Osteoblast-derived oxysterol is a migration-inducing factor for human breast cancer cells.
Bone metastasis is the major reason for death caused by breast cancer. We used human breast cancer (MCF-7) cells that are poorly metastatic but show highly inducible migration to determine bone-derived factors that induce migration of initially non-disseminating breast cancer cells. We have found that a lipid fraction from human osteoblast-like MG63 cell-conditioned medium (MG63CM) contains a migration-inducing factor for MCF-7 cells. In this fraction, we have identified oxysterol (OS) as a lipid mediator for tumor cell migration. In MCF-7 cells, insulin-like growth factor 1 elevates the expression of OS-binding protein-related protein 7. Binding of OS to OS-binding protein or OS-binding protein-related protein is known to trigger elevation of sphingomyelin, a sphingolipid that organizes lipid microdomains in the cell membrane. In MCF-7 cells, OS increases the intracellular concentration of sphingomyelin and other phospholipids and induces the translocation of the small GTPase p21Ras to GM1- and cholesterol-rich membrane areas. The induction of migration by MG63CM is prevented by incubation of MG63 cells with mevinolin, a statin-type cholesterol biosynthesis inhibitor that depletes the conditioned medium of OS. Osteoblast-derived OS may, thus, be a yet unrecognized lipid mediator for bone metastasis of breast cancer and a new target for anti-metastasis chemotherapy with statins.
Institute of Molecular Medicine and Genetics, Department of Medicine, Medical College of Georgia, Augusta, Georgia 30909, USA.
Jeane
J
Silva
Anke
A
Beckedorf
Erhard
E
Bieberich
D016718:Arachidonic Acid / Q000378:metabolism; D001241:Aspirin / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D002784:Cholesterol / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D050356:Lipid Metabolism; D008148:Lovastatin / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis; D010006:Osteoblasts / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D010766:Phosphorylation; D011456:Prostaglandins B / Q000378:metabolism; D021381:Protein Transport; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012685:Sepharose / Q000494:pharmacology; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013107:Sphingolipids / Q000378:metabolism; D013261:Sterols / Q000378:metabolism*; D014357:Trypsin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D018840:HSP70 Heat-Shock Proteins; D010743:Phospholipids; D011456:Prostaglandins B; D013107:Sphingolipids; D013261:Sterols; D016718:Arachidonic Acid; D007334:Insulin-Like Growth Factor I; D012685:Sepharose; D002784:Cholesterol; D008148:Lovastatin; C042026:prostaglandin B2; D014357:Trypsin; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D015232:Dinoprostone; D001241:Aspirin