Expression of thrombospondin-1 (TSP-1), a large
extracellular matrix protein, has been associated with modulation of angiogenesis and
tumor growth. Both pro and antiangiogenic properties of
TSP-1 have been described, and the role of
TSP-1 expression in the growth and progression of human
breast cancer is not clear. Because
estrogens cause progression of many breast
cancers, and
estradiol (E2) downregulates a
TSP-1 receptor, we examined whether
TSP-1 is regulated by
estrogen and involved in
tumor progression. E2 induced
TSP-1 expression in T47-D and MCF-7
breast cancer cells in vitro within 3 to 6 hr; the induction was blocked by the anti-
estrogen ICI 182,780, indicating that
estrogen receptors (ER) are necessary for this effect. Furthermore, E2 caused the production of
TSP-1 protein from
tumor cells in an ER-alpha-dependent manner. The E2-mediated
TSP-1 RNA induction was dose-dependent and blocked by
actinomycin D, indicating that the response to E2 was at least partly transcriptional. Transfection studies with deletion constructs of the
TSP-1 promoter identified an
estrogen-responsive region in the human
TSP-1 promoter, located between -2,200 and -1,792 bp upstream of the transcription start site. An antibody against
TSP-1 restricted the proliferation of E2-dependent MCF-7 cells in vitro and in vivo. A panel of
breast cancer cells proliferated in the presence of low concentrations of exogenous
TSP-1, whereas higher concentrations inhibited proliferation. A real-time PCR analysis showed that E2 also induced
TSP-1 mRNA in the normal mammary glands of immature ovariectomized mice in an ER-dependent manner. In summary, we report the novel observation that
TSP-1 production is directly controlled by
estrogens in ER-positive
breast cancer cells, and the released
protein has pro-growth regulatory functions. Consequently, we propose that
TSP-1 could be a therapeutic target for anti-
tumor therapy in early-stage
tumors. (c) 2009 UICC.