Regulation of thrombospondin-1 by natural and synthetic progestins in human breast cancer cells.

Our recent studies show that progestins induce vascular endothelial growth factor (VEGF) in breast cancer cells that express mutant p53 protein. Here, we show that natural and synthetic progestins also induce thrombospondin-1 (TSP-1) mRNA and protein in T47-D and BT-474 breast cancer cells. Antiprogestin RU-486 inhibits the induction of VEGF and TSP-1 by progestins, suggesting that this effect of progestin is mediated by the progesterone receptor (PR). Actinomycin-D, but not puromycin, also blocks progestin-dependent induction of TSP-1. A putative progestin-response element was identified in the human TSP-1 promoter, which is consistent with the hypothesis that a progestin-PR complex might directly regulate transcription of the TSP-1 gene in human cells. Conditioned medium from progestin-treated breast cancer cells stimulates endothelial cell proliferation in the absence though not in the presence of antibody to TSP-1, indicating that TSP-1 secreted by breast cancer cells could be pro-angiogenic. Since tumor cell-derived TSP-1 has the potential to promote angiogenesis in the tumor microenvironment, it could be a potential target for breast cancer therapy.