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 Cardiff, Aydin Tozeren, Erik S. Knudsen, Andrew Arnold, Richard G. Pestell

Research output: Contribution to journalArticle

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8525-8538
Number of pages14
JournalOncotarget
Volume6
Issue number11
DOIs
StatePublished - Jan 1 2015

Keywords

  • Breast cancer
  • Chromosomal instability
  • Cyclin D1

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Casimiro, M. C., Di Sante, G., Crosariol, M., Loro, E., Dampier, W., Ertel, A., Yu, Z., Saria, E. A., Papanikolaou, A., Li, Z., Wang, C., Addya, S., Lisanti, M. P., Fortina, P., Cardiff, R., Tozeren, A., Knudsen, E. S., Arnold, A., & Pestell, R. G. (2015). Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis. Oncotarget, 6(11), 8525-8538. https://doi.org/10.18632/oncotarget.3267