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

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