The influence of MMP-14, TIMP-2 and MMP-2 expression on breast cancer prognosis.
BACKGROUND
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).


CONCLUSIONS
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.
Têtu
Bernard
B
Department of Pathology, Laval University, Québec, Canada. bernard.tetu@chuq.qc.ca
Brisson
Jacques
J
Wang
Chang Shu
CS
Lapointe
Hélène
H
Beaudry
Geneviève
G
Blanchette
Caty
C
Trudel
Dominique
D
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D017154:Stromal Cells; D016019:Survival Analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D020778:Matrix Metalloproteinase 2