Abstract
IntroductionMatrix metalloproteinase (MMP)-2 is very active at degrading extracellular matrix. It is under the influence of an activator, membrane type 1 MMP (MMP-14), and the tissue inhibitor of metalloproteases (TIMP)-2. We hypothesized that the individual expression of these three markers or their balance may help to predict breast cancer prognosis.MethodsMMP-2, MMP-14 and TIMP-2 expression has been evaluated by 35S mRNA in situ hybridization on paraffin material of 539 breast cancers without distant metastasis at diagnosis and with a median follow-up of 9.2 years.ResultsMMP-2 and MMP-14 mRNA was detected primarily in reactive stromal cells whereas TIMP-2 mRNA was expressed by both stromal and cancer cells. Of the three molecules, an adjusted Cox model revealed that high MMP-14 mRNA (≥ 10% cells) alone predicted a significantly shorter overall survival (p = 0.031) when adjusted for clinical factors (tumor size and number of involved lymph nodes). Prognostic significance was lost when further adjusted for Her-2/neu and urokinase-type plasminogen activator (p = 0.284). Furthermore, when all three components were analyzed together, the survival was worst for patients with high MMP-2/high MMP-14/low TIMP-2 (5 year survival = 60%) and best with low MMP-2/low MMP-14/high TIMP-2 (5 year survival = 74%), but the difference did not reach statistical significance (p = 0.3285).ConclusionOf the MMP-14/TIMP-2/MMP-2 complex, MMP-14 was the factor most significantly associated with the outcome of breast cancer and was an independent factor of poor overall survival when adjusted for clinical prognostic factors, but not for certain ancillary markers.
Highlights
Matrix metalloproteinase (MMP)-2 is very active at degrading extracellular matrix
When all three components were analyzed together, the survival was worst for patients with high matrix metalloproteinase (MMP)-2/high MMP-14/low tissue inhibitor of metalloproteases (TIMP)-2 (5 year survival = 60%) and best with low MMP-2/low MMP-14/high TIMP-2 (5 year survival = 74%), but the difference did not reach statistical significance (p = 0.3285)
Of the MMP-14/TIMP-2/MMP-2 complex, MMP-14 was the factor most significantly associated with the outcome of breast cancer and was an independent factor of poor overall survival when adjusted for clinical prognostic factors, but not for certain ancillary markers
Summary
Matrix metalloproteinase (MMP)-2 is very active at degrading extracellular matrix. It is under the influence of an activator, membrane type 1 MMP (MMP-14), and the tissue inhibitor of metalloproteases (TIMP)-2. Matrix metalloproteinase (MMP)-2 is a protease produced essentially by stromal cells. In vitro studies have clearly demonstrated that it degrades molecules that are abundant in the extracellular matrix (ECM) [1]. Recent literature demonstrates that the mechanism of action of MMP-2 is complex and that other molecules modulate its activity [4,5]. MMP-2 is secreted in an inactive pro-enzymatic form and, unlike other MMPs, its activity is modulated by tissue inhibitor of metalloproteases (TIMP)-2 [6] and the membrane type 1. Breast cancers were found to express higher levels of activated MMP-2 than benign lesions [8,9] and in vitro studies showed that activated MMP2 only is associated with an aggressive potential in breast cancer cell lines [10]
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