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Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis

¹ Molecular Oncology Research Institute and ² Division of Hematology/Oncology, Tufts Medical Center; Departments of ³ Medicine and ⁴ Biochemistry, Tufts University School of Medicine; ⁵ Department of Molecular Medicine, Boston University School of Medicine, Boston, Massachusetts

Requests for reprints: Lidija Covic, Molecular Oncology Research Institute, Division of Hematology/Oncology, Tufts Medical Center, Box 7510, 750 Washington Street, Boston, MA 02111. Phone: 617-636-4665; Fax: 617-636-7855; E-mail: lcovic{at}tuftsmedicalcenter.org.

Key Words: PAR1 • MMP-1 • Akt • pepducin • Taxotere • breast cancer • metastasis

Protease-activated receptor 1 (PAR1) is a G protein–coupled receptor that is not expressed in normal breast epithelia but is up-regulated in invasive breast carcinomas. In the present study, we found that matrix metalloprotease-1 (MMP-1) robustly activates the PAR1-Akt survival pathway in breast carcinoma cells. This process is blocked by a cell-penetrating lipopeptide "pepducin," P1pal-7, which is a potent inhibitor of cell viability in breast carcinoma cells expressing PAR1. Both a MMP-1 inhibitor and P1pal-7 significantly promote apoptosis in breast tumor xenografts and inhibit metastasis to the lungs by up to 88%. Dual therapy with P1pal-7 and Taxotere inhibits the growth of MDA-MB-231 xenografts by 95%. Consistently, biochemical analysis of xenograft tumors treated with P1pal-7 or MMP-1 inhibitor showed attenuated Akt activity. Ectopic expression of constitutively active Akt rescues breast cancer cells from the synergistic cytotoxicity of P1pal-7 and Taxotere, suggesting that Akt is a critical component of PAR1-dependent cancer cell viability. Together, these findings indicate that blockade of MMP1-PAR1 signaling may provide a benefit beyond treatment with Taxotere alone in advanced, metastatic breast cancer. [Cancer Res 2009;69(15):6223–31]