Two faces of the estrogen metabolite 2-methoxyestradiol in vitro and in vivo

Abstract

2-Methoxyestradiol (2-ME), an endogenous metabolite of 17β-estradiol (E2), interacts with estrogen receptors (ERs) and microtubules, however, 2-ME has a low affinity for ERs. Furthermore, 2.-ME has been identified as a potential novel antitumor agent, combining its anti.-proliferative effects on a variety of tumor cell types with its anti.-angiogenic action. Therefore, 2.-ME is of interest due to its potential anticancer therapeutic effects. In the current study, the estrogenic effect of 2.-ME on CaBP.-9k, ERá, and progesterone receptor (PR) mRNA levels in the absence and presence of E2 and progesterone (P4) in in vivo and in vitro models was examined. In GH3 cells, the mRNA level of CaBP.-9k was induced in the E2 treatment group (concentration, 10.-9 M), and the expression of CaBP.-9k was also upregulated in the 2.-ME.-treated group (concentration, 10.-7 M). Uterine lactoferrin (Ltf) mRNA expression was also increased in the 2.-ME group [dose, 40 mg/kg body weight (BW)], which was comparable to the response with E2 (dose, 40 μg/kg BW) observed in mice. As inhibitors of ER and PR activity, ICI 182,780 and mifepristone (RU486) were observed to reverse the E2 or 2.-ME mediated increase of CaBP.-9k and Ltf mRNA expression. In addition, it was found that 2.-ME significantly decreased the levels of ERá and increased PR transcripts. Consistent with the in vitro results, the mRNA levels revealed decreased ERá and increased PR in in vivo treatment of E2 and 2.-ME. These findings demonstrate that the expression of estrogenic markers, CaBP.-9k and Ltf, is regulated by 2.-ME in in vitro and in vivo models, therefore, estrogenic activities of 2-ME may be increased in females during the estrous cycle via the ER and/or PR-mediated signaling pathway.