title: Expression of functional toll like receptor 4 in estrogen receptor/progesterone receptor-negative breast cancer.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Molecular Pathology, Department of Translational Medicine, Lund University, SUS Jan Waldenströmsgata 59, 20502, Malmö, Sweden. Meliha.Mehmeti@med.lu.se.
authors.forename: Meliha
authors.initials: M
authors.lastname: Mehmeti
authors.affiliation: Center for Molecular Pathology, Department of Translational Medicine, Lund University, SUS Jan Waldenströmsgata 59, 20502, Malmö, Sweden. Roni.Allaoui@med.lu.se.
authors.forename: Roni
authors.initials: R
authors.lastname: Allaoui
authors.affiliation: Center for Molecular Pathology, Department of Translational Medicine, Lund University, SUS Jan Waldenströmsgata 59, 20502, Malmö, Sweden. Caroline.Bergenfelz@med.lu.se.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bergenfelz
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. lao.saal@med.lu.se.
authors.forename: Lao H
authors.initials: LH
authors.lastname: Saal
authors.affiliation: Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA. ethier@musc.edu.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Ethier
authors.affiliation: Center for Molecular Pathology, Department of Translational Medicine, Lund University, SUS Jan Waldenströmsgata 59, 20502, Malmö, Sweden. Martin.Johansson@med.lu.se.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Johansson
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. Karin.Jirstrom@med.lu.se.
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.affiliation: Center for Molecular Pathology, Department of Translational Medicine, Lund University, SUS Jan Waldenströmsgata 59, 20502, Malmö, Sweden. Karin.Leandersson@med.lu.se.
authors.forename: Karin
authors.initials: K
authors.lastname: Leandersson
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics*; D011980:Receptors, Progesterone / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: D016328:NF-kappa B; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4