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Breast Cancer Research and Treatment

, Volume 114, Issue 1, pp 85–96 | Cite as

The effect of thrombospondin-1 on breast cancer metastasis

  • Karen O. Yee
  • Caitlin M. Connolly
  • Mark Duquette
  • Shideh Kazerounian
  • Raymond Washington
  • Jack Lawler
Preclinical Study

Abstract

Thrombospondin-1 (TSP-1) has been proposed to have both pro-metastatic and anti-metastatic properties. To elucidate its role in breast cancer metastasis, we compared tumor progression in the polyomavirus middle T antigen (Pyt) transgenic mouse and the TSP-1-null Pyt transgenic mouse. We characterized the tumors in these mice at 45, 60 and 90 days of age. Tumor size, areas of necrosis, macrophage infiltration, levels of active and total TGF-β, vessel morphology, and lung and blood metastasis were measured in these mice. Mammary tumors were larger in the TSP-1-null mouse, and vessels were larger, but fewer in number in these tumors. The level of total TGF-β was significantly higher in the Pyt tumors at 90 days of age. Importantly, significantly fewer metastases were observed in the lungs of the TSP-1-null/Pyt mouse. Primary Pyt tumor cells were more migratory than TSP-1-null Pyt tumor cells on collagen. Treatment of Pyt mice with recombinant proteins that contain the type-1 repeats of TSP-1 resulted in decreased primary tumor growth and metastasis. Sequences that are involved in CD36 binding and those required for TGF-β activation mediated the inhibition of primary tumor growth. Thus, TSP-1 in the mammary tumor microenvironment inhibits angiogenesis and tumor growth, but promotes metastasis to the lung in the Pyt transgenic mouse. The ability of TSP-1 to support metastasis correlates with its ability to promote tumor cell migration.

Keywords

Metastasis Migration Polyomavirus middle T antigen TGF-β Transgenic mouse 

Notes

Acknowledgements

The authors would like to thank fellow lab members Eric Galardi for assistance with the mice and Xuefeng Zhang for helpful discussion on the project. We also would like to thank Ricky Sanchez for sectioning the frozen tumors. Karen Yee was supported by a fellowship from Aid for Cancer Research (Newton, MA). Raymond Washington is supported by a training grant from the National Institute of Health (T32HL007893). This work was supported by grants from the National Institute of Health (CA92644 and HL68003).

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Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Karen O. Yee
    • 1
  • Caitlin M. Connolly
    • 1
  • Mark Duquette
    • 1
  • Shideh Kazerounian
    • 1
  • Raymond Washington
    • 1
  • Jack Lawler
    • 1
  1. 1.The Division of Cancer Biology and Angiogenesis, Department of PathologyBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUSA

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