MT1-MMP (
membrane type-1 matrix metalloproteinase), otherwise known as MMP14 is a
proteolytic enzyme known to be involved in degradating extracellular matrix and assist progression of
cancer invasion and progression. We investigated the impact of targeting the expression of
MT1-MMP in
breast cancer and its clinical relevance. Human
breast cancer cell line MDA-MB-231 was used. Expression of
MT1-MMP in the
breast cancer cell line was manipulated by way of retroviral
ribozyme transgene. The in vitro invasion, growth and cell migration were determined on cell lines transfected with either the transgene or control plasmid.
Protein and message levels of MMP14 was also assessed using immunohistochemistry and real-time quantitative analysis, and correlated with clinical and pathological information of the patients. Retroviral
ribozyme transgene to human
MT1-MMP successfully knocked down the levels of
MT1-MMP mRNA from MDA-MB-231 cells. Reduction of
MT1-MMP from the
breast cancer cells resulted in significant reduction of in vitro invasiveness and loss of response to an invasion stimulus, HGF, compared with control and wild-type cells. The invasion index for
MT1-MMP knockdown cells were 13+/-3.1 (without HGF) and 16.4+/-2.3 (with HGF, p=0.14), and the index for transfection control cells 25.3+/-4.3 (without HGF) and 40.4+/-4.1 (with HGF, p=0.0049). Transfection with the transgenes did not change the rate of cell growth. In clinical
breast cancer,
MT1-MMP staining was both membranous and cytoplasmic. Tumour cells displayed stronger staining compared with normal mammary epithelial cells. Tumour tissues had a marginally higher levels of the MMP14 transcript (8.6+/-1.9), compared with normal tissues (4.7+/-1.4), p=0.13. No significant difference was observed between node positive and node negative tumours (9.0+/-2.2 vs 8.7+/-3.1, p=0.24). Marginally higher levels of the MMP14 transcript were seen in tumours which developed
metastasis and local recurrence. However, tumours from patients who died of
breast cancer related causes had significantly higher levels of the transcript, compared with tumours from patients who remained disease-free 10 years after initial surgery (12.2+/-2.5 vs 6.3+/-1.2, p=0.0091).
MT1-MMP is a
proteolytic enzyme that is pivotal in controlling the invasiveness of
breast cancer cells. It is highly expressed in aggressive breast tumours and is associated with clinical outcome. The
enzyme is a potential therapeutic target in
breast cancer.