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  • Original Paper
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Dominant negative Met reduces tumorigenicity-metastasis and increases tubule formation in mammary cells

Oncogene volume 19, pages 2386–2397 (2000)Cite this article

Abstract

Activation of the Met tyrosine kinase growth factor receptor by its ligand HGF/SF has been shown to increase in vitro invasiveness in epithelial cell lines. To study the effect of Met-HGF/SF signaling in breast cancer cells, we transfected met, hgf/sf and dominant negative (DN) forms of met into the poorly differentiated metastatic murine mammary adenocarcinoma cell line DA3. These cells express moderate levels of endogenous Met, which is rapidly phosphorylated in response to HGF/SF treatment. Met+hgf/sf transfection results in significantly increased tumorigenic and metastatic activity in vivo accompanied by reduced tubule formation. DA3 cells transfected with DN forms of Met (DN-DA3) exhibit reduced Met phosphorylation following exposure to HGF/SF. Furthermore, as compared to the parental cells, the DN-DA3 cells exhibit diminished in vitro scattering and invasiveness, while in vivo they display greatly reduced tumorigenicity and spontaneous metastasis. Tumors emanating from DN-DA3 cells injected to BALB/C mice are highly differentiated and display extensive tubule formation. These results suggest that Met-HGF/SF signaling is a determining factor in the delicate balance between differentiation/tubule formation and tumorigenicity-metastasis.

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Acknowledgements

This work was performed in partial fulfillment of the requirements for a PhD degree of Michal Firon, Sackler Faculty of Medicine, Tel Aviv University, Israel. We wish to thank Dr Tom Kmiecik and Dr Sonia Mendlovic for their professional assistance. We thank Dr Ira Daar and Dr Eli Golomb for critical review of this work. Partially supported by a grant from the United States–Israel Binational Science Foundation, Grant # 93-00072, the Israel Science Foundation founded by the Israel Academy of Sciences & Humanities and by the National Cancer Institute, DHHS, under contract with ABL.

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Authors and Affiliations

  1. Department of Human Microbiology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

    Michal Firon, Miriam Shaharabany, Rom T Altstock, Judith Horev & Ilan Tsarfaty

  2. Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

    Armand Abramovici

  3. ABL-Basic Research Program NCI-Frederick Cancer Research and Development Center, PO Box B, Frederick, 21702-1201, Maryland, MD, USA

    James H Resau & George F Vande Woude

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  1. Michal Firon
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Firon, M., Shaharabany, M., Altstock, R. et al. Dominant negative Met reduces tumorigenicity-metastasis and increases tubule formation in mammary cells. Oncogene 19, 2386–2397 (2000). https://doi.org/10.1038/sj.onc.1203557

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