Concentration-dependent mitogenic and antiproliferative actions of 2-methoxyestradiol in estrogen receptor-positive human breast cancer cells

We compared in this study the effects of 2-methoxyestradiol (2-MeO-E-2) on the growth of two estrogen receptor (ER)-negative human breast cancer cell lines (MDA-MB-231 and MDA-MB-435s) and two ER-positive human breast cancer cell lines (MCF-7 and T-47D). 2-MeO-E-2 exerted a concentration-dependent antiproliferative action in the ER-negative MDA-MB-231 and MDA-MB-435s cells. The presence or absence of exogenous 17beta-estradiol (E-2) in the culture medium did not affect the potency and efficacy of 2-MeO-E-2's antiproliferative action in these ER-negative cells. When the ER-positive MCF-7 and T-47D cells were cultured in a medium supplemented with 10 nM of exogenous E-2, 2-MeO-E-2 at 750 nM to 2 muM concentrations exerted a similar antiproliferative effect. However, when the ER-positive cell lines were cultured in the absence of exogenous El, 2-MeO-E-2 at relatively low concentrations (10-750nM) had a moderate mitogenic effect, with its apparent efficacy 75-80% of that of E2. This mitogenic effect of 2-MeO-E-2 was ER-mediated and largely attributable to 2-MeO-E-2's residual estrogenic activity on the basis of our following findings: (i) its effect was only manifested in the ER-positive cells but not in the ER-negative cells; (ii) its effect in the ER-positive cells was partially or fully abolished when exogenous E-2 was concomitantly present in the culture medium; (iii) 2-MeO-E-2 retained 1-2% of E-2's binding affinity for the human ERalpha and ERbeta, and its mitogenic effect was inhibited in a concentration-dependent manner by ICI-182,780, a pure ER antagonist; and (iv) its effect was not due to its metabolic conversion to 2-hydroxyestradiol. Our timely findings are of importance to the on-going clinical trials designed to evaluate 2-MeO-E-2's effectiveness for the treatment of different types (ER-positive or ER-negative) of human breast cancer. This knowledge will improve the design of clinical trials as well as the interpretation of clinical outcomes when 2-MeO-E-2 is used as a single agent therapy or as part of a combination therapy for human breast cancer. (C) 2004 Elsevier Ltd. All rights reserved.