TBX3, the gene mutated in ulnar-mammary syndrome, promotes growth of mammary epithelial cells via repression of p19ARF, independently of p53

Platonova, N.; Scotti, Maddalena; Babich, Polina S.; Bertoli, Gloria; Mento, E.; Meneghini, Vasco; Egeo, Aliana; Zucchi, Ileana; Merlo, Giorgio R.

doi:10.1007/s00441-006-0364-4

Cited by 28 publications

(32 citation statements)

References 72 publications

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“…Our work is in agreement with that of previous studies with other mammary epithelial cells (MCF-7, MDA-MB-435, HC11) [24, 25] in which TBX3 was shown to have functional effects including inhibition of senescence and promotion of cell survival, proliferation and migration. We present the added novel finding, using a progression series of mammary epithelial cells, that overexpression of TBX3 can trigger non-invasive (DCIS-like, 21NT) cells to become invasive, possibly through an EMT-like process.…”

Section: Discussionsupporting

confidence: 93%

The transcriptional regulator TBX3 promotes progression from non-invasive to invasive breast cancer

et al. 2016

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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.

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Section: Discussionsupporting

confidence: 93%

The transcriptional regulator TBX3 promotes progression from non-invasive to invasive breast cancer

et al. 2016

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“…Together these results suggest that TBX3 functions as a pro-proliferative factor, in part, by promoting transition into G2/M. TBX3 can also promote cell proliferation of mammary epithelial cells (MECs) by repressing 19ARF, which was accompanied by the down-regulation of p21 (52)…”

Section: Tbx3 In Senescence Apoptosis and Proliferationmentioning

confidence: 89%

The T-Box transcription factor 3 in development and cancer

Willmer

Cooper

Peres

et al. 2017

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“…8,[25][26][27] The effect of knocking down TBX3 on levels of several potential pro-senescence factors was therefore analyzed, and our results show that the shTBX3 cells had reduced levels of all pro-senescence factors tested (Fig. 2C).…”

Section: Knocking Down Tbx3 Increases the Proliferative Ability Of Vgmentioning

confidence: 89%

The Highly Homologous T-Box Transcription Factors, TBX2 and TBX3, Have Distinct Roles in the Oncogenic Process

et al. 2010

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The T-box transcription factors TBX2 and TBX3 are overexpressed in several cancers and are able to bypass senescence by repressing ARF and p21 WAF1/CIP1/SDII . Although these studies suggest that they may both contribute to the oncogenic process by repressing common targets, whether they have redundant or distinct roles in cancers where they are both overexpressed remains to be elucidated. Importantly, when Tbx2 function is inhibited in melanoma cells lacking Tbx3, the cells senesce, but whether this is possible in melanoma cells overexpressing both proteins is not known. An understanding of this issue may have important implications for the design of an effective pro-senescence therapy. In this study, the authors used a sh-RNA approach to knock down TBX2 and TBX3 individually in 2 human melanoma cell lines that overexpress both these factors and then examined their specific involvement in the oncogenic process. They demonstrate, using in vitro and in vivo cell proliferation, as well as colony-and tumor-forming ability and cell motility assays, that TBX2 and TBX3 have distinct roles in melanoma progression. In the tested lines, although TBX2 could promote proliferation and transformation and was required by primary melanoma cells for immortality, TBX3 was required for tumor formation and cell migration. These findings were reproducible in a human breast cancer cell line, which confirms that TBX2 and TBX3, although highly homologous, do not have redundant roles in the transformation process of cancers where they are both overexpressed. These results have important implications for the development of new cancer treatments and in particular for melanoma, which is a highly aggressive and intractable cancer.

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TBX3, the gene mutated in ulnar-mammary syndrome, promotes growth of mammary epithelial cells via repression of p19ARF, independently of p53

Cited by 28 publications

References 72 publications

The transcriptional regulator TBX3 promotes progression from non-invasive to invasive breast cancer

The transcriptional regulator TBX3 promotes progression from non-invasive to invasive breast cancer

The T-Box transcription factor 3 in development and cancer

The Highly Homologous T-Box Transcription Factors, TBX2 and TBX3, Have Distinct Roles in the Oncogenic Process

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