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Endogenous Osteonectin/SPARC/BM-40 Expression Inhibits MDA-MB-231 Breast Cancer Cell Metastasis

¹ Craniofacial Developmental Biology and Regeneration Branch and ² Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland; ³ Faculty of Stomatology, Capital University of Medical Sciences, Tian Tan, Beijing, China; ⁴ Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland; ⁵ Jake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and ⁶ Department of Pathology and Comprehensive Cancer Center, University of Alabama-Birmingham, Birmingham, Alabama

Requests for reprints: Hynda K. Kleinman, National Institute of Dental and Craniofacial Research, NIH, Room 433, Building 30, 30 Convent Drive, Bethesda, MD 20892-4370. Phone: 301-496-4069; Fax: 301-402-0897; E-mail: hkleinman{at}mail.nih.gov.

Skeletal metastases occur with high incidence in patients with breast cancer and cause long-term skeletal morbidity. Osteonectin (SPARC, BM-40) is a bone matrix factor that is an in vitro chemoattractant for breast and prostate cancer cells. Increased expression of osteonectin is found in malignant breast tumors. We infected MDA-231 breast cancer cells with an adenovirus expressing osteonectin to examine the role of osteonectin expression in breast cancer cells and its effect on metastasis, in particular to bone. Expression of osteonectin did not affect MDA-231 cell proliferation, apoptosis, migration, cell aggregation, or protease cleavage of collagen IV. However, in vitro invasion of these osteonectin-infected cells through Matrigel and colony formation on Matrigel was decreased. Interestingly, high osteonectin expression in MDA-231 cells inhibited metastasis in a dose-dependent manner to many different organs including bone. The reduction in metastasis may be due to decreased platelet-tumor cell aggregation, because exogenous osteonectin inhibited platelet aggregation in vitro and the high osteonectin expression in MDA-231 cells reduced tumor cell-induced thrombocytopenia in vivo compared with control-infected cells. These studies suggest that high endogenous expression of osteonectin in breast cancer cells may reduce metastasis via reduced invasive activity and reduced tumor cell-platelet aggregation.

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