title: RAGE mediates S100A7-induced breast cancer growth and metastasis by modulating the tumor microenvironment.
abstract: RAGE is a multifunctional receptor implicated in diverse processes including inflammation and cancer. In this study, we report that RAGE expression is upregulated widely in aggressive triple-negative breast cancer (TNBC) cells, both in primary tumors and in lymph node metastases. In evaluating the functional contributions of RAGE in breast cancer, we found that RAGE-deficient mice displayed a reduced propensity for breast tumor growth. In an established model of lung metastasis, systemic blockade by injection of a RAGE neutralizing antibody inhibited metastasis development. Mechanistic investigations revealed that RAGE bound to the proinflammatory ligand S100A7 and mediated its ability to activate ERK, NF-κB, and cell migration. In an S100A7 transgenic mouse model of breast cancer (mS100a7a15 mice), administration of either RAGE neutralizing antibody or soluble RAGE was sufficient to inhibit tumor progression and metastasis. In this model, we found that RAGE/S100A7 conditioned the tumor microenvironment by driving the recruitment of MMP9-positive tumor-associated macrophages. Overall, our results highlight RAGE as a candidate biomarker for TNBCs, and they reveal a functional role for RAGE/S100A7 signaling in linking inflammation to aggressive breast cancer development.
authors.affiliation: Department of Pathology, The Ohio State Medical Center, Columbus, Ohio.
authors.forename: Mohd W
authors.initials: MW
authors.lastname: Nasser
authors.affiliation: Department of Pathology, The Ohio State Medical Center, Columbus, Ohio.
authors.forename: Nissar Ahmad
authors.initials: NA
authors.lastname: Wani
authors.affiliation: Department of Pathology, The Ohio State Medical Center, Columbus, Ohio.
authors.forename: Dinesh K
authors.initials: DK
authors.lastname: Ahirwar
authors.affiliation: Department of Pathology, The Ohio State Medical Center, Columbus, Ohio.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Powell
authors.affiliation: Department of Pathology, The Ohio State Medical Center, Columbus, Ohio.
authors.forename: Janani
authors.initials: J
authors.lastname: Ravi
authors.affiliation: Department of Pathology, The Ohio State Medical Center, Columbus, Ohio.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Elbaz
authors.affiliation: Department of Pathology, The Ohio State Medical Center, Columbus, Ohio.
authors.forename: Helong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Biomed Division, LEITAT Technological Center, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Padilla
authors.affiliation: Centre for Biostatics, The Ohio State Medical Center, Columbus, Ohio.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, The Ohio State Medical Center, Columbus, Ohio.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Shilo
authors.affiliation: Comprehensive Cancer Center, The Ohio State Medical Center, Columbus, Ohio.
authors.forename: Michael
authors.initials: M
authors.lastname: Ostrowski
authors.affiliation: Department of Pathology, The Ohio State Medical Center, Columbus, Ohio.
authors.forename: Charles
authors.initials: C
authors.lastname: Shapiro
authors.affiliation: Comprehensive Cancer Center, The Ohio State Medical Center, Columbus, Ohio. Department of Surgery, The Ohio State Medical Center, Columbus, Ohio.
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
authors.affiliation: Department of Pathology, The Ohio State Medical Center, Columbus, Ohio. Ramesh.Ganju@osumc.edu.
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ganju
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D002478:Cells, Cultured; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D011379:Prognosis; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology*; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins / Q000502:physiology*; D059016:Tumor Microenvironment
chemical_list: D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases