title: CLK2 Is an Oncogenic Kinase and Splicing Regulator in Breast Cancer.
abstract: Genetically activated kinases have been attractive therapeutic targets in cancer due to the relative ease of developing tumor-specific treatment strategies for them. To discover novel putative oncogenic kinases, we identified 26 genes commonly amplified and overexpressed in breast cancer and subjected them to a lentiviral shRNA cell viability screen in a panel of breast cancer cell lines. Here, we report that CLK2, a kinase that phosphorylates SR proteins involved in splicing, acts as an oncogene in breast cancer. Deregulated alternative splicing patterns are commonly observed in human cancers but the underlying mechanisms and functional relevance are still largely unknown. CLK2 is amplified and overexpressed in a significant fraction of breast tumors. Downregulation of CLK2 inhibits breast cancer growth in cell culture and in xenograft models and it enhances cell migration and invasion. Loss of CLK2 in luminal breast cancer cells leads to the upregulation of epithelial-to-mesenchymal transition (EMT)-related genes and a switch to mesenchymal splice variants of several genes, including ENAH (MENA). These results imply that therapeutic targeting of CLK2 may be used to modulate EMT splicing patterns and to inhibit breast tumor growth.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Taku
authors: T
authors: Yoshida
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Seoul National University College of Medicine, Seoul, Korea.
authors: Jee Hyun
authors: JH
authors: Kim
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Kristopher
authors: K
authors: Carver
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Ying
authors: Y
authors: Su
authors: Department of Pathology, Harvard Medical School, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Stanislawa
authors: S
authors: Weremowicz
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Laura
authors: L
authors: Mulvey
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Shoji
authors: S
authors: Yamamoto
authors: Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Cameron
authors: C
authors: Brennan
authors: Center for Functional Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, China.
authors: Shenglin
authors: S
authors: Mei
authors: Center for Functional Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Henry
authors: H
authors: Long
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. MD Anderson Cancer Center, Houston, Texas.
authors: Jun
authors: J
authors: Yao
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Center for Functional Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts. Harvard Stem Cell Institute, Cambridge, Massachusetts. Broad Institute, Cambridge, Massachusetts. Kornelia_polyak@dfci.harvard.edu.
authors: Kornelia
authors: K
authors: Polyak
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D048430:Cell Shape; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*
chemical_list: C066780:Clk dual-specificity kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases