Differential influence of antiestrogens on the in vitro release of gelatinases (type IV collagenases) by invasive and non-invasive breast cancer cells.
Matrix metalloproteinases (MMPs) play an important role in tumor cell invasion and cancer metastasis. Accordingly, a higher level of these enzymes has been associated with the invasive phenotype. In the present study the effect of the antiestrogens, Analog II (AII), ICI-182,780 (ICI), and tamoxifen (TAM), on the in vitro release of MMPs, particularly gelatinases A and B by the MDA-MB-231 (MDA) and MCF-7 (MCF) human breast cancer cell lines was investigated using a solid-phase radioassay and substrate gel zymography. Quantitatively, the enzyme activity was found to be higher in the incubation medium from estrogen receptor (ER)-negative and more metastatic MDA cells compared to ER-positive and less metastatic MCF cells. Tissue inhibitor of metalloproteinases-1 (TIMP-1) reduced the enzyme activity in media from both MDA (56.36%) and MCF (71.03%) cells. Differential antiestrogen effects on the two cell lines were observed following 4 days of treatment of cells at a concentration of 10(-6)M. The enzyme activity from MDA cells was not influenced by treatment with any of the antiestrogens, whereas, in MCF cells, ICI produced the greatest enzyme inhibition (47.93%), followed by AII (36.51%) and TAM (24.05%). Concurrent treatment of MCF cells with 17-beta-estradiol (10(-9)M) partially reversed the AII- and TAM-induced but did not alter ICI-induced inhibition of enzyme activity. Substrate gel zymography revealed that among the MMPs, the MDA cells released predominantly progelatinase A (72 kDa) along with minor bands of activated forms, 62 kDa and 59 kDa, whereas progelatinase B (92 kDa) was detected predominantly in the medium from MCF cells. Comparison of the overall antiestrogen effect indicates that ICI is the most potent inhibitor of enzyme activity in ER-positive MCF cells and that antiestrogen treatment may limit the metastatic potential of ER-positive breast cancer.
Abbas 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
D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D017364:Collagenases / Q000187:drug effects / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D000077267:Fulvestrant; D018093:Gelatinases / Q000187:drug effects / Q000378:metabolism*; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000187:drug effects / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011480:Protease Inhibitors / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D006023:Glycoproteins; D011480:Protease Inhibitors; D011960:Receptors, Estrogen; D019714:Tissue Inhibitor of Metalloproteinases; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; C035174:tamoxifen analog II; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9