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

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