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

TY - JOUR

T1 - Spontaneous metastasis in congenic mice with transgenic breast cancer is unaffected by plasminogen gene ablation

AU - Almholt, Kasper

AU - Juncker-Jensen, Anna

AU - Lærum, Ole Didrik

AU - Johnsen, Morten

AU - Rømer, John

AU - Lund, Leif R.

PY - 2013/3

Y1 - 2013/3

N2 - 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.

AB - 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.

U2 - 10.1007/s10585-012-9534-9

DO - 10.1007/s10585-012-9534-9

M3 - Journal article

C2 - 22996753

SN - 0262-0898

VL - 30

SP - 277

EP - 288

JO - Clinical and Experimental Metastasis

JF - Clinical and Experimental Metastasis

IS - 3

ER -