title: Definition of PKC-α, CDK6, and MET as therapeutic targets in triple-negative breast cancer.
abstract: Triple-negative breast cancer (TNBC) is a highly heterogeneous and recurrent subtype of breast cancer that lacks an effective targeted therapy. To identify candidate therapeutic targets, we profiled global gene expression in TNBC and breast tumor-initiating cells with a patient survival dataset. Eight TNBC-related kinases were found to be overexpressed in TNBC cells with stem-like properties. Among them, expression of PKC-α, MET, and CDK6 correlated with poorer survival outcomes. In cases coexpressing two of these three kinases, survival rates were lower than in cases where only one of these kinases was expressed. In functional tests, two-drug combinations targeting these three kinases inhibited TNBC cell proliferation and tumorigenic potential in a cooperative manner. A combination of PKC-α-MET inhibitors also attenuated tumor growth in a cooperative manner in vivo. Our findings define three kinases critical for TNBC growth and offer a preclinical rationale for their candidacy as effective therapeutic targets in treating TNBC.
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Yi-Hsin
authors: YH
authors: Hsu
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Jun
authors: J
authors: Yao
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
authors: Li-Chuan
authors: LC
authors: Chan
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taipei, Taiwan.
authors: Ting-Jung
authors: TJ
authors: Wu
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Graduate Institute for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan. Department of Biotechnology, Asia University, Taichung, Taiwan.
authors: Jennifer L
authors: JL
authors: Hsu
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taipei, Taiwan.
authors: Yueh-Fu
authors: YF
authors: Fang
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Yongkun
authors: Y
authors: Wei
authors: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Yun
authors: Y
authors: Wu
authors: Department of Surgery, Mackay Memorial Hospital, Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan.
authors: Wen-Chien
authors: WC
authors: Huang
authors: Department of Surgery, Mackay Memorial Hospital, Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan.
authors: Chien-Liang
authors: CL
authors: Liu
authors: Department of Surgery, Mackay Memorial Hospital, Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan.
authors: Yuan-Ching
authors: YC
authors: Chang
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors: Ming-Yang
authors: MY
authors: Wang
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Chia-Wei
authors: CW
authors: Li
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
authors: Jia
authors: J
authors: Shen
authors: The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
authors: Mei-Kuang
authors: MK
authors: Chen
authors: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Aysegul A
authors: AA
authors: Sahin
authors: The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas. Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Anil
authors: A
authors: Sood
authors: The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Gordon B
authors: GB
authors: Mills
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
authors: Dihua
authors: D
authors: Yu
authors: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Gabriel N
authors: GN
authors: Hortobagyi
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas. Graduate Institute for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan. Department of Biotechnology, Asia University, Taichung, Taiwan. mhung@mdanderson.org.
authors: Mien-Chie
authors: MC
authors: Hung
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects; D051571:Protein Kinase C-alpha / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D015996:Survival Rate; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*
chemical_list: D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; D017346:Protein Serine-Threonine Kinases; D051571:Protein Kinase C-alpha; D051361:Cyclin-Dependent Kinase 6