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