Direct activation of oestrogen receptor-alpha by interleukin-6 in primary cultures of breast cancer epithelial cells.
Interleukin 6 (IL-6) is secreted by breast tumours and shows synergistic activity with 17beta-oestradiol (E2), leading to increases in reductive 17beta-hydroxysteroid dehydrogenase activity in breast cancer epithelial cells. However, the mechanisms involved are poorly understood. Using short-term epithelial cultures established from primary breast tumours, we have examined whether IL-6 could directly affect transcriptional activity of oestrogen reception alpha (ERalpha). Tumour epithelial cultures were established from 15 breast tumours, grown to 70% confluence and transiently transfected with a plasmid reporter containing the vitellogenin oestrogen response element and the luciferase coding sequence (ERE-TK-LUC). Following transfection, cells were incubated with E2, IL-6, the pure anti-oestrogen ZM 182780 or combinations of these substances for 48 h. Luciferase activity was then measured in cell lysates. E2 caused a dose-dependent increase in luciferase expression, causing a maximum threefold stimulation at 100 pM. In the presence of IL-6, transcriptional activity was increased by up to 2.5-fold in ERalpha+ cultures (11/15). In combination with E2, synergistic effects were observed with increases in luciferase activity of up to sixfold over controls. This effect could be blocked by treatment with ZM 182780. Pre-incubation of cells with an antibody directed against the signalling component of IL-6, gp130, was ineffective in blocking the E2 response. This antibody reduced, but did not completely block the effect of IL-6 either alone or in combination with E2, suggesting cross-talk between the two signalling pathways. In conclusion, these results provide evidence for direct transcriptional activation of ERalpha by IL-6.
Speirs
V
V
Department of Medicine, University of Hull, UK.
Kerin
M J
MJ
Walton
D S
DS
Newton
C J
CJ
Desai
S B
SB
Atkin
S L
SL
D001943:Breast Neoplasms / Q000473:pathology*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D020239:Receptor Cross-Talk; D011959:Receptors, Estradiol / Q000096:biosynthesis*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D015850:Interleukin-6; D011959:Receptors, Estradiol