THE INFLUENCE OF ANTIESTROGENS ON THE RELEASE OF PLASMINOGEN-ACTIVATOR (UPA) BY MDA-MB-231 AND MCF-7 BREAST-CANCER CELLS

Plasminogen activators are known to be involved in the metastatic spre ad of breast cancer. In the present study we examined the effects of a ntiestrogens [Analog II (1,1-dichloro-cis-2,3-diphenyl cyclopropane) ( AII), ICI-182,780 (ICI) and tamoxifen (TAM)], on the in vitro release of uPA from estrogen receptor (ER)-positive MCF-7 (MCF) and ER-negativ e MDA-MB-231 (MDA) human breast cancer cell Lines. Using a solid-phase radioassay, uPA activity was found to be higher in the culture medium from MDA cells compared to MCF cells. Aminocaproic acid, a specific p lasmin inhibitor, produced a 50-60% reduction in the degradation of la beled substrate, in the solid phase assay, using culture medium from b oth cell lines, thus indicating that most of the proteolysis observed was due to uPA-mediated plasmin generation from plasminogen. In the ab sence of plasminogen, the enzyme activity was not detected in either t he quantitative assay or by zymography. In MDA cells, uPA release was not altered by any of the antiestrogens used alone or in the presence of estradiol. In contrast, in MCF cells, ICI alone produced maximal in hibition (40%) of enzyme release, while estradiol alone produced a 120 % increase in enzyme activity. When co-administered with estradiol, in MCF cultures, each antiestrogen reduced enzyme activity to control le vels. Substrate gel zymography revealed that the urokinase-type PA is the predominant form of PA released by both cell lines. Comparison of the activity of all three antiestrogens used in this study indicates t hat ICI is the most potent inhibitor of enzyme activity in ER-positive MCF cells. (C) 1998 Lippincott-Raven Publishers.