Ectopic Tbx2 expression results in polyploidy and cisplatin resistance

Davis, Emily; Teng, Huajian; Bilican, Bilada; Parker, M. Iqbal; Liu, B.; Carriera, S; Goding, Colin R.; Prince, Sharon

doi:10.1038/sj.onc.1210701

Cited by 44 publications

(49 citation statements)

References 27 publications

(34 reference statements)

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“…TBX2 may serve as a prognostic factor of breast cancer (7,9), melanoma (8), gastric cancer (10), prostate cancer (11), laryngeal squamous cell carcinoma (12), and non-small cell lung cancer (14). TBX2 is associated with resistance to therapeutic drugs such as cisplatin and doxorubicin (15,16), and TBX2 therefore may serve as a therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of TBX2 occurs in breast cancer (7,9), melanoma (8) pancreatic cancer (10), gastric cancer (11), prostate cancer (12), laryngeal squamous cell carcinoma (13), and non-small cell lung cancer (14). The ectopic expression of TBX2 is associated with resistance to the DNA-damaging chemotherapeutic drugs cisplatin and doxorubicin (15,16). However, the mechanism of regulation of expression and the role of TBX2 in ovarian cancer remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

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TBX2 expression is associated with platinum‑sensitivity of ovarian serous carcinoma

et al. 2017

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Abstract. The standard treatment for ovarian serous carcinoma comprises maximum debulking surgery and platinum-based chemotherapy. Despite the high response rate to chemotherapy, the majority of patients will be resistant to first-line agents and the prognosis for these patients is particularly poor. At present there are no reliable methods to determine or predict platinum resistance. T-box 2 (TBX2) is widely expressed in cancer cells and is involved in embryonic development and cell cycle regulation. TBX2 enables cells to bypass senescence through its ability to repress the cell cycle regulators p21 and p14 ARF ; silencing TBX2 induces senescence. Ectopic expression of TBX2 is associated with conferred resistance to the DNA-damaging chemotherapeutic drugs cisplatin and doxorubicin. In the present study the association between TBX2 expression and platinum sensitivity was investigated. A total of 54 patients with ovarian serous carcinoma (FIGO stages III and IV) were treated at Osaka City University Hospital (Osaka, Japan) from January 2005 to December 2012. Patients were divided into platinum-sensitive (n=27) and resistant (n=27) groups, according to the platinum-free interval calculated from the last platinum administration to the time of recurrence. TBX2 expression in human ovarian serous carcinoma cells was inhibited by a TBX2-specific siRNA and changes in cisplatin and carboplatin sensitivity were determined. The TBX2-weighted score was significantly lower in the platinum-sensitive group than the platinum-resistant group (P=0.005) and the low TBX2 expression group was significantly more sensitive to platinum-based chemotherapy (P=0.004). Sensitivity to cisplatin and carboplatin significantly increased when TBX2 expression was inhibited in human ovarian serous carcinoma cells in vitro (P<0.05). TBX2 expression may serve as a predictive marker of the efficacy of platinum-based chemotherapy for patients with ovarian serous carcinoma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TBX2 expression is associated with platinum‑sensitivity of ovarian serous carcinoma

et al. 2017

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“…35 Primary antibodies used were as follows: rabbit polyclonal anti-TBX3 (Zymed, San Francisco, CA) and rabbit polyclonal anti-p38 (Sigma, St. Louis, MO), goat polyclonal anti-TBX2 (sc-17880), rabbit polyclonal antip53 (sc-6243), anti-p21 (sc-756), anti-p18INK4C (sc-865), anti-p16 (sc-759), and anti-p14 (sc-1063) (Santa Cruz Biotechnology, Santa Cruz, CA).…”

Section: Western Blot Analysismentioning

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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“…The cell cycle phase distribution was assessed by measuring DNA content by flow cytometry as described previously. 51 Western blot analyses Cells were harvested and solubilized at 4 C in RIPA buffer (150 mM NaCl, 1% Triton X-100, 0.1% SDS, 20 mM Tris pH 7.5, 1% deoxycholate and a cocktail of protease inhibitors), centrifuged at 12,000g for 20 min at 4 C and the supernatants recovered. Protein were resolved by SDS-PAGE and transferred to Hybond C (Amersham, United Kingdom).…”

Section: Plasmids and Mutagenesismentioning

confidence: 99%

The T-Box factor TBX3 is important in S-phase and is regulated by c-Myc and cyclin A-CDK2

et al. 2015

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The transcription factor, TBX3, is critical for the formation of, among other structures, the heart, limbs and mammary glands and haploinsufficiency of the human TBX3 gene result in ulnar-mammary syndrome which is characterized by hypoplasia of these structures. On the other hand, the overexpression of TBX3 is a feature of a wide range of cancers and it has been implicated in several aspects of the oncogenic process. This includes its ability to function as an immortalizing gene and to promote proliferation through actively repressing negative cell cycle regulators. Together this suggests that TBX3 levels may need to be tightly regulated during the cell cycle. Here we demonstrate that this is indeed the case and that TBX3 mRNA and protein levels peak at S-phase and that the TBX3 protein is predominantly localized to the nucleus of S-phase cells. The increased levels of TBX3 in S-phase are shown to occur transcriptionally through activation by c-Myc at E-box motifs located at ¡1210 and ¡701 bps and post-translationally by cyclin A-CDK2 phosphorylation. Importantly, when TBX3 is depleted by shRNA the cells accumulate in S-phase. These results suggest that TBX3 is required for cells to transit through S-phase and that this function may be linked to its role as a proproliferative factor.

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Ectopic Tbx2 expression results in polyploidy and cisplatin resistance

Cited by 44 publications

References 27 publications

TBX2 expression is associated with platinum‑sensitivity of ovarian serous carcinoma

TBX2 expression is associated with platinum‑sensitivity of ovarian serous carcinoma

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

The T-Box factor TBX3 is important in S-phase and is regulated by c-Myc and cyclin A-CDK2

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