An investigation into the role of TBX3 in breast carcinogenesis and its regulation by the TGF-?1 signalling pathway

Doctoral Thesis

2014

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University of Cape Town

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Cancer is the second leading cause of death among both men and women and accounts for 13% of total deaths worldwide. Enormous efforts have therefore been made to cope with this problem, but unfortunately limited success has been achieved with most of the current therapeutic strategies. The T-box family of developmentally important transcription factors plays a role in the genesis of cancer and shows much promise as a focus for targeted therapeutic approaches to treat cancer. For example, the T-box factor TBX3 is overexpressed in a number of cancers including breast cancer but the mechanism(s) responsible for this upregulation as well as the precise role of TBX3 in the progression of this disease still need to be elucidated. This study provides novel data that show that TBX3 is specifically involved in breast cancer cell proliferation and migration and that its upregulation by the TGF-β1 signalling pathway mediates the TGF-β1-regulated anti-proliferative and pro-migratory effects. Furthermore, this study demonstrates that TBX3 mediates the anti-proliferative function of TGF-β1 through repressing transcription of its homologue, TBX2, which allows for the de-repression of p21 and a G1 cell cycle arrest. The findings of the current study are of great significance as it identifies TBX3 as a potential target for the development of novel breast cancer therapeutics. In order to ascertain the function of upregulated expression of TBX3, cell culture models were established in which TBX3 was either (1) stably silenced in an invasive breast ductal carcinoma cell line (MCF-7) which was previously shown to overexpress TBX3 or (2) overexpressed in a normal human breast epithelial cell line (MCF-12A). The resultant cells were then compared to control cells and tested for key characteristics of cancer. The data generated provide evidence that increased TBX3 levels inhibit breast epithelial cell proliferation in growth curve, BrdU incorporation and MTT assays. However, in vitro motility assays show that TBX3 may contribute to breast cancer progression by enhancing the migratory ability of these cells.
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