TBX2

Gene Summary

Gene:TBX2; T-box transcription factor 2
Aliases: VETD
Location:17q23.2
Summary:This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene product is the human homolog of mouse Tbx2, and shares strong sequence similarity with Drosophila omb protein. Expression studies indicate that this gene may have a potential role in tumorigenesis as an immortalizing agent. Transcript heterogeneity due to alternative polyadenylation has been noted for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:T-box transcription factor TBX2
Source:NCBIAccessed: 30 August, 2019

Ontology:

What does this gene/protein do?
Show (27)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Transcription
  • Staging
  • Gene Amplification
  • Pancreatic Cancer
  • Neoplasm Invasiveness
  • Western Blotting
  • Antineoplastic Agents
  • Transcription Factors
  • Breast Cancer
  • Vimentin
  • Neoplastic Cell Transformation
  • Epithelial Cells
  • Chromatin Immunoprecipitation
  • Signal Transduction
  • Epigenetics
  • TGFA
  • Oncogenes
  • Promoter Regions
  • Immunohistochemistry
  • Apoptosis
  • Young Adult
  • Cancer Gene Expression Regulation
  • Protein Binding
  • siRNA
  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • COS Cells
  • RTPCR
  • Melanocytes
  • Gene Expression Profiling
  • Up-Regulation
  • Molecular Sequence Data
  • DNA Methylation
  • Down-Regulation
  • Melanoma
  • Oligonucleotide Array Sequence Analysis
  • Cellular Senescence
  • Transfection
  • Chromosome 17
  • Bladder Cancer
  • Cell Proliferation
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TBX2 (cancer-related)

Nehme E, Rahal Z, Sinjab A, et al.
Epigenetic Suppression of the T-box Subfamily 2 (
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
(1) The

Decaesteker B, Denecker G, Van Neste C, et al.
TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets.
Nat Commun. 2018; 9(1):4866 [PubMed] Free Access to Full Article Related Publications
Chromosome 17q gains are almost invariably present in high-risk neuroblastoma cases. Here, we perform an integrative epigenomics search for dosage-sensitive transcription factors on 17q marked by H3K27ac defined super-enhancers and identify TBX2 as top candidate gene. We show that TBX2 is a constituent of the recently established core regulatory circuitry in neuroblastoma with features of a cell identity transcription factor, driving proliferation through activation of p21-DREAM repressed FOXM1 target genes. Combined MYCN/TBX2 knockdown enforces cell growth arrest suggesting that TBX2 enhances MYCN sustained activation of FOXM1 targets. Targeting transcriptional addiction by combined CDK7 and BET bromodomain inhibition shows synergistic effects on cell viability with strong repressive effects on CRC gene expression and p53 pathway response as well as several genes implicated in transcriptional regulation. In conclusion, we provide insight into the role of the TBX2 CRC gene in transcriptional dependency of neuroblastoma cells warranting clinical trials using BET and CDK7 inhibitors.

Durbin AD, Zimmerman MW, Dharia NV, et al.
Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry.
Nat Genet. 2018; 50(9):1240-1246 [PubMed] Free Access to Full Article Related Publications
Childhood high-risk neuroblastomas with MYCN gene amplification are difficult to treat effectively

Dhawan D, Hahn NM, Ramos-Vara JA, Knapp DW
Naturally-occurring canine invasive urothelial carcinoma harbors luminal and basal transcriptional subtypes found in human muscle invasive bladder cancer.
PLoS Genet. 2018; 14(8):e1007571 [PubMed] Free Access to Full Article Related Publications
There is growing evidence that molecular subtypes (e.g. luminal and basal subtypes) affect the prognosis and treatment response in patients with muscle invasive urinary bladder cancer (invasive urothelial carcinoma, iUC). Modeling these subtypes in pre-clinical animal studies is essential, but it is challenging to produce these subtypes, along with other critical host and tumor features, in experimentally-induced animal models. This study was conducted to determine if luminal and basal molecular subtypes are present in naturally-occurring canine iUC, a cancer that mimics the human condition in other key aspects. RNA sequencing was performed on 29 canine treatment naive iUC tissue samples and on four normal canine bladder mucosal samples. Data were aligned to CanFam 3.1, and differentially expressed genes were identified. Unsupervised hierarchical clustering of these genes revealed two distinct groups (n = 13, n = 16). When genes that distinguish basal and luminal subtypes in human cancer (n = 2015) were used to probe genes differentially expressed between normal canine bladder and iUC, 829 enriched signature genes were identified. Unsupervised hierarchical clustering of these genes revealed two distinct groups comprised of 18 luminal subtype tumors and 11 basal subtype tumors. The enriched genes included MMP9, SERPINE2, CAV1, KRT14, and RASA3 in basal tumors, and PPARG, LY6E, CTSE, CDK3, and TBX2 in luminal tumors. In supervised clustering, additional genes of importance in human iUC were identified in canine iUC associated with claudin-low and infiltrated tumors. A smaller panel of genes (n = 60) was identified that distinguished canine luminal and basal iUC with overall 93.1% accuracy. Immune signature patterns similar to those in human iUC were also identified with the greatest enrichment of immune genes being in the basal subtype tumors. These findings provide additional compelling evidence that naturally-occurring canine iUC is a highly relevant and much needed model of human iUC for translational research.

