Previous studies demonstrated that metastatic MDA-MB-435 breast carcinoma cells synthesized and secreted less of the extracellular matrix protein thrombospondin 1 (TSP1) than nonmetastatic breast carcinoma cell lines, a trend also observed for melanoma and lung carcinoma cell lines. To directly examine the effect of tumor cell TSP1 expression on tumor growth and metastasis. MDA-MB-435 cells were transfected with full length THBS-1 cDNA linked to a constitutive cytomegalovirus promoter, or with the cytomegalovirus vector alone. Injection of transfected clones that overexpressed TSP1 into the mammary fat pad of nude mice resulted in a dose-dependent inhibition of primary tumor size and an inhibition of spontaneous pulmonary metastases, which occurred in 21-30% of THBS-1 transfectants compared to 44-49% of controls (P = 0.007). An additional clone was identified that overexpressed a COOH-terminally truncated TSP1. This clone produced larger primary tumors and an increase in the occurrence of metastases relative to control transfectants, suggesting the participation of a previously understudied region of TSP1 in the regulation of tumor progression. The THBS-1 and control transfectants did not exhibit significant differences in growth, colonization, or motility in vitro. However, a relative reduction in capillary densities in primary tumors formed by the wild-type THBS-1 transfectants was observed, suggestive of an angiostatic effect. The data indicate that tumor cell production of TSP1 can exert a significant inhibitory effect on tumor progression in the MDA-MB-435 breast carcinoma cell line, which may be attributable in part to a reduction in angiogenesis.