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Published, Version of Record (VoR)CC BY V4.0, Open
Journal article
Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis
Oncotarget, v 6(11), pp 8525-8538
20 Apr 2015
PMID: 25940700
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis
- Creators
- Mathew C Casimiro - Kimmel Cancer CenterGabriele Di Sante - Kimmel Cancer CenterMarco Crosariol - Kimmel Cancer CenterEmanuele Loro - Kimmel Cancer CenterWilliam Dampier - Drexel UniversityAdam Ertel - Sidney Kimmel Cancer CenterZuoren Yu - Kimmel Cancer CenterElizabeth A Saria - University of ConnecticutAlexandros Papanikolaou - University of ConnecticutZhiping Li - Kimmel Cancer CenterChenguang Wang - Kimmel Cancer CenterSankar Addya - Kimmel Cancer CenterMichael P Lisanti - Kimmel Cancer CenterPaolo Fortina - Kimmel Cancer CenterRobert D Cardiff - University of California, DavisAydin Tozeren - Drexel UniversityErik S Knudsen - Kimmel Cancer CenterAndrew Arnold - University of ConnecticutRichard G Pestell - Kazan Federal University
- Publication Details
- Oncotarget, v 6(11), pp 8525-8538
- Grant note
- R01 CA075503 / NCI NIH HHS R01 CA086072 / NCI NIH HHS R01 CA12934 / NCI NIH HHS R01 CA055909 / NCI NIH HHS [R01CA55909 / NCI NIH HHS P30CA56036 / NCI NIH HHS R01CA86072 / NCI NIH HHS R01 CA070896 / NCI NIH HHS P30 CA056036 / NCI NIH HHS [R01CA70896 / NCI NIH HHS R01CA75503 / NCI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; School of Biomedical Engineering, Science, and Health Systems; [Retired Faculty]
- Web of Science ID
- WOS:000358774600007
- Scopus ID
- 2-s2.0-84928753090
- Other Identifier
- 991019167672204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology
- Oncology