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

J Steroid Biochem Mol Biol. 2004 Mar;88(3):265-75. doi: 10.1016/j.jsbmb.2003.12.003.


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 10nM of exogenous E(2), 2-MeO-E(2) at 750 nM to 2 microM concentrations exerted a similar antiproliferative effect. However, when the ER-positive cell lines were cultured in the absence of exogenous E(2), 2-MeO-E(2) at relatively low concentrations (10-750 nM) had a moderate mitogenic effect, with its apparent efficacy 75-80% of that of E(2). 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 2-Methoxyestradiol
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Division / drug effects*
  • Cell Line, Tumor
  • Estradiol / analogs & derivatives*
  • Estradiol / pharmacology*
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Humans
  • Mitogens / pharmacology*
  • Receptors, Estrogen / metabolism


  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Mitogens
  • Receptors, Estrogen
  • Estradiol
  • 2-Methoxyestradiol