Oncotarget

Research Papers:

CDKL2 promotes epithelial-mesenchymal transition and breast cancer progression

Linna Li _, Chunping Liu, Robert J. Amato, Jeffrey T. Chang, Wenliang Li and Wenliang Li

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Oncotarget. 2014; 5:10840-10853. https://doi.org/10.18632/oncotarget.2535

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Abstract

Linna Li1,6, Chunping Liu1, Robert J. Amato2, Jeffrey T. Chang3,4, Guangwei Du3, Wenliang Li1,2,5

1Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas

2Division of Oncology, Department of Internal Medicine, and Memorial Hermann Cancer Center, University of Texas Health Science Center at Houston, Houston, Texas

3Department of Integrative Biology and Pharmacology, School of Medicine, University of Texas Health Science Center at Houston, Houston, Texas

4School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, Texas

5Cancer Biology Program, Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, Texas

6Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing, China

Correspondence to:

Wenliang Li, e-mail: [email protected]

Keywords: cyclin-dependent kinase-like 2 (CDKL2), epithelial–mesenchymal transition (EMT), breast cancer, kinases, CD44

Received: August 23, 2014     Accepted: September 28, 2014     Published: October 21, 2014

ABSTRACT

The epithelial–mesenchymal transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits by epithelial cancer cells. To identify novel regulators of EMT, we carried out cDNA screens that covered 500 human kinases. Subsequent characterization of candidate kinases led us to uncover cyclin-dependent kinase-like 2 (CDKL2) as a novel potent promoter for EMT and breast cancer progression. CDKL2-expressing human mammary gland epithelial cells displayed enhanced mesenchymal traits and stem cell-like phenotypes, which was acquired through activating a ZEB1/E-cadherin/β-catenin positive feedback loop and regulating CD44 mRNA alternative splicing to promote conversion of CD24high cells to CD44high cells. Furthermore, CDKL2 enhanced primary tumor formation and metastasis in a breast cancer xenograft model. Notably, CDKL2 is expressed significantly higher in mesenchymal human breast cancer cell lines than in epithelial lines, and its over-expression/amplification in human breast cancers is associated with shorter disease-free survival. Taken together, our study uncovered a major role for CDKL2 in promoting EMT and breast cancer progression.


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