metastasis in the future. [Mol Cancer Ther 2006;5(11):2747–56]