19
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      MMTV-cre;Ccn6 knockout mice develop tumors recapitulating human metaplastic breast carcinomas

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Metaplastic breast carcinoma is an aggressive form of invasive breast cancer with histological evidence of epithelial to mesenchymal transition (EMT). However, the defining molecular events are unknown. Here we show that CCN6 (WISP3), a secreted matricellular protein of the CCN (CYR61/CTGF/NOV) family, is significantly down regulated in clinical samples of human spindle cell metaplastic breast carcinoma. We generated a mouse model of mammary epithelial-specific Ccn6 deletion by developing a floxed Ccn6 mouse which was bred with an MMTV-Cre mouse. Ccn6 fl/fl ; MMTV-Cre mice displayed severe defects in ductal branching and abnormal age-related involution compared to littermate controls. Ccn6 fl/fl ;MMTV-Cre mice developed invasive high grade mammary carcinomas with bona fide EMT, histologically similar to human metaplastic breast carcinomas. Global gene expression profiling of Ccn6 fl/fl mammary carcinomas and comparison of orthologous genes with a human metaplastic carcinoma signature revealed a significant overlap of 87 genes ( p=5×10 −11). Among the shared deregulated genes between mouse and human are important regulators of epithelial morphogenesis including Cdh1, Ck19, Cldn3 and 4, Ddr1, and Wnt10a. These results document a causal role for Ccn6 deletion in the pathogenesis of metaplastic carcinomas with histological and molecular similarities with human disease. We provide a platform to study new targets in the diagnosis and treatment of human metaplastic carcinomas, and a new disease relevant model in which to test new treatment strategies.

          Related collections

          Most cited references45

          • Record: found
          • Abstract: not found
          • Article: not found

          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets.

            Members of the CCN family of matricellular proteins are crucial for embryonic development and have important roles in inflammation, wound healing and injury repair in adulthood. Deregulation of CCN protein expression or activities contributes to the pathobiology of various diseases - many of which may arise when inflammation or tissue injury becomes chronic - including fibrosis, atherosclerosis, arthritis and cancer, as well as diabetic nephropathy and retinopathy. Emerging studies indicate that targeting CCN protein expression or signalling pathways holds promise in the development of diagnostics and therapeutics for such diseases. This Review summarizes the biology of CCN proteins, their roles in various pathologies and their potential as therapeutic targets.
              Bookmark
              • Record: found
              • Abstract: not found
              • Article: not found

              Linear models and empirical bayes methods for assessing differential expression in microarray experiments.

                Bookmark

                Author and article information

                Journal
                8711562
                6325
                Oncogene
                Oncogene
                Oncogene
                0950-9232
                1476-5594
                20 September 2016
                07 November 2016
                20 April 2017
                07 May 2017
                : 36
                : 16
                : 2275-2285
                Affiliations
                [1 ]Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI
                [2 ]Medical Scientist Training Program and Molecular and Cellular Pathology Graduate Program, University of Michigan, Ann Arbor, MI
                [3 ]Post-baccalaureate Research Education Program, University of Michigan, Ann Arbor, MI
                [4 ]Department of Cancer Biology, University of Cincinnati, Cincinnati, OH
                Author notes
                [* ]Corresponding Author: Celina G. Kleer, M.D., University of Michigan, Department of Pathology, 4217 Comprehensive Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109, Tel: 734-615-3448, kleer@ 123456umich.edu
                Article
                NIHMS815638
                10.1038/onc.2016.381
                5398917
                27819674
                88588902-7c2d-4bb7-bf2e-bb35da55c9d7

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Categories
                Article

                Oncology & Radiotherapy
                ccn6,wisp3,matricellular,microenvironment,metaplastic carcinoma,triple negative,breast cancer

                Comments

                Comment on this article