Δημοσίευση

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

ΤίτλοςKinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis.
Publication TypeJournal Article
Year of Publication2015
AuthorsCasimiro, 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. D., Tozeren A., Knudsen E. S., Arnold A., & Pestell R. G.
JournalOncotarget
Volume6
Issue11
Pagination8525-38
Date Published2015 Apr 20
ISSN1949-2553
Λέξεις κλειδιάAdenocarcinoma, Amino Acid Substitution, Aneuploidy, Animals, Catalytic Domain, Cell Transformation, Neoplastic, Cells, Cultured, Centrosome, Chromosomal Instability, Cyclin D1, Female, Fibroblasts, Genes, bcl-1, Humans, Mammary Neoplasms, Experimental, Mammary Tumor Virus, Mouse, Mice, Mice, Knockout, Mice, Transgenic, Mutation, Piperazines, Pyridines, Recombinant Fusion Proteins, Spindle Apparatus, Transduction, Genetic
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.

DOI10.18632/oncotarget.3267
Alternate JournalOncotarget
PubMed ID25940700
PubMed Central IDPMC4496164
Grant ListP30 CA056036 / CA / NCI NIH HHS / United States
P30CA56036 / CA / NCI NIH HHS / United States
R01 CA12934 / CA / NCI NIH HHS / United States
R01CA75503 / CA / NCI NIH HHS / United States
R01CA86072 / CA / NCI NIH HHS / United States
[R01CA55909 / CA / NCI NIH HHS / United States
[R01CA70896 / CA / NCI NIH HHS / United States

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