The Role of SDF-1 Alpha and CXCR4 in Metastatic Breast Cancer
Abstract
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 (1). 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2005
- Accession Number
- ADA450256
Entities
People
- K. M. Rahman
Organizations
- Wayne State University