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Transforming growth factor-β1 is the predominant isoform required for breast cancer cell outgrowth in bone

Oncogene volume 28, pages 1005–1015 (2009)Cite this article

Abstract

Transforming growth factor (TGF)-β signaling is a potent modulator of the invasive and metastatic behavior of breast cancer cells. Indeed, breast tumor responsiveness to TGF-β is important for the development of osteolytic bone metastases. However, the specific TGF-β isoforms that promote breast cancer outgrowth in bone is unknown. We demonstrate that expression of a TGF-β ligand trap, which neutralizes TGF-β1 and TGF-β3, in MDA-MB-231 breast cancer cells diminished their outgrowth in bone and reduced the severity of osteolytic lesion formation when compared with controls. We further show that a reduction or loss of TGF-β1 expression within the bone microenvironment of TGF-β1+/− and TGF-β1−/− mice significantly reduced the incidence of breast tumor outgrowth compared with wild-type animals. Interestingly, those tumors capable of growing within the tibiae of TGF-β1-deficient mice had upregulated expression of all three TGF-β isoforms. Finally, breast cancer cells expressing the TGF-β ligand trap showed a pronounced reduction in their ability to form osteolytic lesions when injected into the tibiae of TGF-β1+/− mice. Thus, our studies show that both host- and tumor-derived TGF-β expression plays a critical role during the establishment and outgrowth of breast cancer cells in bone.

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Abbreviations

CM:

conditioned media

ECD:

extracellular domain

IL-11:

interleukin-11

PTHrP:

parathyroid hormone-related protein

TβRI:

TGF-β type I receptor

TβRII:

TGF-β type II receptor

TGF-β:

transforming growth factor β

VC:

vector control

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Acknowledgements

We thank Dr Joan Massagué for providing the MDA-MB-231 derivative cell populations used in this study. We are grateful to Caterina Russo for providing excellent technical support, and acknowledge the McGill Centre for Bone and Periodontal Research for routine histological services. We thank Dr Ursini-Siegel, Dr Le Nihouannen and members of the Siegel laboratory for thoughtful discussions and critical reading of the manuscript. This study was supported by grants from the Canadian Breast Cancer Research Alliance (nos. 015333 and MOP-84386). AA Mourskaia is supported by a studentship from Fonds de la Recherche en Santé du Québec and PM Siegel is a research scientist of the National Cancer Institute of Canada.

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Authors and Affiliations

  1. Department of Medicine, McGill University, Montreal, Quebec, Canada

    A A Mourskaia, Z Dong, J C Zwaagstra & P M Siegel

  2. Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada

    S Ng, M D O'Connor-McCourt & P M Siegel

  3. Biotechnology Research Institute, National Research Council of Canada, Montreal, Quebec, Canada

    M Banville, J C Zwaagstra & M D O'Connor-McCourt

  4. Department of Biochemistry, McGill University, Montreal, Quebec, Canada

    M D O'Connor-McCourt & P M Siegel

Authors
  1. A A Mourskaia
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  2. Z Dong
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  4. M Banville
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  7. P M Siegel
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Correspondence to P M Siegel.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Mourskaia, A., Dong, Z., Ng, S. et al. Transforming growth factor-β1 is the predominant isoform required for breast cancer cell outgrowth in bone. Oncogene 28, 1005–1015 (2009). https://doi.org/10.1038/onc.2008.454

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  • DOI: https://doi.org/10.1038/onc.2008.454

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