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Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway

Oncogene volume 27, pages 6322–6333 (2008)Cite this article

Abstract

Transforming growth factor (TGF)-β is known to promote tumor invasion and metastasis. Although bone morphogenetic proteins (BMPs), members of the TGF-β family, are expressed in a variety of human carcinoma cell lines, their roles in tumor progression have not been fully clarified. In this study, we sought to determine the roles of BMPs in the progression of breast cancer bone metastasis using human breast cancer samples and a mouse xenograft model. Immunohistochemical analysis of samples from breast cancer patients as well as a mouse xenograft model of MDA-231-D, highly metastatic human breast cancer cells, revealed phospho-Smad2 and phospho-Smad1/5/8 staining in the nuclei of cancer cells in primary tumor and/or bone metastasis. Using a functional in vivo bioluminescence imaging system, we showed that TGF-β- and BMP-induced transcriptional pathways are active in bone metastatic lesions in vivo. In addition, both TGF-β3 and BMP-2 promoted the motility and invasiveness of the MDA-231-D cells in vitro. Moreover, expression of dominant-negative receptors for TGF-β and/or BMPs in the MDA-231-D cells inhibited invasiveness in vitro and bone metastasis in the xenograft model. These results suggest that BMPs as well as TGF-β promote invasion and bone metastasis of breast cancer.

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Abbreviations

TGF-β:

transforming growth factor-β

BMP:

bone morphogenetic protein

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Acknowledgements

We thank Dr H Miyoshi (RIKEN, Tsukuba) for the lentivirus system, and K Nomura, E Kobayashi, N Kaneniwa and Y Yuuki (The Cancer Institute) for technical assistance. This research was supported by KAKENHI (Grants-in-Aid for Scientific Research) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. TI was supported by the Naito Foundation.

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Authors and Affiliations

  1. Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), Koto-ku, Tokyo, Japan

    Y Katsuno, A Hanyu, K Miyazono & T Imamura

  2. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan

    Y Katsuno, S Ehata & K Miyazono

  3. Department of Pathology, the Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), Koto-ku, Tokyo, Japan

    H Kanda, Y Ishikawa & F Akiyama

  4. Department of Breast Oncology, The Cancer Institute Hospital, Koto-ku, Tokyo, Japan

    T Iwase

  5. Cancer Institute Hospital of the JFCR, Koto-ku, Tokyo, Japan

    E Ogata

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  1. Y Katsuno
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Correspondence to T Imamura.

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

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Katsuno, Y., Hanyu, A., Kanda, H. et al. Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway. Oncogene 27, 6322–6333 (2008). https://doi.org/10.1038/onc.2008.232

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