Elucidation of the mechanisms underlying Cbfa1-mediated MMP-9 upregulation in MDA-MB-231 breast carcinoma cells

• Main Authors: Szu-Yuan Chen, 陳思元
• Other Authors: Yeu Su
• Format: Others
• Language: zh-TW
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/59610477923012600188

碩士 === 國立陽明大學 === 生物藥學研究所 === 93 === Breast cancers are known to preferentially metastasize to skeletal sites, however, its underlying molecular mechanisms remain poorly understood. Recent studies have demonstrated that Cbfa1, a transcription factor essential for bone formation and skeletal homeostasis, not only is expressed in breast cancer cells but is critical for their osteolytic metastasis. To assess the correlation between Cbfa1 expression and the bony metastatic potential of human breast cancer cells, phenotypic changes of the Cbfa1-overexpressing MDA-MB-231 breast cancer cells were examined. We showed that overexpression of Cbfa1 in MDA-MB-231 cells resulted in up-regulated expression of osteopontin (OPN), osteocalcin, parathyroid hormone-related protein (PTHrp), matrix metalloproteinase (MMP) 13, and MMP-9. MMPs are a family of zinc-dependent neutral endopeptidases collectively capable of degrading essentially all matrix components which play critical roles in a variety of cellular events associated with metastasis. Up-regulated expression of MMP-9 has been regarded as an unfavorable prognostic factor in breast cancer patients. Besides degrading matrix, MMP-9 has also been demonstrated to release and activate growth factors such as TGF-�� and VEGF, shed surface ICAM-1, and promote osteoclast migration, each would facilitate the malignant progression of breast cancer cells. A series of experiments were then conducted to elucidate the mechanism underlying Cbfa1-mediated MMP-9 upregulation in human breast cancer cells. We identified a consensus Cbfa1-binding site in the MMP-9 promoter which indeed was bound by Cbfa1 based on gel-shift analysis. In addition, a dose-dependent stimulatory effect of Cbfa1 on the expression of a reporter driven by the MMP-9 promoter was observed in MDA-MB-231 cells. Taken together, our results suggest that overexpression of the osteoblast-specific factor, Cbfa1, transcriptionally upregulates MMP-9 expression which may be crucial for invasion and metastasis of breast cancer cells.