title: MZF-1/Elk-1 interaction domain as therapeutic target for protein kinase Cα-based triple-negative breast cancer cells.
abstract: Recent reports demonstrate that the expression of protein kinase C alpha (PKCα) in triple-negative breast cancer (TNBC) correlates with decreased survival outcomes. However, off-target effects of targeting PKCα and limited understanding of the signaling mechanisms upstream of PKCα have hampered previous efforts to manipulate this ubiquitous gene. This study shows that the expression of both myeloid zinc finger 1 (MZF-1) and Ets-like protein-1 (Elk-1) correlates with PKCα expression in TNBC. We found that the acidic domain of MZF-1 and the heparin-binding domain of Elk-1 facilitate the heterodimeric interaction between the two genes before the complex formation binds to the PKCα promoter. Blocking the formation of the heterodimer by transfection of MZF-160-72 or Elk-1145-157 peptide fragments at the MZF-1 / Elk-1 interface decreases DNA-binding activity of the MZF-1 / Elk-1 complex at the PKCα promoter. Subsequently, PKCα expression, migration, tumorigenicity, and the epithelial-mesenchymal transition potential of TNBC cells decrease. These subsequent effects are reversed by transfection with full-length PKCα, confirming that the MZF-1/Elk-1 heterodimer is a mediator of PKCα in TNBC cells. These data suggest that the next therapeutic strategy in treating PKCα-related cancer will be developed from blocking MZF-1/Elk-1 interaction through their binding domain.
authors.affiliation: Center for Molecular Medicine, China Medical University Hospital, Taichung 40402, Taiwan.
authors.forename: Chia-Jen
authors.initials: CJ
authors.lastname: Lee
authors.affiliation: Institute of Biochemistry, Microbiology and Immunology, Medical College, Chung-Shan Medical University, Taichung 40201, Taiwan.|Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
authors.forename: Li-Sung
authors.initials: LS
authors.lastname: Hsu
authors.affiliation: Department of Surgery, Tungs' Taichung Metro Harbor Hospital, Taichung 435, Taiwan.|Department of Life Science, National Chung Hsing University, Taichung 402, Taiwan.
authors.forename: Chia-Herng
authors.initials: CH
authors.lastname: Yue
authors.affiliation: Department of Life Science, National Chung Hsing University, Taichung 402, Taiwan.
authors.forename: Ho
authors.initials: H
authors.lastname: Lin
authors.affiliation: Emergency Department and Center of Hyperbaric Oxygen Therapy, Tungs' Taichung Metro Harbor Hospital, Taichung 435, Taiwan.
authors.forename: Yung-Wei
authors.initials: YW
authors.lastname: Chiu
authors.affiliation: Graduate Institute of Cancer Biology, China Medical University, Taichung 40402, Taiwan.
authors.forename: Yu-Yu
authors.initials: YY
authors.lastname: Lin
authors.affiliation: Graduate Institute of Chinese Medical Science, School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan.|Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan.|Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Center for Molecular Medicine, China Medical University Hospital, Taichung 40402, Taiwan.|Graduate Institute of Cancer Biology, China Medical University, Taichung 40402, Taiwan.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Center for Molecular Medicine, China Medical University Hospital, Taichung 40402, Taiwan.|Graduate Institute of Cancer Biology, China Medical University, Taichung 40402, Taiwan.
authors.forename: Jer-Yuh
authors.initials: JY
authors.lastname: Liu
mesh_terms: D063646:Carcinogenesis; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D000072417:Protein Domains / Q000235:genetics; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051741:Kruppel-Like Transcription Factors; C085969:MZF1 protein, human; D010446:Peptide Fragments; D050807:ets-Domain Protein Elk-1; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha
keywords: Elk-1; MZF-1; PKCα; triple-negative breast cancer cells