Abstract
BackgroundTBX3 is a T-box transcription factor repressor that is elevated in metastatic breast cancer and is believed to promote malignancy of tumor cells, possibly by promoting cell survival and epithelial-mesenchymal transition.MethodsThe relative expression of TBX3 was assessed in the 21T cell lines which were derived from an individual patient and represent three distinct stages of breast cancer progression: 21PT, atypical ductal hyperplasia; 21NT, ductal carcinoma in situ; and 21MT-1, invasive mammary carcinoma. Two different isoforms of TBX3 (TBX3iso1 and TBX3iso2) were overexpressed to evaluate cell survival/colony forming ability, growth, and invasion in the ductal carcinoma in situ-like 21NT cell line using an in vitro Matrigel model of cancer progression. In addition, TBX3 expression was knocked down to evaluate the effects of downregulating TBX3 on the invasive mammary carcinoma-like 21MT-1 cell line. Finally, PCR array profiling was used to assess alterations in gene expression due to TBX3 overexpression in the 21NT cells.ResultsTBX3 is abundant in the invasive 21MT-1 cell line, while being minimally expressed in the non-invasive 21NT and 21PT cell lines. Overexpression of either TBX3iso1 or TBX3iso2 in 21NT cells resulted in increased cell survival/colony forming ability, growth vs. apoptosis and invasion in Matrigel. In contrast, short hairpin RNA-mediated knockdown of TBX3 in the 21MT-1 cells resulted in smaller colonies, with a more regular, less dispersed (less infiltrative) morphology. Array profiling of the 21NT TBX3 iso1 and iso2 transfectants showed that there are common alterations in expression of several genes involved in signal transduction, cell cycle control/cell survival, epithelial-mesenchymal transition and invasiveness.ConclusionsOverall, these results indicate that TBX3 (isoform 1 or 2) expression can promote progression in a model of early breast cancer by altering cell properties involved in cell survival/colony formation and invasiveness, as well as key regulatory and EMT/invasiveness-related gene expressions.
Highlights
T-box 3 (TBX3) is a T-box transcription factor repressor that is elevated in metastatic breast cancer and is believed to promote malignancy of tumor cells, possibly by promoting cell survival and epithelial-mesenchymal transition
We examined whether either or both isoforms of TBX3 could influence breast cancer progression, in particular the transition from non-invasive to invasive disease. We show that both isoforms of TBX3 have a similar functional effect in promoting breast cancer progression to a more malignant phenotype, and identify TBX3-induced changes in expression of genes involved in signal transduction, cell cycle control/cell survival and epithelial-mesenchymal transition (EMT)/invasiveness that may play a role in this progression
By using the 21T cell line series to model the effects of putative drivers of the transition from pre-invasive to invasive breast cancer progression, we are able to demonstrate that overexpression of TBX3 can promote the transition of Ductal carcinoma in situ (DCIS) to Invasive mammary carcinoma (IMC)
Summary
TBX3 is a T-box transcription factor repressor that is elevated in metastatic breast cancer and is believed to promote malignancy of tumor cells, possibly by promoting cell survival and epithelial-mesenchymal transition. The most critical stage of early breast cancer progression is the transition from in situ (ductal carcinoma in situ, DCIS) to invasive (invasive mammary carcinoma, IMC) disease. We previously identified Tbox transcription factor 3 (TBX3) as a potential regulator of progression from DCIS to IMC, using the 21T cell lines which represent distinct stages of breast cancer progression [7]. We found that invasive, metastatic 21MT-1 cells expressed higher levels of TBX3 than noninvasive, DCIS-like 21NT cells or non-invasive, atypical ductal hyperplasia (ADH)-like 21PT cells [7]. A model has emerged in which TBX3 expression is both induced and maintained in early mammary gland initiation by Wnt and fibroblast growth factor (FGF) [8]. Ulnarmammary syndrome, a congenital autosomal dominant disorder, is caused by mutations that result in haploinsufficiency of TBX3 and is characterized by upper-limb anomalies and mammary gland hypoplasia [9]
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