Direct activation of oestrogen receptor- α by interleukin-6 in primary cultures of breast cancer epithelial cells

Abstract

Interleukin 6 (IL-6) is secreted by breast tumours and shows synergistic activity with 17β-oestradiol (E2), leading to increases in reductive 17β-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 α (ERα). 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 p M. In the presence of IL-6, transcriptional activity was increased by up to 2.5-fold in ERα+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 ERα by IL-6. © 2000 Cancer Research Campaign

Oncostatin M suppresses oestrogen receptor-α expression and is associated with poor outcome in human breast cancer

“…Nevertheless, little is known regarding the direct effects of cytokines on ER expression. IL6 and tumour necrosis factor alpha (TNF-a) are reported to suppress ER expression (Bhat-Nakshatri et al 2004, D'Anello et al 2010, but other studies have presented conflicting results (Speirs et al 2000, Rubio et al 2006. In our hands, IL6 had little effect on ER expression (Fig.…”

Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients

“…Although IL-6 expression in early-stage breast carcinomas has been correlated with low grade, oestrogen receptor status and good prognosis (Fontanini et al, 1999;Karczewska et al, 2000), several studies have shown that IL-6 may contribute to disease progression, particularly in advanced breast cancer patients. Indeed, IL-6 can modulate steroid hormone responsiveness by increasing aromatase activity and oestradiol 17 beta-hydroxysteroid dehydrogenase activity in malignant tissue and by activating oestrogen receptor-a (Duncan et al, 1994;Singh et al, 1999;Speirs et al, 2000). IL-6 may promote cell migration by activating the mitogen-dependent protein kinase pathway, and increase chemotherapeutic resistance by inhibiting the activation of proteases involved in apoptosis (Lotem and Sachs, 1997;Badache and Hynes, 2001).…”

Inhibition of gp130 Signaling in Breast Cancer Blocks Constitutive Activation of Stat3 and Inhibits in Vivo Malignancy

“…IL-6 and oncostatin M induce disruption of cell adhesion and increased motility of breast cancer cells (15,16). IL-6 has also been reported to activate the estrogen receptor in breast cancer cells (17).…”