We have transfected a full-lenght cDNA-encoding human tissue inhibitor of metalloproteinases-1 (TIMP-1) by lipofection in highly invasive F3II mouse mammary sarcomatoid carcinoma cells. In vitro, overexpression of TIMP-1 was associated with abrogation of metalloproteinase activity, extended doubling time, and a more flattened, epithelioid polyhedric morphology. Female Balb/c mice inoculated subcutaneously with TIMP-1 transfectant exhibited a prolonged tumor latency and tumor burden was significantly lower in early stages of tumor growth. Control F3II cells grew by invading the muscular and adipose layers of the subcutis, dermis, and dermal papillae. On the contrary, mammary carcinoma cells transfected with TIMP-1 grew without signs of active invasion of dermis. Tumors also revealed a decreased amount of necrosis and host inflammatory cell infiltrates. However, histological analysis did not demonstrate any change in vascular density. Animals bearing F3II tumors overexpressing TIMP-1 showed a significant reduction in the size of metastatic lung nodules. These data suggested that TIMP-1 overexpression may reduce local invasion and delay the progression of the metastatic disease in the present mammary tumor model.

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