title: CDKL2 promotes epithelial-mesenchymal transition and breast cancer progression.
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 CD24(high) cells to CD44(high) 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.
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas. Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Linna
authors.initials: L
authors.lastname: Li
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Chunping
authors.initials: C
authors.lastname: Liu
authors.affiliation: Division of Oncology, Department of Internal Medicine, and Memorial Hermann Cancer Center, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Amato
authors.affiliation: Department of Integrative Biology and Pharmacology, School of Medicine, University of Texas Health Science Center at Houston, Houston, Texas. School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Chang
authors.affiliation: Department of Integrative Biology and Pharmacology, School of Medicine, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Guangwei
authors.initials: G
authors.lastname: Du
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas. Division of Oncology, Department of Internal Medicine, and Memorial Hermann Cancer Center, University of Texas Health Science Center at Houston, Houston, Texas. Cancer Biology Program, Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Wenliang
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D049109:Cell Proliferation; D018844:Cyclin-Dependent Kinases; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; D018398:Homeodomain Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C103570:CDKL2 protein, human; D018844:Cyclin-Dependent Kinases