AGONIST ACTIVITY OF ANTIESTROGEN-RECEPTOR COMPLEXES TO REGULATE UROKINASE PLASMINOGEN-ACTIVATOR (UPA) AND PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-I (PAI-1) ENDOGENOUS GENE-EXPRESSION IN BREAST-CANCER CELLS

We have shown that 4-hydroxytamoxifen (4-OHT) has estrogen-like effect s on induction of TGF alpha mRNA in estrogen receptor (ER)-negative MD A-MB-231 human breast cancer cells, transfected with either wildtype ( S30 cells) or a codon 351(asp-->tyr) mutant ER (BC-2 cells). The mutan t receptor used to produce the stable transfectants was identified in a tamoxifen-stimulated human breast tumor. We have also demonstrated t hat raloxifene exhibits a gene-specific estrogen-like effect with muta nt ER (BC-2 cells) but not with wildtype ER (S30 cells) (Levenson, A.S ., Catherino, W.H. and Jordan, V.C. (1997) Estrogenic activity is incr eased for an antiestrogen by a natural mutation of the estrogen recept or. J. Steroid Biochem. Mol. Biol., 60, 261-268). We now describe the regulation of urokinase plasminogen activator (uPA) and plasminogen ac tivator inhibitor type 1 (PAI-1) endogenous gene expression by estradi ol (E2) and different antiestrogens in BC-2 cells. Northern blot analy ses revealed that 4-OHT and raloxifene have concentration-dependent ag onistic (E2-like) effects on the regulation of these genes. In contras t, the pure antiestrogen ICI 182780 alone had no effect but could bloc k the action of E2, 4-OHT and raloxifene. The E2-like effects of non-s teroidal antiestrogens in this model system cannot be explained by the mutation in the ER alone because 4-OHT acts as an agonist with wildty pe receptor as well. We propose that the clear cut biological expressi on of estrogen-like qualities with different antiestrogens will in the future serve as an important model to dissect the signal transduction pathway. (C) 1998 Elsevier Science Ireland Ltd.