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      p53 Loss in Breast Cancer Leads to Myc Activation, Increased Cell Plasticity, and Expression of a Mitotic Signature with Prognostic Value

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          Summary

          Loss of p53 function is invariably associated with cancer. Its role in tumor growth was recently linked to its effects on cancer stem cells (CSCs), although the underlying molecular mechanisms remain unknown. Here, we show that c-myc is a transcriptional target of p53 in mammary stem cells (MaSCs) and is activated in breast tumors as a consequence of p53 loss. Constitutive Myc expression in normal mammary cells leads to increased frequency of MaSC symmetric divisions, extended MaSC replicative-potential, and MaSC-reprogramming of progenitors, whereas Myc activation in breast cancer is necessary and sufficient to maintain the expanding pool of CSCs. Concomitant p53 loss and Myc activation trigger the expression of 189 mitotic genes, which identify patients at high risk of mortality and relapse, independently of other risk factors. Altogether, deregulation of the p53:Myc axis in mammary tumors increases CSC content and plasticity and is a critical determinant of tumor growth and clinical aggressiveness.

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          Highlights

          • Myc is overexpressed and deregulated in breast tumors because of p53 signaling attenuation

          • Myc activation favors SC symmetric divisions and SC reprogramming of progenitors

          • Myc activation is necessary and sufficient to sustain the cancer SC phenotype

          • Expression of 189 mitotic p53:Myc targets identifies high-risk breast cancer patients

          Abstract

          Santoro et al. demonstrate the existence of a regulatory axis instructed by the tumor-suppressor p53, executed by the Myc oncogene, and involving 189 p53:Myc targets. The authors show that activation of this axis maintains the expanding pool of cancer stem cells (SCs), thus promoting tumor growth, and predicts adverse prognosis.

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          Most cited references48

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          Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

          The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
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            NIH Image to ImageJ: 25 years of image analysis.

            For the past 25 years NIH Image and ImageJ software have been pioneers as open tools for the analysis of scientific images. We discuss the origins, challenges and solutions of these two programs, and how their history can serve to advise and inform other software projects.
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              Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.

              Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.
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                Author and article information

                Contributors
                Journal
                Cell Rep
                Cell Rep
                Cell Reports
                Cell Press
                2211-1247
                15 January 2019
                15 January 2019
                15 January 2019
                : 26
                : 3
                : 624-638.e8
                Affiliations
                [1 ]IEO, European Institute of Oncology IRCCS, Department of Experimental Oncology, Via Adamello 16, 20139 Milan, Italy
                [2 ]Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Via Adamello 16, 20139 Milan, Italy
                [3 ]Department of Biomedical Informatics, Harvard Medical School, 10 Shattuck Street, Boston, MA 02115, USA
                [4 ]BioPharma Excellence, Agnes-Pockels-Bogen 1, 80922 Munich, Germany
                [5 ]Department of Oncology and Hemato-Oncology, University of Milan, Via Santa Sofia 9, 20142 Milan, Italy
                Author notes
                []Corresponding author piergiuseppe.pelicci@ 123456ieo.it
                [6]

                These authors contributed equally

                [7]

                Lead Contact

                Article
                S2211-1247(18)32016-3
                10.1016/j.celrep.2018.12.071
                6334229
                30650356
                da5061c3-7d67-4265-978f-04ca029c498d
                © 2018 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 5 April 2018
                : 26 June 2018
                : 14 December 2018
                Categories
                Article

                Cell biology
                p53,myc,cscs,mammary gland,sc self-renewal,cancer maintenance,reprogramming
                Cell biology
                p53, myc, cscs, mammary gland, sc self-renewal, cancer maintenance, reprogramming

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