Sequential activation and production of matrix metalloproteinase-2 during breast cancer progression

The proteolytic processes are thought to be the critical point in tumor invasion and metastasis, mainly by matrix metalloproteinases (MMPs) and serine proteases. We measured the activity of MMP-2 from 28 normal, 12 benign and 126 breast cancer tissues using gelatin zymography. Inactive MMP-2 (72kD) was expressed in 53.6% of the normal and 66.6% of the cancer tissues, respectively (P = 0.77), while active MMP-2 (62 kD) was expressed in 28.6% and 73.0%, respectively (P = 0.003). The enzymatic activity of active MMP-2 (62 kD) measured in the gel band area was 4.0 ± 7.2 mm² in normal breasts, 7.7 ± 9.8 mm² in benign breast diseases, 9.5 ± 8.5 mm² in ductal carcinoma in situ (DCIS), and 12.0 ± 13.7 mm² in invasive cancers. The MMP-2 activation ratio (62 kD/62 kD + 72 kD) was 0.12 ± 0.18 in normal tissues, 0.10 ± 0.20 in benign diseases, 0.61 ± 0.22 in DCIS, and 0.50 ± 0.28 in invasive cancers. In conclusion, MMP-2 activation was the main cause of the increased 62 kD MMP-2 activity during the early phase of breast cancer, while production of MMP-2 supplemented the increased 62 kD activity in the late phase. We suggest, therefore, that these differential expressions of MMP-2 activation and production during the different stages of breast cancer progression are potential therapeutic targets for biological or gene therapy under the concept of stage-oriented cancer treatment.