title: Activation of the FGFR-STAT3 pathway in breast cancer cells induces a hyaluronan-rich microenvironment that licenses tumor formation.
abstract: Aberrant activation of fibroblast growth factor receptors (FGFR) contributes to breast cancer growth, progression, and therapeutic resistance. Because of the complex nature of the FGF/FGFR axis, and the numerous effects of FGFR activation on tumor cells and the surrounding microenvironment, the specific mechanisms through which aberrant FGFR activity contributes to breast cancer are not completely understood. We show here that FGFR activation induces accumulation of hyaluronan within the extracellular matrix and that blocking hyaluronan synthesis decreases proliferation, migration, and therapeutic resistance. Furthermore, FGFR-mediated hyaluronan accumulation requires activation of the STAT3 pathway, which regulates expression of hyaluronan synthase 2 (HAS2) and subsequent hyaluronan synthesis. Using a novel in vivo model of FGFR-dependent tumor growth, we demonstrate that STAT3 inhibition decreases both FGFR-driven tumor growth and hyaluronan levels within the tumor. Finally, our results suggest that combinatorial therapies inhibiting both FGFR activity and hyaluronan synthesis is more effective than targeting either pathway alone and may be a relevant therapeutic approach for breast cancers associated with high levels of FGFR activity. In conclusion, these studies indicate a novel targetable mechanism through which FGFR activation in breast cancer cells induces a protumorigenic microenvironment.
authors.affiliation: Authors' Affiliations: Department of Lab Medicine and Pathology; Masonic Cancer Center; Biostatistics and Bioinformatics Core, Masonic Cancer Center; Microbiology, Immunology and Cancer Biology Graduate Program; Graduate Program in Molecular, Cellular, Developmental Biology, and Genetics; BioNet, Academic Health Center, University of Minnesota, Minneapolis; Hamline University, Biology Department, Saint Paul, Minnesota; and Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Bohrer
authors.forename: Pavlina
authors.initials: P
authors.lastname: Chuntova
authors.forename: Lindsey K
authors.initials: LK
authors.lastname: Bade
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Beadnell
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Leon
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brady
authors.forename: Yungil
authors.initials: Y
authors.lastname: Ryu
authors.forename: Jodi E
authors.initials: JE
authors.lastname: Goldberg
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Schmechel
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Koopmeiners
authors.forename: James B
authors.initials: JB
authors.lastname: McCarthy
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Schwertfeger
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism*; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D050796:STAT3 Transcription Factor; D006820:Hyaluronic Acid