Matrix metalloproteinase-8 is a regulator of the clinical aggressiveness of mammary tumours

Protease genes are involved in multiple steps of cancer progression, including cell growth, migration and angiogenesis. These genes are valuable as prognostic and/or diagnostic markers of disease and are potential therapeutic targets.

We used TaqMan^® real-time quantitative PCR to conduct the first detailed quantitative expression profiling of the entire family of metalloprotease and serine protease genes and their inhibitors in breast cancer (over 380 genes). Using a bank of 60 samples (50 cancer and 10 normal mammary tissue) collected at the Norfolk and Norwich University Hospital [1] we have identified a number of genes that show significant disregulation in tumour samples compared with normal breast tissue. Expression correlates either positively or negatively with tumour grade in many genes.

A further cohort of 229 Dutch patients with more extensive clinical history [2] was profiled in a subset of the metalloproteinase genes. Among the genes that showed significant aberrant expression, Matrix metalloproteinase-8 (MMP8) emerged as a candidate to play a protective role during tumour progression. MMP8 was found to have significant prognostic value and was strongly correlated with prolonged survival. MMP8 is prognostic as a continuous variable for relapse-free survival (hazard ratio = 0.76, P = 0.045) and for overall survival (hazard ratio = 0.69, P = 0.025). Expression of MMP8 also correlated with lymph node involvement, reduced expression equating to greater nodal spread (P = 0.001). Expression of MMP8 was independent of tumour grade. These data show that MMP8 is prognostic in breast cancer, and suggest that the function of MMP8 antagonizes metastasis.