Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis

// Mathew C. Casimiro 1, 4 , Gabriele Di Sante 1, 4 , Marco Crosariol 1, 4 , Emanuele Loro 1, 4 , William Dampier 5 , Adam Ertel 1, 4 , Zuoren Yu 1, 4 , Elizabeth A. Saria 6 , Alexandros Papanikolaou 6 , Zhiping Li 1, 4 , Chenguang Wang 3, 4 , Sankar Addya 1, 4 , Michael P. Lisanti 3, 4 , Paolo Fortina 1, 4 , Robert D. Cardiff 7 , Aydin Tozeren 5 , Erik S. Knudsen 1, 4 , Andrew Arnold 6 , Richard G. Pestell 1, 2, 4, 8 1 Departments of Cancer Biology, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA 2 Medical Oncology, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA 3 Stem Cell and Regenerative Medicine, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA 4 Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA 5 Center for Integrated Bioinformatics, School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, USA 6 Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA 7 Department of Pathology and Laboratory Medicine, UC Davis Center for Comparative Medicine, University of California, Davis CA 95616, USA 8 Kazan Federal University, Kazan 420008, Republic of Tatarstan, Russian Federation Correspondence to: Richard G. Pestell, e-mail: Richard.Pestell@Jefferson.edu Keywords: Cyclin D1, breast cancer, chromosomal instability Received: January 14, 2015 Accepted: January 31, 2015 Published: March 25, 2015 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 D1 WT or cyclin D1 KE in the mammary gland was sufficient to induce a high CIN score within 7 days. Sustained expression of cyclin D1 KE induced mammary adenocarcinoma with similar kinetics to that of the wild-type cyclin D1. ChIP-Seq studies demonstrated recruitment of cyclin D1 WT and cyclin D1 KE 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.