title: TRIM29 suppresses TWIST1 and invasive breast cancer behavior.
abstract: TRIM29 (ATDC) exhibits a contextual function in cancer, but seems to exert a tumor-suppressor role in breast cancer. Here, we show that TRIM29 is often silenced in primary breast tumors and cultured tumor cells as a result of aberrant gene hypermethylation. RNAi-mediated silencing of TRIM29 in breast tumor cells increased their motility, invasiveness, and proliferation in a manner associated with increased expression of mesenchymal markers (N-cadherin and vimentin), decreased expression of epithelial markers (E-cadherin and EpCAM), and increased expression and activity of the oncogenic transcription factor TWIST1, an important driver of the epithelial-mesenchymal transition (EMT). Functional investigations revealed an inverse relationship in the expression of TRIM29 and TWIST1, suggesting the existence of a negative regulatory feedback loop. In support of this relationship, we found that TWIST1 inhibited TRIM29 promoter activity through direct binding to a region containing a cluster of consensus E-box elements, arguing that TWIST1 transcriptionally represses TRIM29 expression. Analysis of a public breast cancer gene-expression database indicated that reduced TRIM29 expression was associated with reduced relapse-free survival, increased tumor size, grade, and metastatic characteristics. Taken together, our results suggest that TRIM29 acts as a tumor suppressor in breast cancer through its ability to inhibit TWIST1 and suppress EMT.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida. UF-Health Cancer Center, University of Florida College of Medicine, Gainesville, Florida. lingbao@ufl.edu kdbrown1@ufl.edu.
authors.forename: Lingbao
authors.initials: L
authors.lastname: Ai
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida. UF-Health Cancer Center, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Wan-Ju
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida. UF-Health Cancer Center, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Merve
authors.initials: M
authors.lastname: Alpay
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida. UF-Health Cancer Center, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Ming
authors.initials: M
authors.lastname: Tang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida. UF-Health Cancer Center, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Carolina E
authors.initials: CE
authors.lastname: Pardo
authors.affiliation: Department of Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Shigetsugu
authors.initials: S
authors.lastname: Hatakeyama
authors.affiliation: UF-Health Cancer Center, University of Florida College of Medicine, Gainesville, Florida. Department of Medicine, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: W Stratford
authors.initials: WS
authors.lastname: May
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida. UF-Health Cancer Center, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kladde
authors.affiliation: UF-Health Cancer Center, University of Florida College of Medicine, Gainesville, Florida. Department of Medicine, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Coy D
authors.initials: CD
authors.lastname: Heldermon
authors.affiliation: Division of Population Sciences, Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Siegel
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida. UF-Health Cancer Center, University of Florida College of Medicine, Gainesville, Florida. lingbao@ufl.edu kdbrown1@ufl.edu.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Brown
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D015820:Cadherins / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D024721:E-Box Elements / Q000235:genetics; D000071858:Epithelial Cell Adhesion Molecule; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D051879:Twist-Related Protein 1 / Q000235:genetics*; D014746:Vimentin / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D015820:Cadherins; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D009687:Nuclear Proteins; C087296:TRIM29 protein, human; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D014746:Vimentin