TBX3 is overexpressed in breast cancer and represses p14ARF by interacting with histone deacetylases

TRX3 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 TRX3 might be associated with breast cancer. Here, we show that TRX3 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 TRX3 completely abolishes its interaction with HDAC5. Endogenous TRX3 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 TRX3 represses expression of p14(ARF) tumor suppressor and that a HDAC inhibitor is able to reverse the TRX3 repressive function in a dosage-dependant manner. This study suggests that TRX3 may function by recruiting HDACs to the T-box binding site in the promoter region. TRX3 repression to its targets is dependent on HDAC activity. TRX3 may serve as a biomarker for breast cancer and have significant applications in both breast cancer diagnosis and treatment.