Matrix-metalloproteinases 1, 2 and 3 and their tissue inhibitors 1 and 2 in benign and malignant breast lesions: an in situ hybridization study

Invasive growth requires degradation of extracellular matrix. Altered expre ssion of matrix degrading enzymes may indicate an increased potential for i nvasive growth. We determined the expression patterns of matrix-metalloprot einases (MMP)-1, -2, and -3 and of the tissue inhibitors of metalloproteina ses (TIMP)-1 and -2 by in situ hybridization with isotopically labeled RNA probes in normal breast tissue (n=6), fibrocystic disease (n=20), five case s of which contained radial scars, lobular carcinoma in situ (CLIS; n=5), d uctal carcinoma in situ (DCIS; n=9) and invasive carcinomas (n=24). Only a few cells displayed MMP-1- and MMP-2-specific labeling in normal breast tis sue and fibrocystic disease. Noninvasive ductal carcinomas showed elevated MMP-2 transcript levels in peritumor stromal cells in the absence of signif icant MMP-1 specific signals. In general, compared with adjacent normal bre ast tissue, a gradual increase of MMP-2 was found in noninvasive to invasiv e cancers. Invasive ductal and lobular carcinomas displayed co-expression o f MMP-1 and MMP-2 by stromal cells, mainly of the invasion front, with high signal intensity particularly in high-grade invasive carcinomas. Tumor cel ls and peritumor stroma showed low MMP-3 transcript levels, especially in m edullary carcinomas. TIMP-1 and -2 transcript levels were increased in inva sive carcinomas correlating with the histological grade. These RNA expressi on patterns suggest an increased invasive potential in breast carcinomas ev en prior to histologically overt invasive growth.