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

Abstract

IntroductionToll-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 patters; 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.MethodsIn 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.ResultsWe 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0640-x) contains supplementary material, which is available to authorized users.

Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

“…The current study adds to the previous knowledge by revealing a strong potentiating influence of S100A4, which is expressed at elevated levels in basal‐like/TNBC as also reported previously (Egeland et al ., 2017). Furthermore, TNBC shows elevated expression of TLR4 and RAGE receptors (Mehmeti et al ., 2015; Nasser et al ., 2015), which have been linked to S100A4‐trigged cytokine induction (Cerezo et al ., 2014; Haase‐Kohn et al ., 2011). …”

Increased Toll-Like Receptor-Myeloid Differentiation Factor 88 Expression at the Maternal-Fetal Interface Is Associated with Spontaneous Abortion

“…When damaged cells or tissues release DAMPs, they can be recognized by PRRs and trigger innate immunity, resulting in a "sterile" inflammatory response [37]. Importantly, TLRs are crucial PRRs for DAMPs [38]. This mechanism works via 2 scenarios: (1) by alerting the body to remove dead cells and cancer cells [38]; and (2) to excessively activate sterile inflammation with a potential to induce autoimmune disease [37].…”

“…Importantly, TLRs are crucial PRRs for DAMPs [38]. This mechanism works via 2 scenarios: (1) by alerting the body to remove dead cells and cancer cells [38]; and (2) to excessively activate sterile inflammation with a potential to induce autoimmune disease [37]. Pregnancy is the process of semi-allogeneic implantation, and apoptosis in the cells of the maternal-fetal interface occurs in many situations [39,40].…”

Toll-like receptors and breast cancer

“…TLR4 plays important roles in the migration of cancer cells [18]. TLR4 prompts human breast cancer cells invasiveness and leads to induction of pro-inflammatory and chemokine genes.…”