Signalling networks associated with urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 in breast cancer tissues: new insights from protein microarray analysis

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Abstract
The urokinase‐type plasminogen activator (uPA) and the main uPA inhibitor PAI‐1 play important roles in cell migration and invasion in both physiological and pathological contexts. Both factors are clinically applicable predictive markers in node‐negative breast cancer patients that are used to stratify patients for adjuvant chemotherapy. In addition to their classical functions in plasmin regulation, both factors are key components in cancer‐related cell signalling. Such signalling cascades are well described in cell culture systems, but a better understanding of uPA‐ and PAI‐1‐associated signalling networks in clinical tissues is needed. We examined the expression of uPA, PAI‐1, and 21 signalling molecules in 201 primary breast cancer tissues using protein microarrays. Expression of uPA was significantly correlated with the expression of ERK and Stat3, while expression of PAI‐1 was correlated with the uPA receptor and Akt activation, presumably via integrin and HER‐receptor signalling. Analysis of uPA expression did not reveal any significant correlation with staging, grading or age of the patients. The PAI‐1 expression was correlated with nodal stage. Network monitoring for uPA and PAI‐1 in breast cancer reveals interactions with main signalling cascades and extends the findings from cell culture experiments. Our results reveal possible mechanisms underlying cancer development. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.