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Open Access Highly Accessed Research article

Downregulation of TFPI in breast cancer cells induces tyrosine phosphorylation signaling and increases metastatic growth by stimulating cell motility

Benedicte Stavik12, Grethe Skretting3, Hans-Christian Aasheim1, Mari Tinholt1, Lillian Zernichow1, Marit Sletten1, Per Morten Sandset23 and Nina Iversen1*

Author Affiliations

1 Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

2 Institute of Clinical Medicine, University of Oslo, Oslo, Norway

3 Department of Haematology, Oslo University Hospital, Oslo, Norway

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BMC Cancer 2011, 11:357  doi:10.1186/1471-2407-11-357

Published: 17 August 2011

Abstract

Background

Increased hemostatic activity is common in many cancer types and often causes additional complications and even death. Circumstantial evidence suggests that tissue factor pathway inhibitor-1 (TFPI) plays a role in cancer development. We recently reported that downregulation of TFPI inhibited apoptosis in a breast cancer cell line. In this study, we investigated the effects of TFPI on self-sustained growth and motility of these cells, and of another invasive breast cancer cell type (MDA-MB-231).

Methods

Stable cell lines with TFPI (both α and β) and only TFPIβ downregulated were created using RNA interference technology. We investigated the ability of the transduced cells to grow, when seeded at low densities, and to form colonies, along with metastatic characteristics such as adhesion, migration and invasion.

Results

Downregulation of TFPI was associated with increased self-sustained cell growth. An increase in cell attachment and spreading was observed to collagen type I, together with elevated levels of integrin α2. Downregulation of TFPI also stimulated migration and invasion of cells, and elevated MMP activity was involved in the increased invasion observed. Surprisingly, equivalent results were observed when TFPIβ was downregulated, revealing a novel function of this isoform in cancer metastasis.

Conclusions

Our results suggest an anti-metastatic effect of TFPI and may provide a novel therapeutic approach in cancer.

Keywords:
TFPI-1; adhesion; migration; invasion; tumor suppressor