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      RKIP and HMGA2 regulate breast tumor survival and metastasis through Lysyl Oxidase and Syndecan-2

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          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 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, 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 down-regulation 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.

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          R: A Language and Environment for Statistical Computing.

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            Strong Time Dependence of the 76-Gene Prognostic Signature for Node-Negative Breast Cancer Patients in the TRANSBIG Multicenter Independent Validation Series

            Recently, a 76-gene prognostic signature able to predict distant metastases in lymph node-negative (N(-)) breast cancer patients was reported. The aims of this study conducted by TRANSBIG were to independently validate these results and to compare the outcome with clinical risk assessment. Gene expression profiling of frozen samples from 198 N(-) systemically untreated patients was done at the Bordet Institute, blinded to clinical data and independent of Veridex. Genomic risk was defined by Veridex, blinded to clinical data. Survival analyses, done by an independent statistician, were done with the genomic risk and adjusted for the clinical risk, defined by Adjuvant! Online. The actual 5- and 10-year time to distant metastasis were 98% (88-100%) and 94% (83-98%), respectively, for the good profile group and 76% (68-82%) and 73% (65-79%), respectively, for the poor profile group. The actual 5- and 10-year overall survival were 98% (88-100%) and 87% (73-94%), respectively, for the good profile group and 84% (77-89%) and 72% (63-78%), respectively, for the poor profile group. We observed a strong time dependence of this signature, leading to an adjusted hazard ratio of 13.58 (1.85-99.63) and 8.20 (1.10-60.90) at 5 years and 5.11 (1.57-16.67) and 2.55 (1.07-6.10) at 10 years for time to distant metastasis and overall survival, respectively. This independent validation confirmed the performance of the 76-gene signature and adds to the growing evidence that gene expression signatures are of clinical relevance, especially for identifying patients at high risk of early distant metastases.
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              R: A Lenguage and Environment for Statisctical Computing

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                Author and article information

                Journal
                8711562
                6325
                Oncogene
                Oncogene
                Oncogene
                0950-9232
                1476-5594
                1 May 2014
                26 August 2013
                3 July 2014
                03 January 2015
                : 33
                : 27
                : 3528-3537
                Affiliations
                [1 ]Ben May Department for Cancer Research, Genomics and System Biology, University of Chicago, Chicago, IL 60637, USA
                [2 ]Department of Medicine, Genomics and System Biology, University of Chicago, Chicago, IL 60637, USA
                [3 ]Committee On Genetics, Genomics and System Biology, University of Chicago, Chicago, IL 60637, USA
                [4 ]Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA
                [5 ]Division of Hematology/Oncology, Department of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
                Author notes
                [* ]To whom correspondence should be sent: Marsha Rich Rosner, Ben May Department for Cancer Research, University of Chicago, GCIS W421C, 929 E 57th ST, Chicago, IL 60637, USA. m-rosner@ 123456uchicago.edu ; Tel: 773-702-0380; Fax: 773-702-6260
                Article
                NIHMS550219
                10.1038/onc.2013.328
                4096871
                23975428
                0f5c195e-f940-4389-aa6a-78e3aec28b92

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                Article

                Oncology & Radiotherapy
                rkip,hmga2,lox,sdc2,mir-200,breast,metastasis
                Oncology & Radiotherapy
                rkip, hmga2, lox, sdc2, mir-200, breast, metastasis

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