Phytoestrogen-mediated inhibition of proliferation of the human T47D breast cancer cells depends on the ER alpha/ER beta ratio

This Study investigates the importance of the intracellular ratio of the two estrogen receptors ER alpha and ER beta for the ultimate potential of the phytoestrogens genistein and quercetin to stimulate or inhibit cancer cell proliferation. This is of importance because (i) ER beta has been postulated to play a role in modulating ER alpha-mediated cell proliferation, (ii) genistein and quercetin may be agonists for both receptor types and (iii) the ratio of ER alpha to ER is known to vary between tissues. Using human osteosarcoma (U2OS) ER alpha or ER beta reporter cells it was shown that compared to estradiol (E2), genistein and quercetin have not only a relatively greater preference for ER beta but also a higher maximal potential for activating ER beta-mediated gene expression. Using the human T47D breast cancer cell line with tetracycline-dependent ER beta expression (T47D-ER beta), the effect of a varying intracellular ER alpha/ER beta ratio on E2- or pythoestrogen-induced cell proliferation was characterised. E2-induced proliferation of cells in which ER beta expression was inhibited was similar to that of the T47D wild type cells, whereas this E2-induced cell proliferation was no longer observed when ER beta expression was increased. With increased expression of ER beta the phytoestrogen-induced cell proliferation was also reduced. These results point at the importance of the cellular ER alpha/ER beta ratio for the ultimate effect of(phyto)estrogens on cell proliferation. (C) 2008 Elsevier Ltd. All rights reserved