Priority Research Papers:

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

Mathew C. Casimiro, Gabriele Di Sante, Marco Crosariol, Emanuele Loro, William Dampier, Adam Ertel, Zuoren Yu, Elizabeth A. Saria, Alexandros Papanikolaou, Zhiping Li, Chenguang Wang, Sankar Addya, Michael P. Lisanti, Paolo Fortina, Robert D. Cardiff, Aydin Tozeren, Erik S. Knudsen, Andrew Arnold, Richard G. Pestell _

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Oncotarget. 2015; 6:8525-8538. https://doi.org/10.18632/oncotarget.3267

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Mathew C. Casimiro1,4, Gabriele Di Sante1,4, Marco Crosariol1,4, Emanuele Loro1,4, William Dampier5, Adam Ertel1,4, Zuoren Yu1,4, Elizabeth A. Saria6, Alexandros Papanikolaou6, Zhiping Li1,4, Chenguang Wang3,4, Sankar Addya1,4, Michael P. Lisanti3,4, Paolo Fortina1,4, Robert D. Cardiff7, Aydin Tozeren5, Erik S. Knudsen1,4, Andrew Arnold6, Richard G. Pestell1,2,4,8

1Departments of Cancer Biology, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA

2Medical Oncology, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA

3Stem Cell and Regenerative Medicine, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA

4Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA

5Center for Integrated Bioinformatics, School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, USA

6Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA

7Department of Pathology and Laboratory Medicine, UC Davis Center for Comparative Medicine, University of California, Davis CA 95616, USA

8Kazan 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


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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