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TBX3 is overexpressed in breast cancer and represses p14 ARF by interacting with histone deacetylases.

TBX3 is a transcription factor of the T-box gene family. Mutations in the TBX3 gene can cause hypoplastic or absent mammary glands. Previous studies have shown that TBX3 might be associated with breast cancer. Here, we show that TBX3 is overexpressed in malignant cells of primary breast cancer tissues by immunohistochemistry. TBX3 interacts with histone deacetylases (HDAC) 1, 2, 3, and 5. TBX3 interacts with HDAC1, 2, and 3 via two distinct binding sites. However, deletion of the repression domain (amino acids 566-624) of TBX3 completely abolishes its interaction with HDAC5. Endogenous TBX3 and HDACs interaction and colocalization are found in a breast cancer cell line by coimmunoprecipitation and immunofluorescence, respectively. The functional significance of the interaction between TBX3 and HDAC is also tested in a p14(ARF)-luciferase reporter system. Results indicate that TBX3 represses expression of p14(ARF) tumor suppressor and that a HDAC inhibitor is able to reverse the TBX3 repressive function in a dosage-dependent manner. This study suggests that TBX3 may function by recruiting HDACs to the T-box binding site in the promoter region. TBX3 repression to its targets is dependent on HDAC activity. TBX3 may serve as a biomarker for breast cancer and have significant applications in both breast cancer diagnosis and treatment.

Pubmed ID: 18245468

Authors

  • Yarosh W
  • Barrientos T
  • Esmailpour T
  • Lin L
  • Carpenter PM
  • Osann K
  • Anton-Culver H
  • Huang T

Journal

Cancer research

Publication Data

February 1, 2008

Associated Grants

  • Agency: NCI NIH HHS, Id: 1R01 CA121876
  • Agency: NCI NIH HHS, Id: P30 CA062203
  • Agency: NCI NIH HHS, Id: R03CA110034
  • Agency: NICHD NIH HHS, Id: T32HD07029

Mesh Terms

  • Animals
  • Breast Neoplasms
  • COS Cells
  • Cell Line, Tumor
  • Cercopithecus aethiops
  • Female
  • Histone Deacetylases
  • Humans
  • Immunohistochemistry
  • Isoenzymes
  • Middle Aged
  • Promoter Regions, Genetic
  • Protein Structure, Tertiary
  • T-Box Domain Proteins
  • Transfection
  • Tumor Suppressor Protein p14ARF
  • Up-Regulation