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Breast cancer cells with inhibition of p38α have decreased MMP-9 activity and exhibit decreased bone metastasis in mice

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Abstract

p38 belongs to a family of mitogen-activated protein kinases, which transfer extracellular signals into intracellular responses. p38 is also frequently detected in clinical breast cancer specimens, but its role as a prognostic factor is not known. Of the various p38 isoforms, p38β has been shown to mediate the in vitro invasiveness of breast cancer cells through up-regulation of urokinase plasminogen activator (uPA). We studied the role of p38β in breast cancer bone metastases, using dominant negative blockade approach. Human MDA-MB-231 breast cancer clones stably expressing dominant negative p38β (p38/AF) exhibited decreased basal MMP-9 activity. TGF-β 1-induced MMP-9 activity was also blunted in these clones, as compared with controls in which TGF-β 1 up-regulated MMP-9 activity. Consistent with these findings, SB202190, a specific p38 inhibitor, also inhibited TGF-β1-induced MMP-9 activity in parental cells. The p38/AF clones exhibited also reduced uPA production after growth on vitronectin and decreased cell motility, as compared with controls. VEGF production levels in all the studied clones were similar. The p38/AF clone, which had similar in vitro growth rate as the control pcDNA3 clone, formed significantly less bone metastases in a mouse model, as compared with the control clone. In conclusion, inhibition of the p38β pathway results in decreased MMP-9 activity, impaired uPA expression and decreased motility, all of which may contribute to the decreased formation of bone metastasis.

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology-Oncology, University of Alabama at Birmingham, WTI T558, 1824 6th Avenue South, Birmingham, AL 35294-3300, USA

    Catalina Suarez-Cuervo, Melinda A. Merrell, Latania Watson, Kevin W. Harris, Eben L. Rosenthal, H. Kalervo. Väänänen & Katri S. Selander

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  1. Catalina Suarez-Cuervo
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  2. Melinda A. Merrell
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Suarez-Cuervo, C., Merrell, M.A., Watson, L. et al. Breast cancer cells with inhibition of p38α have decreased MMP-9 activity and exhibit decreased bone metastasis in mice. Clin Exp Metastasis 21, 525–533 (2004). https://doi.org/10.1007/s10585-004-3503-x

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