Transcriptome analysis reveals an osteoblast-like phenotype for human osteotropic breast cancer cells
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Metastatic breast cancer cells exhibit the selective ability to seed and grow in the skeleton. We and others have previously reported that human breast tumors which metastasize to the skeleton overexpress bone matrix extracellular proteins. In an attempt to reveal the osteoblast-like phenotype of osteotropic breast cancer cells, we performed a microarray study on a model of breast cancer bone metastasis consisting of the MDA-MB-231 human cell line and its variant B02 selected for its high capacity to form bone metastases in vivo. Analysis of B02 cells transcriptional profile revealed that 11 and 9 out of the 50 most up- and down-regulated mRNAs, respectively, corresponded to genes which expression has been previously associated with osteoblastic differentiation process. Thus, osteoblast specific cadherin 11 which mediates the differentiation of mesenchymal cells into osteoblastic cells is up-regulated in B02. While S100A4, recently described as a key negative regulator of osteoblast differentiation, is the most down-regulated gene in B02 cells. RT-PCR and western blotting experiments allowed the validation of the modulation of several genes of interest. Using immunohistochemistry, performed on human breast primary tumors and their matched liver and bone metastases, we were able to confirm that the osteoblast-like pattern of gene expression observed in our model holds true in vivo. This is the first report demonstrating a gene-expression pattern corresponding to the acquisition of an osteomimetic phenotype by bone metastatic breast cancer cells.
KeywordsBone Breast cancer Metastases Osteoblast Osteomimicry
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The authors thank Mrs P. Heneaux, S. Thonard and S. Pierard for expert technical assistance. A. Bellahcène is a Research Associate and C. Detry is a “Télévie” Research Fellow of the National Fund for Scientific Research (NFSR, Belgium). This work was partially supported by grants from the NFSR, the Inter-University Attraction Pole (IAP-P5/31), the University of Liège (Fonds spéciaux), Belgium, l’Association pour la Recherche contre le Cancer (no. 7853) and la Ligue contre le Cancer, France. We acknowledge the support of the European Commission through contract METABRE (CEE LSHC-CT-2004-503049). The authors thank Dr. D. Waltregny and Dr. M.V. Chavez (Metastasis Research Laboratory, University of Liège) for critical reading of the manuscript and all the partners of the METABRE consortium for their participation to fruitful discussions: M. Bracke (Ghent University Hospital, Belgium), R.␣Buccione (Consorzio mario Negri Sud, Italy), P. Clément-Lacroix (Prostrakan, France), S. Eccles (Institute of Cancer Research, UK), A. Sierra (Institut De Recerca Oncologica, Spain), A. Teti (University of l’Aquila, Italy), M. Ugorski (Wroclaw Agriculture University, Poland) and G. van der Pluijm (Leiden University Medical Center, The Netherlands).
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