Expression of functional toll like receptor 4 in estrogen receptor/progesterone receptor-negative breast cancer

• DOI: 10.1186/s13058-015-0640-x
• Publication Date: 2015-09-21T19:55:04Z
• Authors: Meliha Mehmeti; Roni Allaoui; Caroline Bergenfelz; Lao H. Saal; Stephen P. Ethier; Martin E. Johansson; Karin Jirström; Karin Leandersson
• Keywords: Medicine(all); 0303 health sciences; NF-kappa B; Gene Expression; Breast Neoplasms; Toll-Like Receptor 2; 3. Good health; Toll-Like Receptor 4; 03 medical and health sciences; Receptors, Estrogen; Cell Line, Tumor; MCF-7 Cells; Humans; Female; Receptors, Progesterone; Research Article; Signal Transduction

Toll-like receptors (TLRs) are a family of pattern recognition receptors that are expressed on cells of the innate immune system. The ligands can be pathogen derived (pathogen associated molecular patterns; PAMPs) or endogenous (damage associated molecular patterns; DAMPs) that when bound induces activation of nuclear factor kappa B (NF-κB) and transcription of pro-inflammatory genes. TLRs have also been discovered in various malignant cell types, but with unknown function.In this study we performed a detailed analysis of TLR and co-receptor expression pattern and function in breast cancer. Expression patterns were examined using real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) on three estrogen receptor-positive (ER(+)) and four estrogen receptor/progesterone receptor-negative (ER(-)/PR(-); ER/PR-negative) breast cancer cell lines, and a breast cancer cohort consisting of 144 primary breast cancer samples. The function was investigated using in vitro assays comprising PAMP/DAMP-stimulation, downstream signaling and TLR-silencing experiments.We found that TLR4 was expressed in a biologically active form and responded to both PAMPs and DAMPs primarily in ER/PR-negative breast cancers. Stimulation of TLR2/4 in vitro induced expression of pro-inflammatory genes and a gene expression analysis of primary breast cancers showed a strong correlation between TLR4 expression and expression of pro-inflammatory mediators. In line with this, TLR4 protein expression correlated with a decreased survival.These findings suggest that TLR4 is expressed in a functional form in ER/PR-negative breast cancers. Studies regarding TLR4-antagonist therapies should be focusing on ER/PR-negative breast cancer particularly.