Evidence for transcriptional activation of ERalpha by IL-1beta in breast cancer cells.
Estrogen is mitogenic in breast cancer where IL-1beta also fulfils a role. The aim of this study was to determine any relationship between IL-1beta and ERalpha in breast cancer. By RT-PCR, 26/77 tumours expressed IL-1beta, and 57/77 expressed ERalpha. Samples which were IL-1beta positive were categorised against those which expressed ERalpha. Of the 26 tumours which expressed IL-1beta, all were ERalpha positive. We next examined whether IL-1beta could directly activate ERalpha. MCF-7 cells stably transfected with a plasmid reporter (ERE-TK-LUC) were incubated with either 17beta-estradiol (E2, 10-9-10-13 M), IL-1beta (10 ng/ml), the pure antiestrogen ZM 182780 (10 nM) or combinations of these substances. Transcriptional activity was measured in cell lysates 48 h later. E2 caused a dose-dependent increase in luciferase activity. With IL-1beta, transcriptional activity was typically half of the E2 response. To determine the role of the IL-1 receptor, parallel cultures were incubated with IL-1 receptor antagonist. This reduced, but did not completely block the effect of IL-1beta, suggesting that IL-1beta was affecting transcriptional activity via another pathway. Confirmation that the effect was via ERalpha was verified using the pure antiestrogen, ZM 182370, which completely abrogated the effects of E2, when added alone or in combination with IL-1beta. These results provide compelling evidence for direct transcriptional activation of ERalpha by IL-1beta. Interactions of these factors may thus modulate hormonal activity in human breast tumours.
Speirs
V
V
Medical Research Laboratory, Wolfson Building, University of Hull, Hull HU6 7RX, UK.
Kerin
M J
MJ
Newton
C J
CJ
Walton
D S
DS
Green
A R
AR
Desai
S B
SB
Atkin
S L
SL
D001943:Breast Neoplasms / Q000473:pathology / Q000503:physiopathology*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000494:pharmacology*; D008156:Luciferases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D007375:Interleukin-1; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D000077267:Fulvestrant; D004958:Estradiol; D008156:Luciferases