title: Low TLR9 expression defines an aggressive subtype of triple-negative breast cancer.
abstract: Toll-like receptor-9 (TLR9) is a DNA receptor widely expressed in cancers. Although synthetic TLR9 ligands induce cancer cell invasion in vitro, the role of TLR9 in cancer pathophysiology is unclear. We discovered that low tumor TLR9 expression is associated with significantly shortened disease-specific survival in patients with triple negative but not with ER+ breast cancers. A likely mechanism of this clinical finding involves differential responses to hypoxia. Our pre-clinical studies indicate that while TLR9 expression is hypoxia-regulated, low TLR9 expression has different effects on triple negative and ER+ breast cancer invasion in hypoxia. Hypoxia-induced invasion is augmented by TLR9 siRNA in triple negative, but not in ER+ breast cancer cells. This is possibly due to differential TLR9-regulated TIMP-3 expression, which remains detectable in ER+ cells but disappears from triple-negative TLR9 siRNA cells in hypoxia. Our results demonstrate a novel role for this innate immunity receptor in cancer biology and suggest that TLR9 expression may be a novel marker for triple-negative breast cancer patients who are at a high risk of relapse. Furthermore, these results suggest that interventions or events, which induce hypoxia or down-regulate TLR9 expression in triple-negative breast cancer cells may actually induce their spread.
authors: Department of Medicine, Division of Hematology-Oncology, University of Alabama at Birmingham, SHEL 514, 1825 University Blvd, Birmingham, AL 35294-3300, USA.
authors: Johanna
authors: J
authors: Tuomela
authors: Jouko
authors: J
authors: Sandholm
authors: Peeter
authors: P
authors: Karihtala
authors: Joanna
authors: J
authors: Ilvesaro
authors: Katri S
authors: KS
authors: Vuopala
authors: Joonas H
authors: JH
authors: Kauppila
authors: Saila
authors: S
authors: Kauppila
authors: Dongquan
authors: D
authors: Chen
authors: Christine
authors: C
authors: Pressey
authors: Pirkko
authors: P
authors: Härkönen
authors: Kevin W
authors: KW
authors: Harris
authors: David
authors: D
authors: Graves
authors: Päivi K
authors: PK
authors: Auvinen
authors: Ylermi
authors: Y
authors: Soini
authors: Arja
authors: A
authors: Jukkola-Vuorinen
authors: Katri S
authors: KS
authors: Selander
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden; D015854:Up-Regulation
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053505:Matrix Metalloproteinases, Secreted; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D019717:Tissue Inhibitor of Metalloproteinase-3; D051217:Toll-Like Receptor 9; C497442:HIF1A protein, human; C088390:TIMP3 protein, human; C495371:TLR9 protein, human; C508053:ERBB2 protein, human