title: S100A9 expressed in ER(-)PgR(-) breast cancers induces inflammatory cytokines and is associated with an impaired overall survival.
abstract: BACKGROUND
  Breast cancer is the most common cancer form among women today. Depending on hormone receptor status, breast cancers are divided into different subtypes with vastly varying prognosis. S100A9 is a calcium-binding protein that is associated with inflammation and expressed not only in myeloid cells but also in some tumours. The role for S100A9 in the malignant cells is not well characterised; however, previous studies have shown that the protein could have important immune-modulating properties.
  
  
  METHODS
  Using a human breast cancer cohort consisting of 144 tumour samples and in vitro analysis of human breast cancer cell lines, we investigated the expression and function of S100A9 in human breast cancer.
  
  
  RESULTS
  We show that S100A9 expression in breast cancer correlated with the ER(-)PgR(-) breast tumour subtype (P<0.001) and with Ki67 (P=0.024) and was expressed both in the malignant cells and in the tumour-infiltrating anti-inflammatory CD163(+) myeloid cells (P<0.001). Stromal expression of S100A9 also correlated to nodal stage, tumour size and Her2 positivity. Within the ER(-)PgR(-) subgroup, all Her2(+) and EGFR(+) tumours expressed S100A9 in the cytoplasm. Both cytoplasmic staining in the malignant cells as well as stromal S100A9 expression in myeloid cells correlated with a decreased overall survival in breast cancer patients. Furthermore, rS100A9 homodimers induced expression of pro-inflammatory cytokines (IL-6, IL-8 and IL-1β) in a TLR4- and EGFR-dependent manner in human breast cancer cells in vitro.
  
  
  CONCLUSIONS
  We suggest that S100A9 could be viewed as a novel therapeutic target for patients with ER(-)PgR(-) breast cancers.
authors.affiliation: Center for Molecular Pathology, Department of Translational Medicine, Lund University, Lund, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bergenfelz
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gaber
authors.affiliation: Center for Molecular Pathology, Department of Translational Medicine, Lund University, Lund, Sweden.
authors.forename: Roni
authors.initials: R
authors.lastname: Allaoui
authors.affiliation: Center for Molecular Pathology, Department of Translational Medicine, Lund University, Lund, Sweden.
authors.forename: Meliha
authors.initials: M
authors.lastname: Mehmeti
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.affiliation: Division of Immunology, Department of Experimental Medicine, Lund University, Lund, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Leanderson
authors.affiliation: Center for Molecular Pathology, Department of Translational Medicine, Lund University, Lund, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Leandersson
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D040502:Calgranulin B / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D061986:MCF-7 Cells; D022423:Myeloid Cells / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D040502:Calgranulin B; D016207:Cytokines; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011956:Receptors, Cell Surface; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D051197:Toll-Like Receptor 4; D000098902:CD163 Antigen; C495345:TLR4 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human