Role of estradiol receptor-alpha in differential expression of 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible genes in the RL95-2 and KLE human endometrial cancer cell lines

The present study was conducted to investigate the mechanism of the respons e of human uterine endometrial carcinoma cells, RL95-2 and KLE, to 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD), RL95-2 cells were highly responsive to TCDD in terms of cytochrome P4501A1 (CYP1A1), cytochrome P4501B1 (CYP1B1), and plasminogen activator inhibitor-2 (PAI-2), whereas KLE cells showed lit tle stimulatory effects only at high doses. Neither showed any growth inhib ition upon exposure to TCDD. KLE cells expressed higher levels of aryl hydr ocarbon receptor (AhR) than RL95-2 and gel mobility shift assay also identi fied more liganded AhR-ARNT complex bound to xenobiotic response elements ( XRE), TCDD had no down-regulatory effects on the expression of either AhR o r the estradiol receptor (ER). Though both cell types expressed ER-alpha al most equally, immunofluorescence demonstrated a defect in its nuclear trans location in KLE cells where ER-alpha was mainly cytoplasmic and estradiol-1 7 beta (E-2) was unable to translocate it to the nucleus. However, both cel ls were nonresponsive to E-2 in terms of transcriptional activation and tra nsient expression of normal ER-alpha restored the E-2 responsiveness. Trans ient expression of ER-alpha in KLE cells also restored its responsiveness t o TCDD on transcriptional activation. Collectively, these results indicate that ER-alpha acts as a positive modulator in regulation of the TCDD-induci ble genes. (C) 1999 Academic Press.