Interplay of Interleukin-1β and Curcumin on VEGF Expression in Breast Cancer CellsOA

Objectives:Vascular endothelial growth factor(VEGF)regulates tumor vascularization in response to hypoxia and inflammatory signals.The polyphenol curcumin is supposed to interfere with inflammation-induced VEGF secretion and might therefore support anti-VEGF-based treatments.We aimed to investigate the interaction between curcumin and the inflammatory cytokine Interleukin-1β(IL-1β)for VEGF secretion in breast cancer cell lines representing major breast cancer subtypes.Methods:VEGF in cell cultures was detected by Western blot and enzyme-linked immunosorbent assay(ELISA).Kinase phosphorylation was investigated by Western blotting.Gene expressions were analyzed by correlation tests.VEGF was evaluated in a retrospective breast cancer cohort by immunohistochemistry.Survival analysis was performed by the Kaplan-Meier algorithm.Results:VEGF secretion and kinase signaling in response to IL-1βand curcumin varied significantly for the cell lines MCF-7(Luminal A),SK-BR-3(HER2/neu+),MDA-MB-231,and UACC-3199(triple negative breast cancer).All cell lines increased VEGF secretion under hypoxia,but IL-1βincreased VEGF secretion only in MCF-7 cells.Curcumin inhibited VEGF secretion in MDA-MB-231,but increased it in MCF-7 and UACC-3199 cells.Curcumin induced phosphorylation of extracellular signal-regulated kinase(ERK)and p38-mitogen-activated protein kinase(p38-MAPK).However,inhibitor experiments demonstrated that ERK was more important for VEGF secretion.In gene expression data from the METABRIC study,no clear correlation of hypoxia-induced factor(HIF1A),IL-1β,and VEGF mRNA expression was observed;however,a suggested crosstalk of hypoxia and inflammatory pathways was observed.Conclusion:These dissimilar responses of breast cancer cell lines suggest that therapy efficiency with anti-VEGF,anti-IL-1β,or curcumin will also vary within breast cancers.