17 beta-estradiol- and 4-hydroxytamoxifen-induced transactivation in breast, endometrial and liver cancer cells is dependent on ER-subtype, cell and promoter context.
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The pattern of transcriptional activation by 17beta-estradiol (E2) and 4-hydroxytamoxifen (4-OHT) was determined in ZR-75 and MDA-MB-231 breast, ECC1 and HEC1A endometrial and HepG2 liver cancer cell lines cotransfected with E2-responsive constructs and wild-type estrogen receptor alpha (ER alpha) or ER beta (ER beta) or variant forms of ER alpha expressing activation function 1, AF1 (ER alpha-AF1) or activation function 2, AF2 (ER alpha-AF2). The E2-responsive constructs contained promoter inserts from the human complement C3 (pC3), human cathepsin D (pCD) and rat creatine kinase B (pCKB) genes. Minimal ER beta-dependent transactivation (<2.5-fold induction) was observed for E2 only in ECC1 and MDA-MB-231 cells transfected with pCKB or pC3, whereas 4-OHT was inactive as an ER beta agonist for all promoters in the four cell lines. The ER alpha agonist and/or antagonist activities for E2 and 4-OHT were highly variable and the transactivation was dependent on ER subtype, ER alpha variant expressed, gene promoter, and cell context. For example, E2 did not activate pCD in HepG2 cells transfected with wild-type or variant ER alpha, whereas E2 activated reporter gene activity in the four endometrial and breast cancer cell lines transfected with ER alpha and pCD, pCKB or pC3. Hormone activation of these constructs by ER alpha-AF1 or ER alpha-AF2 was highly variable among the different cell lines and even in the same cell line transfected with the three E2-responsive constructs. Similar variability was observed for 4-OHT. For example, 4-OHT activates pC3 in HepG2 cells transfected with ER alpha or ER alpha-AF1, and pCKB in HEC1A cells. However, AF1-dependent activation by 4-OHT is not observed for pCKB in ECC1 cells or for pC3 and pCD in HEC1A or ECC1 endometrial cancer cells. The results of this study suggest that transcriptional activation by E2 and 4-OHT induces recruitment of different transcription factor complexes that are dependent on the cell type and also the gene promoter.
