ESTROGENIC ACTIONS OF RU486 IN HORMONE-RESPONSIVE MCF-7 HUMAN BREAST-CANCER CELLS

Previously, we demonstrated that the progestin components (19-nortestosterone derivatives) in oral contraceptives are able to stimulate human breast cancer cell proliferation via an estrogen receptor (ER)-mediated mechanism. We now examine RU486, an antiprogestin, to determine whether it has estrogenic properties because it is also a 19-nortestosterone derivative. We found that RU486 stimulated the growth of MCF-7 human breast cancer cells at a concentration of 10(-6) M, which is similar to the pharmacological concentration (micromolar range) found in women taking RU486. The antiestrogens 4-hydroxytamoxifen and ICI 164,384 blocked RU486-induced cell proliferation. The estrogenic activity of RU486 is not due to impurities or aromatization to estrogenic metabolites. To determine whether the proliferative action of RU486 was mediated through the ER, cells were transfected with a chloramphenicol acetyltransferase reporter gene under the control of an estrogen response element derived from the Xenopus laevis vitellogenin 2A gene. We found that RU486 was able to induce chloramphenicol acetyltransferase activity at the concentrations that stimulated cell proliferation, and this induction was blocked by the addition of 4-hydroxytamoxifen and ICI 164,384. The estrogenic potential of RU486 to regulate ER target gene expression was also investigated. We found that, like 17beta-estradiol (E2), RU486 was able to alter the expression and synthesis of progesterone receptor. The level of progesterone receptor (145 and 186 fmol/mg cytosol protein, respectively) was increased significantly compared to the control value (3 fmol/mg cytosol protein) with the addition of 10(-6) M RU486 or 10(-10) M E2, as determined by an enzyme immunoassay. The levels of transforming growth factor-beta2 (TGFbeta2) and TGFbeta3 mRNA, but not TGFbeta1 mRNA, were decreased dramatically with the addition of 10(-6) M RU486. This is consistent with the effects of E2 on TGFbeta expression. Therefore, RU486 has estrogen-like activities in its regulation of ER target gene expression. These results demonstrate that RU486 is a weak estrogen in human breast cancer cells and suggest that the RU486-induced cell proliferation is mediated via ER. The novel finding that RU486 exhibits some estrogen-like activity may be important for the interpretation of its action at high dosages as an abortifacient and also if RU486 is going to be evaluated clinically, again at high doses, for the treatment of breast cancer.