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Cancer Res. 2015 Apr 1;75(7):1516-26. doi: 10.1158/0008-5472.CAN-14-2443. Epub 2015 Feb 10.

CLK2 Is an Oncogenic Kinase and Splicing Regulator in Breast Cancer.

Author information

1
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.
2
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.
3
Department of Pathology, Harvard Medical School, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
5
Memorial Sloan Kettering Cancer Center, New York, New York.
6
Center for Functional Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, China.
7
Center for Functional Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
8
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.
9
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.

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.

PMID:
25670169
DOI:
10.1158/0008-5472.CAN-14-2443
[Indexed for MEDLINE]
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