MBoC | ARTICLE The oncogenic TBX3 is a downstream target and mediator of the TGF-β1 signaling pathway

ABSTRACT The T-box transcription factor, TBX3, plays an important role in embryonic devel-opment, and haploinsufficiency of TBX3 causes ulnar–mammary syndrome. Overexpression of TBX3, on the other hand, is associated with several cancers, and preliminary evidence sug-gests that increased levels of TBX3 may inhibit cell proliferation but promote tumor migra-tion and invasion. Although this suggests that deregulated levels of TBX3 are deleterious in development and promotes disease, very little is known about the signaling pathways that regulate TBX3 expression. Here we show that overexpressing TBX3 inhibits proliferative abil-ity while promoting the migration of breast epithelial cells. We demonstrate that the trans-forming growth factor β1 (TGF-β1) pathway up-regulates TBX3 protein and mRNA levels and show a detailed transcriptional mechanism by which this occurs. Using in vitro and in vivo as-says, we show that Smad3/4 and JunB bind and cooperatively regulate TBX3 promoter activ-ity through a Smad-binding element at −67 base pairs. Further, we show that TBX3 plays a pivotal role in mediating the antiproliferative and promigratory role of TGF-β1 in breast epi-thelial and skin keratinocytes. This study identifies the TGF-β1 signaling pathway as a poten-tially important player in the regulation of TBX3 in development and cancer