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Volume 10 Supplement 2

Breast Cancer Research 2008

Stromal fibroblasts with nuclear β-catenin are present within breast tumours and increase proliferation and invasion of epithelial breast cancer cells

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Background

β-catenin, when located within the nucleus, acts as an oncoprotein by activating TCF/LEF transcription factors, which in turn regulate transcription of a wide range of growth and proliferation-associated genes. Nuclear β-catenin is frequently seen in epithelial cancer cells as a result of either inappropriate Wnt signalling or inactivating mutations in genes for key β-catenin regulators or for β-catenin itself. Breast tumours are unusual, however, in that nuclear β-catenin is relatively rare in epithelial breast cancer cells. On the other hand, nuclear β-catenin expression has been documented in fibroblasts within breast fibroadenomas and benign phyllodes tumours [1]. Preliminary observations within our laboratory indicated that stromal fibroblasts in and around breast carcinomas also frequently express nuclear β-catenin. Our aim in the present work was to validate this observation, and to determine how fibroblasts with nuclear β-catenin might influence cancer behaviour.

Methods

We performed immunohistochemistry for β-catenin on whole sections of breast cancers from 200 individual cases. A scoring system based on the number of fibroblasts expressing nuclear β-catenin was devised and fibroblasts around tumour and normal breast tissue were scored. To examine the potential influence of nuclear β-catenin-positive fibroblasts on breast tumour behaviour, we have developed a tissue culture model. With appropriate controls, fibroblasts (MRC5/immortalised primary breast fibroblasts) were transfected to overexpress β-catenin and the influence of these cells on breast cancer cells (MCF7/MDA-MB-231) in vitro was determined. First, proliferation rates of breast cancer cells treated with conditioned media from transfected fibroblasts were determined (MTT assays). Secondly, invasion assays were carried out in transwell plates; fibroblasts were β-catenin or control transfected in lower chambers and breast cancer cells were seeded into upper chambers onto membranes coated with extracellular matrix (Matrigel/ECMatrix). Epithelial cells invading through membranes were quantified (cell counting/fluorometric assay using CyQuant GR dye).

Results and conclusion

We found that fibroblasts expressing nuclear β-catenin are frequent in and around breast tumours, while they are very rare around normal breast. In our tissue culture model, β-catenin-transfected fibroblasts stimulated both proliferation and invasion of breast cancer cells. In conclusion, nuclear β-catenin within stromal fibroblasts may have a potent influence on breast cancer behaviour. This influence further highlights the importance of stromal–epithelial interactions in breast carcinogenesis.

References

  1. 1.

    Sawyer EJ, Hanby AM, Rowan AJ, Gillett CE, Thomas RE, Poulsom R, Lakhani SR, Ellis IO, Ellis P, Tomlinson IP: The Wnt pathway, epithelial–stromal interactions, and malignant progression in phyllodes tumours. J Pathol. 2002, 196: 437-444. 10.1002/path.1067.

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Verghese, E., Shenoy, H., Shaaban, A. et al. Stromal fibroblasts with nuclear β-catenin are present within breast tumours and increase proliferation and invasion of epithelial breast cancer cells. Breast Cancer Res 10, P43 (2008) doi:10.1186/bcr1927

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Keywords

  • Breast Cancer Cell
  • Breast Tumour
  • Phyllode Tumour
  • Stromal Fibroblast
  • Epithelial Cancer Cell