The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis

Matrix metalloproteinases (MMPs) are invariably upregulated in the stromal compartment of epithelial cancers and appear to promote invasion and metast asis. Here we report that phenotypically normal mammary epithelial cells wi th tetracycline-regulated expression of MMP3/stromelysin-1 (Str1) form epit helial glandular structures in vivo without Str1 but form invasive mesenchy mal-like tumors with Str1. Once initiated, the tumors become independent of continued Str1 expression. Str1 also promotes spontaneous premalignant cha nges and malignant conversion in mammary glands of transgenic mice. These c hanges are blocked by coexpression of a TIMP1 transgene. The premalignant a nd malignant lesions have stereotyped genomic changes unlike those seen in other murine mammary cancer models. These data indicate that Str1 influence s tumor initiation and alters neoplastic risk.