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J. Biol. Chem., Vol. 278, Issue 28, 25376-25385, July 11, 2003

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Osteoblast-derived Oxysterol Is a Migration-inducing Factor for Human Breast Cancer Cells^*

Jeane Silva , Anke Beckedorf   and Erhard Bieberich  ¶ ||

From the Institute of Molecular Medicine and Genetics, ^¶Department of Medicine, Medical College of Georgia, Augusta, Georgia 30909 and Westfälische Wilhelms Universität-Münster (University of Muenster), Institute of Medical Physics and Biophysics, Robert Koch Strasse 31, 48149 Muenster, Germany

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.

Received for publication, February 4, 2003 , and in revised form, April 22, 2003.

^* This work was supported in part by National Institutes of Health Grant MH61934-04 (to E. B.) and NS11853 (to R. K. Yu). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th St., Rm. CB-2803, Augusta, GA 30909.

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