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      Mechanism of irradiation‐induced mammary cancer metastasis: A role for SAP‐dependent Mkl1 signaling

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          Abstract

          Radiotherapy is a standard treatment after conservative breast cancer surgery. However, cancers relapsing within a previously irradiated area have an increased probability to metastasize. The mechanisms responsible for this aggressiveness remain unclear. Here, we used the clinically relevant 4T1 breast cancer model mimicking aggressive local relapse after radiotherapy to identify differences between tumors grown in untreated versus preirradiated mammary glands. Tumors grown within preirradiated beds were highly enriched in transcripts encoding collagens and other proteins building or modifying the extracellular matrix, such as laminin‐332, tenascins, lysyl oxidases and matrix metalloproteinases. Type I collagen, known to directly contribute to tissue stiffening, and the pro‐metastatic megakaryoblastic leukemia‐1 (Mkl1) target gene tenascin‐C were further investigated. Mammary tissue preirradiation induced Mkl1 nuclear translocation in the tumor cells in vivo, indicating activation of Mkl1 signaling. Transcript profiling of cultured 4T1 cells revealed that the majority of the Mkl1 target genes, including tenascin‐C, required serum response factor (SRF) for their expression. However, application of dynamic strain or matrix stiffness to 4T1 cells converted the predominant SRF/Mkl1 action into SAP domain‐dependent Mkl1 signaling independent of SRF, accompanied by a switch to SAP‐dependent tumor cell migration. 4T1 tumors overexpressing intact Mkl1 became more metastatic within preirradiated beds, while tumors expressing Mkl1 lacking the SAP domain exhibited impaired growth and metastatic spread, and decreased Mkl1 target gene expression. Thus, we identified SAP‐dependent Mkl1 signaling as a previously unrecognized mediator of aggressive progression of mammary tumors locally relapsing after radiotherapy, and provide a novel signaling pathway for therapeutic intervention.

          Highlights

          • Stroma irradiation results in tumors with increased extracellular matrix deposition.

          • Irradiation induces Mkl1 nuclear translocation, tumor growth and lung metastases.

          • Matrix stiffness and cyclic mechanical strain trigger SAP‐dependent Mkl1 signaling.

          • Strain and irradiation induce SAP‐dependent cell migration and tumor progression.

          • Radiation‐induced SAP‐dependent Mkl1 action: a new target for breast cancer therapy.

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          Most cited references66

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          Tensional homeostasis and the malignant phenotype.

          Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.
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            Normalization of cDNA microarray data.

            Normalization means to adjust microarray data for effects which arise from variation in the technology rather than from biological differences between the RNA samples or between the printed probes. This paper describes normalization methods based on the fact that dye balance typically varies with spot intensity and with spatial position on the array. Print-tip loess normalization provides a well-tested general purpose normalization method which has given good results on a wide range of arrays. The method may be refined by using quality weights for individual spots. The method is best combined with diagnostic plots of the data which display the spatial and intensity trends. When diagnostic plots show that biases still remain in the data after normalization, further normalization steps such as plate-order normalization or scale-normalization between the arrays may be undertaken. Composite normalization may be used when control spots are available which are known to be not differentially expressed. Variations on loess normalization include global loess normalization and two-dimensional normalization. Detailed commands are given to implement the normalization techniques using freely available software.
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              Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH.

              Acidosis of the tumor microenvironment is typical of a malignant phenotype, particularly in hypoxic tumors. All cells express multiple isoforms of carbonic anhydrase (CA), enzymes catalyzing the reversible hydration of carbon dioxide into bicarbonate and protons. Tumor cells express membrane-bound CAIX and CAXII that are controlled via the hypoxia-inducible factor (HIF). Despite the recognition that tumor expression of HIF-1alpha and CAIX correlates with poor patient survival, the role of CAIX and CAXII in tumor growth is not fully resolved. To understand the advantage that tumor cells derive from expression of both CAIX and CAXII, we set up experiments to either force or invalidate the expression of these enzymes. In hypoxic LS174Tr tumor cells expressing either one or both CA isoforms, we show that (a) in response to a "CO(2) load," both CAs contribute to extracellular acidification and (b) both contribute to maintain a more alkaline resting intracellular pH (pH(i)), an action that preserves ATP levels and cell survival in a range of acidic outside pH (6.0-6.8) and low bicarbonate medium. In vivo experiments show that ca9 silencing alone leads to a 40% reduction in xenograft tumor volume with up-regulation of ca12 mRNA levels, whereas invalidation of both CAIX and CAXII gives an impressive 85% reduction. Thus, hypoxia-induced CAIX and CAXII are major tumor prosurvival pH(i)-regulating enzymes, and their combined targeting shows that they hold potential as anticancer targets.
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                Author and article information

                Contributors
                maria.asparuhova@fmi.ch
                chiara.secondini@unifr.ch
                curzio.ruegg@unifr.ch
                Ruth.Chiquet@fmi.ch
                Journal
                Mol Oncol
                Mol Oncol
                10.1002/(ISSN)1878-0261
                MOL2
                Molecular Oncology
                John Wiley and Sons Inc. (Hoboken )
                1574-7891
                1878-0261
                30 April 2015
                October 2015
                : 9
                : 8 ( doiID: 10.1002/mol2.2015.9.issue-8 )
                : 1510-1527
                Affiliations
                [ 1 ]Friedrich Miescher Institute for Biomedical Research, Affiliated with the Novartis Institutes for Biomedical Research and the University of Basel, Maulbeerstrasse 66, 4058 Basel, Switzerland
                [ 2 ]Department of Medicine, Faculty of Science, University of Fribourg, Rue Albert Gockel 1, 1700 Fribourg, Switzerland
                [ 3 ]University of Basel, Faculty of Science, Basel, Switzerland
                Author notes
                [*] [* ]Corresponding author. Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. Tel.: +41 61 697 24 94; fax: +41 61 697 39 76.
                Article
                MOL22015981510
                10.1016/j.molonc.2015.04.003
                5528797
                25999144
                6c640da1-9614-4f81-abe4-b5a66140b3a2
                © 2015 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 18 December 2014
                : 19 March 2015
                : 11 April 2015
                Page count
                Figures: 8, Tables: 1, Equations: 0, References: 100, Pages: 18, Words: 14933
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                mol22015981510
                October 2015
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.4 mode:remove_FC converted:25.07.2017

                Oncology & Radiotherapy
                myocardin‐related transcription factor‐a (mrtf‐a),extracellular matrix,tumor rigidity,cyclic mechanical strain,gene regulation

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