The aim of this study was to analyze the transcriptional regulation of different ERs via alternative cis-elements. For this purpose we performed transient transfections with a luciferase reporter plasmid for estrogen-responsive elements (ERE) and AP-1 elements, and expression plasmids for ER-α, ER-β1 and ER-β2. Cells were left unstimulated or stimulated with E2, tamoxifen or raloxifen. We found that, in the breast cancer cell line SKBR3, ER-β1 lead to a significant inhibition of AP-1 activity by E2, whereas through ER-β2 E2 lead to a stimulation of transcriptional activity. Antiestrogens inhibited transcription through ER-β1 but did not exhibit an effect through ER-β2. When transfecting ER-β1 in SKBR3 cells the basal transcriptional activity increased, in contrast to the results obtained when transfecting the human osteosarcoma cell line U2OS with the same receptor. E2 in SKBR3 cells leads to a significant transcriptional inhibition, whereas this effect is not seen in U2OS cells. Also the antiestrogens tamoxifen and raloxifen exhibit in SKBR3 cells via the same receptor a transcriptional inhibition, but in contrast in U2OS cells they lead to a stimulation of transcription. In summary, splice variants of ER-β are able to regulate the actvity of the AP-1 complex differentially, indicating that the relative expression of these variants in a tumor could modulate its hormonal sensitvity.
Sponsored by DFG Ha 2404/2-1.