Toll-Iike Receptor-3 Activation Enhances Malignant Traits In Human Breast Cancer Cells Through Hypoxia-Inducible Factor-1 Alpha

Background/Aim: Hypoxia-inducible factor 1 (HIF1) inhibitors have been proposed as therapeutic agents for several tumor types. HIF1 alpha is induced by hypoxia and by pathogens in normoxia through toll-like receptors (TLRs). The TLR3 activator polyinosinic:polycytidylic acid [poly(I:C)] induces apoptosis in various types of cancer but not in the most aggressive breast cancer cell lines. We hypothesized that the failure of TLR3 stimulation to induce apoptosis in these cells might be due to an elevated HIF1 alpha level and this link might be exploited. Materials and Methods: Poly(I:C)-induced signaling pathway and expression of HIF1 alpha and HIF1 alpha targets were studied in MDA MB-231 and MCF-7 breast cancer cell lines by western blot. Flow cytometry was used for apoptotic responses and vasculogenic mimicry as bioassay. Results: Poly(I:C) increased expression of HIF1a and its targets BCL2 apoptosis regulator and c-MYC. Moreover, using pharmacological or genetic HIF1 inhibition, reduction of poly(I:C)-induced expression of HIF1 alpha was paralleled by lowering of c-MYC and increased sensitivity to poly(I:C)-induced apoptosis, demonstrating the crucial role of this factor. We provide the first evidence in breast cancer cells that TLR3 stimulation induces HIF1-alpha-dependent vasculogenic mimicry. By using specific inhibitors, we identified a signaling cascade upstream of HIF1 alpha induction. Conclusion: Combined treatment with poly(I: C) and HIF1 inhibitors deserves consideration as an effective strategy in breast cancer therapy.