Authors

Mathew C Casimiro, Department of Cancer Biology and Medical Oncology, Kimmel Cancer Center, Thomas Jefferson UniversityFollow
Gabriele Disante, Department of Cancer Biology, Thomas Jefferson UniversityFollow
Marco Crosariol, Sidney Kimmel Cancer Center; Departments of Cancer Biology, Thomas Jefferson University and Hospital
Emanuele Loro, Sidney Kimmel Cancer Center; Departments of Cancer Biology, Thomas Jefferson University and Hospital
William Dampier, Center for Integrated Bioinformatics, School of Biomedical Engineering, Science and Health Systems, Drexel University
Adam Ertel, Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PAFollow
Zuoren Yu, Sidney Kimmel Cancer Center; Departments of Cancer Biology, Thomas Jefferson University and Hospital
Elizabeth A Saria, Center for Molecular Medicine, University of Connecticut Health Center
Alexandros Papanikolaou, Center for Molecular Medicine, University of Connecticut Health Center
Z Li, Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson UniversityFollow
Chenguang Wang, Kimmel Cancer Center, Thomas Jefferson UniversityFollow
Sankar Addya, Kimmel Cancer Center, Department of Cancer Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PennsylvaniaFollow
Michael P. Lisanti, Thomas Jefferson UniversityFollow
Paolo Fortina, Thomas Jefferson UniversityFollow
Robert D Cardiff, Department of Pathology and Laboratory Medicine, UC Davis Center for Comparative Medicine, University of California
Aydin Tozeren, Center for Integrated Bioinformatics, School of Biomedical Engineering, Science and Health Systems, Drexel University
Erik S Knudsen, Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PAFollow
Andrew Arnold, Center for Molecular Medicine, University of Connecticut Health Center
Richard Pestell, Sidney Kimmel Cancer Center; Medical Oncology, Departments of Cancer Biology, Thomas Jefferson University and Hospital; Kazan Federal UniversityFollow

Document Type

Article

Publication Date

4-20-2015

Comments

This article has been peer reviewed. It was published in: Oncotarget.

Volume 6, Issue 11, 2015, Pages 8525-8538.

The published version is available at http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=3267

Copyright © 2015 The Authors

Abstract

Cyclin D1 is an important molecular driver of human breast cancer but better understanding of its oncogenic mechanisms is needed, especially to enhance efforts in targeted therapeutics. Currently, pharmaceutical initiatives to inhibit cyclin D1 are focused on the catalytic component since the transforming capacity is thought to reside in the cyclin D1/CDK activity. We initiated the following study to directly test the oncogenic potential of catalytically inactive cyclin D1 in an in vivo mouse model that is relevant to breast cancer. Herein, transduction of cyclin D1-/- mouse embryonic fibroblasts (MEFs) with the kinase dead KE mutant of cyclin D1 led to aneuploidy, abnormalities in mitotic spindle formation, autosome amplification, and chromosomal instability (CIN) by gene expression profiling. Acute transgenic expression of either cyclin D1WT or cyclin D1KE in the mammary gland was sufficient to induce a high CIN score within 7 days. Sustained expression of cyclin D1KE induced mammary adenocarcinoma with similar kinetics to that of the wild-type cyclin D1. ChIP-Seq studies demonstrated recruitment of cyclin D1WT and cyclin D1KE to the genes governing CIN. We conclude that the CDK-activating function of cyclin D1 is not necessary to induce either chromosomal instability or mammary tumorigenesis.

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