title: RKIP and HMGA2 regulate breast tumor survival and metastasis through lysyl oxidase and syndecan-2.
abstract: Elucidating targets of physiological tumor metastasis suppressors can highlight key signaling pathways leading to invasion and metastasis. To identify downstream targets of the metastasis suppressor Raf-1 kinase inhibitory protein (RKIP/PEBP1), we utilized an integrated approach based upon statistical analysis of tumor gene expression data combined with experimental validation. Previous studies from our laboratory identified the architectural transcription factor and oncogene, high mobility group AT-hook 2 (HMGA2), as a target of inhibition by RKIP. Here we identify two signaling pathways that promote HMGA2-driven metastasis. Using both human breast tumor cells and an MMTV-Wnt mouse breast tumor model, we show that RKIP induces and HMGA2 inhibits expression of miR-200b; miR-200b directly inhibits expression of lysyl oxidase (LOX), leading to decreased invasion. RKIP also inhibits syndecan-2 (SDC2), which is aberrantly expressed in breast cancer, via downregulation of HMGA2; but this mechanism is independent of miR-200. Depletion of SDC2 induces apoptosis and suppresses breast tumor growth and metastasis in mouse xenografts. RKIP, LOX and SDC2 are coordinately regulated and collectively encompass a prognostic signature for metastasis-free survival in ER-negative breast cancer patients. Taken together, our findings reveal two novel signaling pathways targeted by the metastasis suppressor RKIP that regulate remodeling of the extracellular matrix and tumor survival.
authors: 1] Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA [2] Committee On Genetics, Genomics and System Biology, University of Chicago, Chicago, IL, USA.
authors: M
authors: M
authors: Sun
authors: Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.
authors: S
authors: S
authors: Gomes
authors: Department of Medicine, University of Chicago, Chicago, IL, USA.
authors: P
authors: P
authors: Chen
authors: Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.
authors: C A
authors: CA
authors: Frankenberger
authors: Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ, USA.
authors: D
authors: D
authors: Sankarasharma
authors: Division of Hematology/Oncology, Department of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: C H
authors: CH
authors: Chung
authors: Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ, USA.
authors: K K
authors: KK
authors: Chada
authors: 1] Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA [2] Committee On Genetics, Genomics and System Biology, University of Chicago, Chicago, IL, USA.
authors: M R
authors: MR
authors: Rosner
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D049488:Phosphatidylethanolamine Binding Protein / Q000378:metabolism*; D011379:Prognosis; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D053669:Syndecan-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D025743:HMGA2 Protein; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D053669:Syndecan-2; D008249:Protein-Lysine 6-Oxidase
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