Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis.
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.
Departments of Cancer Biology, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA.|Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.
Mathew C
MC
Casimiro
Departments of Cancer Biology, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA.|Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.
Gabriele
G
Di Sante
Departments of Cancer Biology, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA.|Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.
Marco
M
Crosariol
Departments of Cancer Biology, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA.|Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.
Emanuele
E
Loro
Center for Integrated Bioinformatics, School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, USA.
William
W
Dampier
Departments of Cancer Biology, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA.|Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.
Adam
A
Ertel
Departments of Cancer Biology, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA.|Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.
Zuoren
Z
Yu
Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA.
Elizabeth A
EA
Saria
Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA.
Alexandros
A
Papanikolaou
Departments of Cancer Biology, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA.|Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.
Zhiping
Z
Li
Stem Cell and Regenerative Medicine, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA.|Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.
Chenguang
C
Wang
Departments of Cancer Biology, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA.|Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.
Sankar
S
Addya
Stem Cell and Regenerative Medicine, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA.|Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.
Michael P
MP
Lisanti
Departments of Cancer Biology, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA.|Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.
Paolo
P
Fortina
Department of Pathology and Laboratory Medicine, UC Davis Center for Comparative Medicine, University of California, Davis CA 95616, USA.
Robert D
RD
Cardiff
Center for Integrated Bioinformatics, School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, USA.
Aydin
A
Tozeren
Departments of Cancer Biology, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA.|Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.
Erik S
ES
Knudsen
Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA.
Andrew
A
Arnold
Departments of Cancer Biology, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA.|Medical Oncology, Thomas Jefferson University & Hospital, Philadelphia, PA 19107, USA.|Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA.|Kazan Federal University, Kazan 420008, Republic of Tatarstan, Russian Federation.
Richard G
RG
Pestell
D000230:Adenocarcinoma / Q000235:genetics*; D019943:Amino Acid Substitution; D000782:Aneuploidy; D000818:Animals; D020134:Catalytic Domain / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D018385:Centrosome / Q000648:ultrastructure; D043171:Chromosomal Instability / Q000235:genetics; D019938:Cyclin D1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D005347:Fibroblasts; D019940:Genes, bcl-1; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics*; D008324:Mammary Tumor Virus, Mouse / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D008941:Spindle Apparatus / Q000648:ultrastructure; D014161:Transduction, Genetic
C530104:CCND1 protein, human; C530105:Ccnd1 protein, mouse; D010879:Piperazines; D011725:Pyridines; D011993:Recombinant Fusion Proteins; D019938:Cyclin D1; C500026:palbociclib
breast cancer; chromosomal instability; cyclin D1