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The influence of MMP-14, TIMP-2 and MMP-2 expression on breast cancer prognosis
Bernard Têtu1, Jacques Brisson, Chang Shu Wang
1Department of Pathology, Laval University, Québec, Canada. bernard.tetu@chuq.qc.ca
Introduction:
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. We hypothesized that the individual expression of these three markers or their balance may help to predict breast cancer prognosis.
Methods:
MMP-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.
Results:
MMP-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 (> or = 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).
Conclusion:
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.
Insights
High expression of membrane type 1 Matrix metalloproteinase (MMP)-14 in breast cancer predicts poorer survival. This MMP-14 marker is a significant indicator of overall survival, especially when adjusted for clinical factors.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Matrix metalloproteinase (MMP)-2 degrades extracellular matrix and is regulated by membrane type 1 MMP (MMP-14) and tissue inhibitor of metalloproteases (TIMP)-2.
- The balance and expression of MMP-2, MMP-14, and TIMP-2 may influence breast cancer prognosis.
Purpose of the Study:
- To investigate the prognostic significance of MMP-2, MMP-14, and TIMP-2 expression and their interplay in breast cancer patients.
- To determine if these markers can predict overall survival in early-stage breast cancer.
Main Methods:
- Evaluated MMP-2, MMP-14, and TIMP-2 mRNA expression using 35S mRNA in situ hybridization.
- Analyzed data from 539 breast cancer patients without distant metastasis at diagnosis.
- Utilized Cox regression models adjusted for clinical factors and ancillary markers.
Main Results:
- MMP-14 mRNA expression in stromal cells was significantly associated with shorter overall survival (p = 0.031) when adjusted for tumor size and lymph node status.
- Prognostic significance of MMP-14 was lost upon further adjustment for Her-2/neu and urokinase-type plasminogen activator.
- Combinations of MMP-2, MMP-14, and TIMP-2 levels showed trends but did not reach statistical significance in predicting survival differences.
Conclusions:
- MMP-14 expression is the most significant factor among the studied complex associated with breast cancer outcomes.
- MMP-14 serves as an independent predictor of poor overall survival when adjusted for clinical prognostic factors.
- The prognostic value of MMP-14 may be influenced by other ancillary markers in breast cancer.
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