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Spontaneous metastasis in congenic mice with transgenic breast cancer is unaffected by plasminogen gene ablation

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Abstract

Plasminogen (Plg) plays a central role in tissue remodeling during ontogeny, development, and in pathological tissue remodeling following physical injury, inflammation and cancer. Plg/plasmin is, however, not critical for these processes, as they all occur to a varying extent in its absence, suggesting that there is a functional redundancy with other proteases. To explore this functional overlap in the transgenic MMTV-PyMT breast cancer metastasis model, we have combined Plg deficiency and a pharmacological metalloprotease inhibitor, which is known to reduce metastasis in this model, and has been shown to synergistically inhibit other tissue remodeling events in Plg-deficient mice. While metalloprotease inhibition dramatically reduced metastasis, we found no effect of Plg deficiency on metastasis, either independently or in combination with metalloprotease inhibition. We further show that Plg gene deficiency is of no significant consequence in this metastasis model, when analyzed in two different congenic strains: the FVB strain, and a F1 hybrid of the FVB and C57BL/6J strains. We suggest that the extensive backcrossing performed prior to our studies has eliminated the confounding effect of a known polymorphic metastasis modifier gene region located adjacent to the Plg gene.

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Abbreviations

B6:

C57BL/6J

H&E:

Hematoxylin and eosin

MMP:

Matrix metalloprotease

MMTV:

Mouse mammary tumor virus promoter

Plg:

Plasminogen

PyMT:

Polyomavirus middle T oncogene

SNP:

Single-nucleotide polymorphism

uPA:

Urokinase-type Plg activator

uPAR:

Urokinase receptor

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Acknowledgments

The authors are indebted to Dr. William J. Muller for generously providing us with the FVB-PyMT mice, and Dr. Thomas Bugge for providing the Plg-deficient mice. The authors acknowledge Dr. Michael Ploug for western blotting analyses, and Mr. Ib J. Christensen for assistance with statistical analyses, and Ms. Agnieszka Ingvorsen, Ms. Lotte Frederiksen, Ms. Kirsten L. Jakobsen, Ms. Mette M. Andersen, and Ms. Gitte Juhl-Funch for expert technical assistance. The study was supported by The European Commission (LSHC-CT-2003-503297, Cancerdegradome). K. Almholt received support from the Danish Cancer Society, the Danish Cancer Research Foundation, the Capital Region of Denmark, and the Novo Nordisk Foundation.

Conflict of interest

KA and JR are full time employees and minor shareholders of Novo Nordisk A/S.

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Authors and Affiliations

  1. Finsen Laboratory, Rigshospitalet, Copenhagen Biocenter, Copenhagen, Denmark

    Kasper Almholt, Anna Juncker-Jensen, Ole Didrik Lærum, Morten Johnsen, John Rømer & Leif Røge Lund

  2. Department of Histology, Biopharmaceuticals Research Unit, Novo Nordisk A/S, Novo Nordisk Park, 2760, Maaloev, Denmark

    Kasper Almholt & John Rømer

  3. Department of Biology, University of Copenhagen, Copenhagen Biocenter, Copenhagen, Denmark

    Morten Johnsen

  4. Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark

    Leif Røge Lund

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  1. Kasper Almholt
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  2. Anna Juncker-Jensen
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Correspondence to Kasper Almholt.

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Almholt, K., Juncker-Jensen, A., Lærum, O.D. et al. Spontaneous metastasis in congenic mice with transgenic breast cancer is unaffected by plasminogen gene ablation. Clin Exp Metastasis 30, 277–288 (2013). https://doi.org/10.1007/s10585-012-9534-9

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  • DOI: https://doi.org/10.1007/s10585-012-9534-9

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