title: A novel cell-penetrating peptide suppresses breast tumorigenesis by inhibiting β-catenin/LEF-1 signaling.
abstract: The inhibition of β-catenin/LEF-1 signaling is an emerging strategy in cancer therapy. However, clinical targeted treatment of the β-catenin/LEF-1 complex remains relatively ineffective. Therefore, development of specific molecular targets is a key approach for identifying new cancer therapeutics. Thus, we attempted to synthesize a peptide (TAT-NLS-BLBD-6) that could interfere with the interaction of β-catenin and LEF-1 at nuclei in human breast cancer cells. TAT-NLS-BLBD-6 directly interacted with β-catenin and inhibited breast cancer cell growth, invasion, migration, and colony formation as well as increased arrest of sub-G1 phase and apoptosis; it also suppressed breast tumor growth in nude mouse and zebrafish xenotransplantation models, showed no signs of toxicity, and did not affect body weight. Furthermore, the human global gene expression profiles and Ingenuity Pathway Analysis software showed that the TAT-NLS-BLBD-6 downstream target genes were associated with the HER-2 and IL-9 signaling pathways. TAT-NLS-BLBD-6 commonly down-regulated 27 candidate genes in MCF-7 and MDA-MB-231 cells, which are concurrent with Wnt downstream target genes in human breast cancer. Our study suggests that TAT-NLS-BLBD-6 is a promising drug candidate for the development of effective therapeutics specific for Wnt/β-catenin signaling inhibition.
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Tsung-Hua
authors.initials: TH
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Cheng-Fang
authors.initials: CF
authors.lastname: Tsai
authors.affiliation: Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chien-Chih
authors.initials: CC
authors.lastname: Chiu
authors.affiliation: Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shih-Shin
authors.initials: SS
authors.lastname: Liang
authors.affiliation: Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Tsu-Nai
authors.initials: TN
authors.lastname: Wang
authors.affiliation: Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Kuo
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Cheng-Yu
authors.initials: CY
authors.lastname: Long
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.|Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Eing-Mei
authors.initials: EM
authors.lastname: Tsai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D057846:Cell-Penetrating Peptides / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D019913:Nuclear Localization Signals / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish; D051176:beta Catenin / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism
chemical_list: D057846:Cell-Penetrating Peptides; D051821:Lymphoid Enhancer-Binding Factor 1; D019913:Nuclear Localization Signals; D011993:Recombinant Fusion Proteins; D051176:beta Catenin; D054322:tat Gene Products, Human Immunodeficiency Virus