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

被引：38

作者：

Casimiro, Mathew C. ^{[1
,4
]}

Di Sante, Gabriele ^{[1
,4
]}

Crosariol, Marco ^{[1
,4
]}

Loro, Emanuele ^{[1
,4
]}

Dampier, William ^{[5
]}

Ertel, Adam ^{[1
,4
]}

Yu, Zuoren ^{[1
,4
]}

Saria, Elizabeth A. ^{[6
]}

Papanikolaou, Alexandros ^{[6
]}

Li, Zhiping ^{[4
]}

Wang, Chenguang ^{[3
,4
]}

Addya, Sankar ^{[1
,4
]}

Lisanti, Michael P. ^{[3
,4
]}

Fortina, Paolo ^{[1
,4
]}

Cardiff, Robert D. ^{[7
]}

Tozeren, Aydin ^{[5
]}

Knudsen, Erik S. ^{[1
,4
]}

Arnold, Andrew ^{[6
]}

Pestell, Richard G. ^{[1
,2
,4
,8
]}

机构：

[1] Thomas Jefferson Univ & Hosp, Dept Canc Biol, Philadelphia, PA 19107 USA

[2] Thomas Jefferson Univ & Hosp, Med Oncol, Philadelphia, PA 19107 USA

[3] Thomas Jefferson Univ & Hosp, Stem Cell & Regenerat Med, Philadelphia, PA 19107 USA

[4] Sidney Kimmel Canc Ctr, Philadelphia, PA 19107 USA

[5] Drexel Univ, Sch Biomed Engn Sci & Hlth Syst, Ctr Integrated Bioinformat, Philadelphia, PA 19104 USA

[6] Univ Connecticut, Ctr Hlth, Ctr Mol Med, Farmington, CT 06030 USA

[7] Univ Calif Davis, Dept Pathol & Lab Med, UC Davis Ctr Comparat Med, Davis, CA 95616 USA

[8] Kazan Fed Univ, Kazan 420008, Russia

来源：

ONCOTARGET | 2015年 / 6卷 / 11期

基金：

美国国家卫生研究院;

关键词：

Cyclin D1; breast cancer; chromosomal instability; BREAST-CANCER; ESTROGEN-RECEPTOR; TRANSCRIPTIONAL ROLE; GENE-EXPRESSION; PROTEIN; BINDING; CARCINOMA; PHOSPHORYLATION; OVEREXPRESSION; TRANSFORMATION;

D O I：

10.18632/oncotarget.3267

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：8525 / 8538

页数：14

共 52 条

[1]

Activation of the cyclin D1 gene by the EPA-associated protein p300 through AP-1 inhibits cellular apoptosis [J].