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 spread of breast cancer. In the present study we examined the effects of antiestrogens [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-negative 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 plasmin inhibitor, produced a 50-60% reduction in the degradation of labeled substrate, in the solid phase assay, using culture medium from both cell lines, thus indicating that most of the proteolysis observed was due to uPA-mediated plasmin generation from plasminogen. In the absence of plasminogen, the enzyme activity was not detected in either the 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 inhibition (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 levels. 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 that ICI is the most potent inhibitor of enzyme activity in ER-positive MCF cells.
Abidi
S M
SM
Department of Pharmacology and Toxicology, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City 73190, USA.
Howard
E W
EW
Dmytryk
J J
JJ
Pento
J T
JT
D001943:Breast Neoplasms / Q000201:enzymology*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D000077267:Fulvestrant; D006801:Humans; D009361:Neoplasm Invasiveness; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D004965:Estrogen Antagonists; D005353:Fibronectins; D013629:Tamoxifen; C075421:1,1-dichloro-2,3-diphenyl-2-(4-methoxyphenyl)cyclopropane; D000077267:Fulvestrant; D004958:Estradiol; D014568:Urokinase-Type Plasminogen Activator