title: Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes.
abstract: Toll-like receptors (TLRs) are pattern recognition receptors mainly expressed by cells of the immune system but also by epithelial tumor cells. Little is known about expression patterns of TLR genes in breast tumors, and their clinical significance is unclear. The aim of our study was to investigate expression of TLRs pathway components in pre-invasive breast lesions and invasive breast carcinomas (IBCs). We used RT-PCR assays to quantify mRNA levels of the 10 TLR genes and genes involved in TLR pathways in 350 breast tumors from patients with known clinical/pathological status and long-term outcome. Sets of 158 breast samples were also analyzed by immunochemistry including; 40 early noninvasive breast lesions, 38 IBCs and 80 triple negative carcinomas subtype (TNCs). We identified TLR9 as the major TLR gene family member upregulated in breast tumors and more particularly in TNCs. Immunohistochemical studies demonstrated that TLR9 protein was expressed in tumor epithelial and stromal cells of the TLR9 mRNA-overexpressing tumors. TLR9 overexpression appears very early during breast carcinogenesis. High TLR9 levels were associated with favorable outcome in the TNC sub-group. TLR9 overexpression was associated with alterations of down-stream components of the TLR9 signaling pathway, epithelio-mesenchymal transition (EMT) induction and EGFR pathway deregulation. TNCs with TLR9 overexpression were significantly correlated with development of a fibrous and inflammatory microenvironment with variable status of nuclear phosphoSTAT3. Our results suggest that TLR9 could play a role in TNC carcinogenesis and could be useful as predictive biomarker and therapeutic target.
authors.affiliation: Unit of Pharmacogenomics, Curie Institute, 26 rue d'Ulm, F-75248, Paris Cedex 05, France. didier.meseure@curie.fr.|Platform of Investigative Pathology, Curie Institute, Paris, France. didier.meseure@curie.fr.|Department of Biopathology, Curie Institute, Paris, France. didier.meseure@curie.fr.
authors.forename: Didier
authors.initials: D
authors.lastname: Meseure
authors.affiliation: Unit of Pharmacogenomics, Curie Institute, 26 rue d'Ulm, F-75248, Paris Cedex 05, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vacher
authors.affiliation: Platform of Investigative Pathology, Curie Institute, Paris, France.
authors.forename: Kinan
authors.initials: K
authors.lastname: Drak Alsibai
authors.affiliation: Department of Biopathology, Curie Institute, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Trassard
authors.affiliation: Platform of Investigative Pathology, Curie Institute, Paris, France.
authors.forename: André
authors.initials: A
authors.lastname: Nicolas
authors.affiliation: Department of Biopathology, Curie Institute, Paris, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Leclere
authors.affiliation: Unit of Pharmacogenomics, Curie Institute, 26 rue d'Ulm, F-75248, Paris Cedex 05, France.|Department of Medical Oncology, Curie Institute, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Lerebours
authors.affiliation: Department of Biopathology, Curie Institute, Paris, France.
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Guinebretiere
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
authors.affiliation: Unit of Pharmacogenomics, Curie Institute, 26 rue d'Ulm, F-75248, Paris Cedex 05, France.
authors.forename: Rosette
authors.initials: R
authors.lastname: Lidereau
authors.affiliation: Unit of Pharmacogenomics, Curie Institute, 26 rue d'Ulm, F-75248, Paris Cedex 05, France.|EA 7331, University of Paris Descartes, Paris, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bieche
keywords: Breast cancer subtypes; EMT; Toll-like receptor 9; Tumor microenvironment signaling pathways