The roles and regulation of TBX3 in development and disease.

TBX3, a member of the ancient and evolutionary conserved T-box transcription factor family, is a critical developmental regulator of several structures including the heart, mammary glands, limbs and lungs. Indeed, mutations in the human TBX3 lead to ulnar mammary syndrome which is characterized by several clinical malformations including hypoplasia of the mammary and apocrine glands, defects of the upper limb, areola, dental structures, heart and genitalia. In contrast, TBX3 has no known function in adult tissues but is frequently overexpressed in a wide range of epithelial and mesenchymal derived cancers. This overexpression greatly impacts several hallmarks of cancer including bypass of senescence, apoptosis and anoikis, promotion of proliferation, tumour formation, angiogenesis, invasion and metastatic capabilities as well as cancer stem cell expansion. The debilitating consequences of having too little or too much TBX3 suggest that its expression levels need to be tightly regulated. While we have a reasonable understanding of the mutations that result in low levels of functional TBX3 during development, very little is known about the factors responsible for the overexpression of TBX3 in cancer. Furthermore, given the plethora of oncogenic processes that TBX3 impacts, it must be regulating several target genes but to date only a few have been identified and characterised. Interestingly, while there is compelling evidence to support oncogenic roles for TBX3, a few studies have indicated that it may also have tumour suppressor functions in certain contexts. Together, the diverse functional elasticity of TBX3 in development and cancer is thought to involve, in part, the protein partners that it interacts with and this area of research has recently received some attention. This review provides an insight into the significance of TBX3 in development and cancer and identifies research gaps that need to be explored to shed more light on this transcription factor.

COL1A2 is a TBX3 target that mediates its impact on fibrosarcoma and chondrosarcoma cell migration.

The developmentally important T-box transcription factor TBX3, is overexpressed in several cancers and contributes to tumorigenesis as either a tumour promoter or tumour suppressor. For example, TBX3 promotes cell proliferation, migration and invasion of chondrosarcoma cells but inhibits these processes in fibrosarcoma cells. This suggests that the cellular context influences TBX3 oncogenic functions, but the mechanism(s) involved has not been elucidated. COL1A2 encodes type I collagen and, like TBX3, plays important roles during embryogenesis and can act as either oncogene or tumour suppressor. Here we explore the possibility that COL1A2 may be a TBX3 target gene responsible for mediating its opposing oncogenic roles in chondrosarcoma and fibrosarcoma cells. Results from qRT-PCR, western blotting, luciferase reporter and chromatin immunoprecipitation assays show that TBX3 binds and activates the COL1A2 promoter. Furthermore, we show that TBX3 levels are regulated by AKT1 and that pseudo-phosphorylation of TBX3 at an AKT consensus serine site, enhances its ability to activate COL1A2. Importantly, we demonstrate that COL1A2 mediates the pro- and anti-migratory effects of TBX3 in chondrosarcoma and fibrosarcoma cells respectively. Our data reveal that the AKT1/TBX3/COL1A2 axis plays an important role in sarcomagenesis.

The T-Box transcription factor 3 in development and cancer.

T-box factors comprise an archaic family of evolutionary conserved transcription factors that regulate patterns of gene expression essential for embryonic development. The T-box transcription factor 3 (TBX3), a member of this family, is expressed in several tissues and plays critical roles in, among other structures, the heart, mammary gland and limbs and haploinsufficiency of the human TBX3 gene is the genetic basis for the autosomal dominant disorder, ulnar-mammary syndrome. Overexpression of TBX3 on the other hand has been linked to several cancers including melanoma, breast, pancreatic, liver, lung, head and neck, ovarian, bladder carcinomas and a number of sarcoma subtypes. Furthermore, there is strong evidence that TBX3 promotes oncogenesis by impacting proliferation, tumour formation, metastasis as well as cell survival and drug resistance. More recently, TBX3 was however shown to also have tumour suppressor activity in fibrosarcomas and thus its functions in oncogenesis appear to be context dependent. Identification of the upstream regulators of TBX3 and the molecular mechanism(s) underpinning its oncogenic roles will make valuable contributions to cancer biology.