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

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, p38 beta has been shown...

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Published in:Clinical & experimental metastasis 2004-10, Vol.21 (6), p.525-533
Main Authors: Suarez-Cuervo, Catalina, Merrell, Melinda A., Watson, Latania, Harris, Kevin W., Rosenthal, Eben L., Väänänen, H. Kalervo, Selander, Katri S.
Format: Article
Language:English
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Summary: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, p38 beta 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 p38 beta in breast cancer bone metastases, using dominant negative blockade approach. Human MDA-MB-231 breast cancer clones stably expressing dominant negative p38 beta (p38/AF) exhibited decreased basal MMP-9 activity. TGF- beta sub(1)-induced MMP-9 activity was also blunted in these clones, as compared with controls in which TGF- beta sub(1) up-regulated MMP-9 activity. Consistent with these findings, SB202190, a specific p38 inhibitor, also inhibited TGF- beta sub(1)-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 p38 beta 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.
ISSN:0262-0898
1573-7276
DOI:10.1007/s10585-004-3503-x