Breast cancer; tumor neovasculature and the effect of tissue inhibitor of metalloproteinases-1 (TIMP-1) on angiogenesis.

Microvessel density has been proposed as a prognostic factor in breast carcinoma. In paired samples of human breast carcinoma and the adjacent non-neoplastic tissue, proliferating microvessels were associated with in situ ductal and lobular carcinomas. In invasive carcinomas, the microvessels were located within the tumor stroma. Recombinant tissue inhibitor of metalloproteinases-1 (rTIMP-1) was produced in a baculovirus system to examine its effect on angiogenesis. When present as a molecule of 29 kDa, rTIMP-1 inhibited matrix metalloproteinase (MMP) activity. However, a 66 kDa aggregate of TIMP-1 did not block MMP activity, although it inhibited in vitro angiogenesis as the 29 kDa form did. Studies have been initiated to characterize the effects of overexpression of TIMP-1 on breast carcinoma cells. Preliminary findings show TIMP-1 mediated changes in morphology and downregulation of MMP activity. These findings suggest that the angiogenesis inhibitory activity of TIMP-1 is unrelated to its antimetalloproteinase activity and that TIMP-1 may affect cellular function in different ways.