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

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


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.

bone metastasis breast cancer MMP-9 motility p38β urokinase plasminogen activator 


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Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Catalina Suarez-Cuervo
    • 1
  • Melinda A. Merrell
    • 1
  • Latania Watson
    • 1
  • Kevin W. Harris
    • 1
  • Eben L. Rosenthal
    • 1
  • H. Kalervo. Väänänen
    • 1
  • Katri S. Selander
    • 1
  1. 1.Department of Medicine, Division of Hematology-OncologyUniversity of Alabama at BirminghamBirminghamUSA

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