Royer-Pokora B, Beier M, Brandt A, et al.
Chemotherapy and terminal skeletal muscle differentiation in WT1-mutant Wilms tumors.
Cancer Med. 2018; 7(4):1359-1368 [PubMed] Free Access to Full Article Related Publications
Wilms tumors (WT) with WT1 mutations do not respond well to preoperative chemotherapy by volume reduction, suggesting resistance to chemotherapy. The histologic pattern of this tumor subtype indicates an intrinsic mesenchymal differentiation potential. Currently, it is unknown whether cytotoxic treatments can induce a terminal differentiation state as a direct comparison of untreated and chemotherapy-treated tumor samples has not been reported so far. We conducted gene expression profiling of 11 chemotherapy and seven untreated WT1-mutant Wilms tumors and analyzed up- and down-regulated genes with bioinformatic methods. Cell culture experiments were performed from primary Wilms tumors and genetic alterations in WT1 and CTNNB1 analyzed. Chemotherapy induced MYF6 165-fold and several MYL and MYH genes more than 20-fold and repressed many genes from cell cycle process networks. Viable tumor cells could be cultivated when patients received less than 8 weeks of chemotherapy but not in two cases with longer treatments. In one case, viable cells could be extracted from a lung metastasis occurring after 6 months of intensive chemotherapy and radiation. Comparison of primary tumor and metastasis cells from the same patient revealed up-regulation of RELN and TBX2, TBX4 and TBX5 genes and down-regulation of several HOXD genes. Our analyses demonstrate that >8 weeks of chemotherapy can induce terminal myogenic differentiation in WT1-mutant tumors, but this is not associated with volume reduction. The time needed for all tumor cells to achieve the terminal differentiation state needs to be evaluated. In contrast, prolonged treatments can result in genetic alterations leading to resistance.

Yi J, Wei X, Li X, et al.
A genome-wide comprehensive analysis of alterations in driver genes in non-small-cell lung cancer.
Anticancer Drugs. 2018; 29(1):10-18 [PubMed] Related Publications
Lung cancer is one of the most common malignancies and the leading cause of cancer-related deaths worldwide. Although many oncogenes and tumor suppressors have been uncovered in the past decades, the pathogenesis and mechanisms of lung tumorigenesis and progression are unclear. The advancement of high-throughput sequencing technique and bioinformatics methods has led to the discovery of some unknown important protein-coding genes or noncoding RNAs in human cancers. In this study, we tried to identify and validate lung cancer driver genes to facilitate the diagnosis and individualized treatment of patients with this disease. To analyze distinct gene profile in lung cancer, the RNA sequencing data from TCGA and microarray data from Gene Expression Omnibus were used. Then, shRNA-pooled screen data and CRISPR-Cas9-based screen data in lung cancer cells were used to validate the functional roles of identified genes. We found that thousands of gene expression patterns are altered in lung cancer, and genomic alterations contribute to the dysregulation of these genes. Furthermore, we identified some potential lung cancer driver genes, such as TBX2, MCM4, SLC2A1, BIRC5, and CDC20, whose expression is significantly upregulated in lung cancer, and the copy number of these genes is amplified in the genome of patients with lung cancer. More importantly, overexpression of these genes is associated with poorer survival of patients with lung cancer, and knockdown or knockout of these genes results in decreased cell proliferation in lung cancer cells. Taken together, the genomewide comprehensive analysis combined with screen data analyses may provide a valuable help for identifying cancer driver genes for diagnosis and prevention of patients with lung cancer.

