TBX3 and Its Isoform TBX3+2a Are Functionally Distinctive in Inhibition of Senescence and Are Overexpressed in a Subset of Breast Cancer Cell Lines

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Abstract
TBX3 is a transcription factor of the T-box gene family. Mutations of TBX3 cause ulnar-mammary syndrome (MIM 181450) in humans, an autosomal dominant disorder characterized by the absence or underdevelopment of the mammary glands and other congenital anomalies. It recently was found that TBX3 was able to immortalize mouse embryo fibroblast (MEF) cells. In addition, TBX2, a homologue of TBX3, is active in preventing senescence in rodent cells and was found to be amplified in some human breast cancers, suggesting TBX3 plays a role in breast cancer. This study examined the function of TBX3 and its isoform, TBX3 + 2a. TBX3 + 2a differs from TBX3 in the DNA binding domain with an extra 20 amino acids produced by alternative splicing. We first examined the tissue expression and alternative splicing patterns of these two isoforms. We found that TBX3 and TBX3 + 2a are widely expressed in humans and mice, and alternative splicing could be tissue specific and species specific. Overexpression of TBX3 is able to immortalize MEF cells, whereas TBX3 + 2a shows an acceleration of senescence, a functional difference that may be explained by the fact that these two isoforms may have different downstream targets. TBX3, but not TBX3 + 2a, is able to bind to the previously identified T-box binding site in a gel shift assay. A subset of human breast cancer cell lines overexpresses TBX3. Our results indicate that TBX3 and TBX3 + 2a are functionally distinctive in inhibition of senescence of MEF cells and may play a role in breast cancer.