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

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.

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.

VEGF secretion and kinase signaling in response to IL-1β and 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-1β increased 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.

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.