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

Abstract

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 osteonectininfected cells through Matrigel and colony formation on Matrigel was decreased. Interestingly, high osteonectin expression in MDA-231 cells inhibited metastasis in a dosedependent manner to many different organs including bone. The reduction in metastasis may be due to decreased platelettumor 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. (Cancer Res 2005; 65(16): 7370-7)

Common deleted genes in the 5q− syndrome: thrombocytopenia and reduced erythroid colony formation in SPARC null mice

“…15,16 Recently, SPARC was shown to inhibit breast cancer cell invasion, platelet aggregation and metastasis. 17 Increased methylation of SPARC in lung and pancreatic tumors is consistent with its role as a potential tumor suppressor gene that is silenced in selected cancers. 18,19 However, the role of SPARC in hematopoiesis remains unknown.…”

Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases

“…However, as SPARC has the potential to function both as a tumor promoter and tumor suppressor, decreasing SPARC expression may not be beneficial for all tumor types or stages. For example, SPARC induces apoptosis in ovarian cancer cells (Yiu et al, 2001) and inhibits proliferation and metastasis of breast cancer cells (Koblinski et al, 2005), but breast tumor expression of SPARC is linked to increased patient metastases and poor patient survival (Jones et al, 2004;Watkins et al, 2005). When we overexpressed SPARC in HeLa cells or a genetically engineered human breast cancer model (HMEC), SPARC-expressing cells suffered a dramatic inhibition of tumor formation when implanted into immunocompromised rodents (data not shown).…”

The role of MMP-9 in the anti-angiogenic effect of secreted protein acidic and rich in cysteine

“…An inhibitory effect of SPARC on proliferation and migration has been found in breast and ovarian carcinoma cells (Dhanesuan et al, 2002). Infection of MDA-231 breast carcinoma cells with osteonectin decreased the in vitro invasion of these cells through Matrigel (Koblinski et al, 2005). Overexpression of SPARC by ovarian carcinoma cells led to increased tumour cell apoptosis, and the levels of SPARC were inversely correlated with tumour progression in vivo (Yiu et al, 2001).…”