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Flotillin-2 deficiency leads to reduced lung metastases in a mouse breast cancer model

Oncogene volume 32, pages 4989–4994 (2013)Cite this article

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Abstract

Flotillin microdomains, specialized lipid raft domains in cell membranes, serve as physical platforms for many different molecules important in crucial intracellular signaling pathways. Flotillin-2 (Flot2), together with flotillin-1, is a marker for lipid raft microdomains distinct from caveolar lipid rafts, and has been implicated in the progression of cancer and metastasis formation. Based largely on studies in xenograft models, flotillin-2 has been implicated in the progression of multiple types of human tumors, including breast cancer. In our studies, we identified flotillin-2 as highly amplified in a high-throughput comparative genomic hybridization screen of human breast cancer cell lines and breast tumor samples. Short hairpin RNA-mediated reduction of flotillin-2 protein levels significantly reduced the tumorigenicity and metastatic capability of a human breast cancer cell line in vivo. We generated mice deficient for flotillin-2 and also found a reduction of flotillin-1 protein levels and complete absence of flotillin-specific membrane microdomains in these mice. To examine the role of Flot2 in mammary tumorigenesis and lung metastasis, we used an in vivo molecular genetics approach, crossing a well-characterized transgenic mouse model of breast cancer, the MMTV-PyMT (mouse mammary tumor virus-polyoma middle T antigen) mouse, with gene-targeted Flot2−/− mice. Flotillin-2 deficiency lead to a striking reduction in the number of lung metastasis observed, but had no influence on primary tumor formation in this model. Our results indicate, using a novel in vivo animal model approach, that Flot2 is an important regulator of mammary tumor-derived lung metastasis.

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Acknowledgements

We thank Lily Zhou for expert technical assistance, and Dr Mary Saunders for insightful scientific editing. This work was supported by grant no. 179815 from the Canadian Institutes of Health Research to TWM. This research was funded in part by the Ontario Ministry of Health and Long Term Care. The views expressed do not necessarily reflect those of the OMOHLTC. ES is in part supported by Ontario Research Fund (GL2-01-030) to IJ, and IJ was in part supported by Canada Research Chair Program.

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Author notes

  1. T Berger and T Ueda: These authors contributed equally to this work.

Authors and Affiliations

  1. The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada

    T Berger, T Ueda, E Arpaia, I I C Chio, E A Shirdel, A You-Ten, J Haight, A Wakeham & T W Mak

  2. Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    T Ueda

  3. Techna Institute, University Health Network and IBM Life Sciences Discovery Centre, Toronto, ON, Canada

    E A Shirdel & I Jurisica

  4. Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, ON, Canada

    I Jurisica & T W Mak

  5. Department of Computer Science, University of Toronto, Toronto, ON, Canada

    I Jurisica

  6. Okada Projects at the Center for AIDS Research, Kumamoto University, Kumamoto, Japan

    K Hamada

  7. Department of Pathology, University Health Network, Toronto, ON, Canada

    C C Cheung

  8. Ontario Cancer Institute, University Health Network, Toronto, ON, Canada

    T W Mak

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  1. T Berger
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Correspondence to T W Mak.

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Berger, T., Ueda, T., Arpaia, E. et al. Flotillin-2 deficiency leads to reduced lung metastases in a mouse breast cancer model. Oncogene 32, 4989–4994 (2013). https://doi.org/10.1038/onc.2012.499

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  • DOI: https://doi.org/10.1038/onc.2012.499

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