Increased expression of cSHMT, Tbx3 and utrophin in plasma of ovarian and breast cancer patients

Lomnytska, Marta; Dubrovska, Anna; Hellman, Ulf; Volodko, Natalya; Souchelnytskyi, Serhiy

doi:10.1002/ijc.21332

Cited by 66 publications

(61 citation statements)

References 21 publications

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“…We also found high levels of TBX3 in the cytoplasm. The elevated cytoplasmic TBX3 protein levels in our result suggest that TBX3 ''leaks'' into the cytoplasm and, subsequently, enters the blood stream from the tumor tissue, which results in elevated serum levels in cancer patients (8). This result further suggests that TBX3 is involved in breast cancer and can serve as a biomarker for breast cancer.…”

Section: Discussionmentioning

confidence: 50%

“…Previously, we have shown that TBX3 is overexpressed in a number of breast cancer cell lines (7). In the search for breast cancer biomarkers in blood, one study showed that serum TBX3 protein levels were abnormally high in patients with breast cancer (8). This suggests that serum TBX3 levels could serve as a biomarker and it warrants a more extensive evaluation of the role of TBX3 in breast cancer and the pathogenesis of this disease in humans.…”

Section: Introductionmentioning

confidence: 99%

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TBX3 Is Overexpressed in Breast Cancer and Represses p14ARF by Interacting with Histone Deacetylases

Yarosh¹,

Barrientos²,

Esmailpour³

et al. 2008

Cancer Research

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TBX3 is a transcription factor of the T-box gene family. Mutations in the TBX3 gene can cause hypoplastic or absent mammary glands. Previous studies have shown that TBX3 might be associated with breast cancer. Here, we show that TBX3 is overexpressed in malignant cells of primary breast cancer tissues by immunohistochemistry. TBX3 interacts with histone deacetylases (HDAC) 1, 2, 3, and 5. TBX3 interacts with HDAC1, 2, and 3 via two distinct binding sites. However, deletion of the repression domain (amino acids 566-624) of TBX3 completely abolishes its interaction with HDAC5. Endogenous TBX3 and HDACs interaction and colocalization are found in a breast cancer cell line by coimmunoprecipitation and immunofluorescence, respectively. The functional significance of the interaction between TBX3 and HDAC is also tested in a p14 ARF -luciferase reporter system. Results indicate that TBX3 represses expression of p14 ARF tumor suppressor and that a HDAC inhibitor is able to reverse the TBX3 repressive function in a dosage-dependant manner. This study suggests that TBX3 may function by recruiting HDACs to the T-box binding site in the promoter region. TBX3 repression to its targets is dependent on HDAC activity. TBX3 may serve as a biomarker for breast cancer and have significant applications in both breast cancer diagnosis and treatment. [Cancer Res 2008;68(3):693-9]

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Section: Discussionmentioning

confidence: 50%

Section: Introductionmentioning

confidence: 99%

TBX3 Is Overexpressed in Breast Cancer and Represses p14ARF by Interacting with Histone Deacetylases

Yarosh¹,

Barrientos²,

Esmailpour³

et al. 2008

Cancer Research

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“…Both these factors are also overexpressed in a subset of pancreatic cancers (18,19) and melanomas (15,20). In addition, Tbx3 has been implicated in bladder (21), liver, (22) and ovarian cancers (23). One mechanism by which Tbx3 may be involved in oncogenesis has been suggested by a study that showed that Tbx3 can cooperate with oncogenic Myc and Ras to induce cellular transformation and suppress apoptosis through repression of p19 ARF expression and p53 protein levels (24).…”

Section: Waf1/cip1/sdiimentioning

confidence: 99%

UV-mediated Regulation of the Anti-senescence Factor Tbx2

Abrahams

Mowla

Parker

et al. 2008

Journal of Biological Chemistry

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Several lines of evidence have implicated members of the developmentally important T-box gene family in cell cycle regulation and in cancer. Importantly, the highly related T-box factors Tbx2 and Tbx3 can suppress senescence through repressing the cyclindependent kinase inhibitors p19 ARF and p21 WAF1/CIP1/SDII. Furthermore, Tbx2 is up-regulated in several cancers, including melanomas where it was shown to function as an anti-senescence factor, suggesting that this may be one of the mechanisms by which T-box proteins contribute to the oncogenic process. However, very little is known about whether Tbx2 is regulated by p21-mediated stress-induced senescence signaling pathways. In this study, using the MCF-7 breast cancer cell line known to overexpress Tbx2, we show that in response to stress induced by ultraviolet irradiation the Tbx2 protein is specifically phosphorylated by the p38 mitogen-activated protein kinase. Using sitedirected mutagenesis and in vitro kinase assays, we have identified serine residues 336, 623, and 675 in the Tbx2 protein as the p38 target sites and show that these sites are phosphorylated in vivo. Importantly, we show by Western blotting, immunofluorescence, and reporter assays that this phosphorylation leads to increased Tbx2 protein levels, predominant nuclear localization of the protein, and an increase in the ability of Tbx2 to repress the p21 WAF1/CIP1/SDII promoter. These results show for the first time that the ability of Tbx2 to repress the p21 gene is enhanced in response to a stress-induced senescence pathway, which leads to a better understanding of the regulation of the anti-senescence function of Tbx2.

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“…[8][9][10][11] Additionally, both factors are overexpressed in numerous human cancers, including ovarian, cervical, pancreatic, breast, and melanoma. 9,[11][12][13][14][15][16][17][18][19] Although these studies suggest that TBX2 and TBX3 may contribute to the oncogenic process by bypassing senescence through their ability to repress common targets, whether they have redundant or distinct roles in cancers where they are both overexpressed has not yet been elucidated. Importantly, when Tbx2 function is inhibited in mouse melanoma cells lacking Tbx3, the cells senesce, 18 but whether this is possible in human melanoma cells overexpressing both proteins is not known.…”

Section: Introductionmentioning

confidence: 99%

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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Increased expression of cSHMT, Tbx3 and utrophin in plasma of ovarian and breast cancer patients

Cited by 66 publications

References 21 publications

TBX3 Is Overexpressed in Breast Cancer and Represses p14ARF by Interacting with Histone Deacetylases

TBX3 Is Overexpressed in Breast Cancer and Represses p14ARF by Interacting with Histone Deacetylases

UV-mediated Regulation of the Anti-senescence Factor Tbx2

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

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