Influence of cellular ER alpha/ER beta ratio on the ER alpha-agonist induced proliferation of human T47D breast cancer cells

Breast cancer cells show overexpression of estrogen receptor (ER) alpha relative to ER beta compared to normal breast tissues. This observation has lead to the hypothesis that ER beta may modulate the proliferative effect of ER alpha. This study investigated how variable cellular expression ratios of the ER alpha and ER beta modulate the effects on cell proliferation induced by ER alpha or ER beta agonists, respectively. Using human osteosarcoma (U2OS) ER alpha or ER beta reporter cells, propyl-pyrazole-triol (PPT) was shown to be a selective ER alpha and diarylpropionitrile (DPN) a preferential ER beta modulator. The effects of these selective estrogen receptor modulators (SERMs) and of the model compound E2 on the proliferation of T47D human breast cancer cells with tetracycline-dependent expression of ER beta (T47D-ER beta) were characterized. E2-induced cell 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 in the T47D-ER beta cells was increased. In the T47D-ER beta cell line, DPN also appeared to be able to suppress cell proliferation when levels of ER beta expression were high. In the T47D-ER beta cell line, PPT was unable to suppress cell proliferation at all ratios of ER alpha/ER beta expression, reflecting its ability to activate only ER alpha and not ER beta. It is concluded that effects of estrogen-like compounds on cell proliferation are dependent on the actual ER alpha/ER beta expression levels in these cells or tissues and the potential of the estrogen agonists to activate ER alpha and/or ER beta