Wu HC, Yang HI, Wang Q, et al.
Plasma DNA methylation marker and hepatocellular carcinoma risk prediction model for the general population.
Carcinogenesis. 2017; 38(10):1021-1028 [PubMed] Free Access to Full Article Related Publications
Metastases in the later stages of hepatocellular carcinoma (HCC) cause the majority of deaths associated with the disease, making early detection crucial to patient survival. Risk models assessing HCC risk in the general population can be used for risk stratification for further HCC surveillance, however, none have been validated externally. Methylation of circulating DNA shows potential for non-invasive diagnosis of HCC. We conducted a prospective case-control study nested within a community-based cohort. We measured methylation levels in six genes (CDKN2A, RASSF1A, STEAP4, TBX2, VIM and ZNF154) which were identified in our previous work, using pre-diagnostic plasma DNA from 237 HCC cases and 257 matched controls. We found TBX2 hypermethylation was associated with increased HCC risk, with ORs (95% CI) of 3.2 (1.8-6.0). The associations were mainly among high-risk subjects; among subjects infected with HBV/HCV, the OR (95% CI) of TBX2 methylation was 5.3 (2.2-12.7). Among subjects with high risk scores, the ORs (95% CIs) were 7.8 (1.5-38.6) for Wen-HCC model ≥16, 5.8 (2.2-15.5) for Hung-HCC ≥15 and 7.5 (2.2-26.0) for Michikawa-HCC ≥8. Adding TBX2 methylation improved the accuracy of risk models for a high-risk population, with the area under the curve (AUC) of 76% for Wen-HCC score with TBX2 methylation compared with 69% with Wen-HCC alone. The AUCs were 63% for Hung-HCC score plus TBX2 methylation, and 53% for Hung-HCC alone, 65% for Michikawa-HCC score plus TBX2 methylation and 58% for Michikawa-HCC alone. Our findings suggest the potential increase in risk assessment discrimination and accuracy from incorporation of DNA methylation.

Du WL, Fang Q, Chen Y, et al.
Effect of silencing the T‑Box transcription factor TBX2 in prostate cancer PC3 and LNCaP cells.
Mol Med Rep. 2017; 16(5):6050-6058 [PubMed] Free Access to Full Article Related Publications
T‑Box (TBX)‑2 is a member of the T‑box gene family, which is aberrantly expressed in numerous types of malignant tumors, and has previously been demonstrated to be conducive to tumor progression by acting as a transcription factor. However, specific information regarding the expression and function of TBX2 in prostate cancer cells remains to be elucidated. The present study demonstrated that silencing of TBX2 by TBX2 small interfering RNA inhibited cell proliferation and promoted cell senescence. It was demonstrated that knockdown of TBX2 inhibited cell metastatic abilities by upregulating E‑cadherin and downregulating N‑cadherin, Vimentin and fibronectin. In addition, the expression of TBX2 in prostate cancer tissues and tumor adjacent tissues was detected by immunohistochemistry. The results indicated that the expression rates of TBX2 were significantly increased in the cancerous tissues, compared with the healthy tumor adjacent tissue, and TBX2 increased staining was associated with the clinical stage and pathological grade. The findings of the present study therefore suggest that TBX2 expression is markedly increased in prostate cancer and TBX2 may act as a potential beneficial therapeutic target for the future treatment of prostate cancer.

Rani L, Mathur N, Gupta R, et al.
Genome-wide DNA methylation profiling integrated with gene expression profiling identifies
Clin Epigenetics. 2017; 9:57 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In chronic lymphocytic leukemia (CLL), epigenomic and genomic studies have expanded the existing knowledge about the disease biology and led to the identification of potential biomarkers relevant for implementation of personalized medicine. In this study, an attempt has been made to examine and integrate the global DNA methylation changes with gene expression profile and their impact on clinical outcome in early stage CLL patients.
RESULTS: The integration of DNA methylation profile (
CONCLUSIONS: The DNA methylation changes associated with mRNA expression of

Al-Zahrani M, Savage KJ
Peripheral T-Cell Lymphoma, Not Otherwise Specified: A Review of Current Disease Understanding and Therapeutic Approaches.
Hematol Oncol Clin North Am. 2017; 31(2):189-207 [PubMed] Related Publications
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), corresponds with a heterogeneous group of mature T-cell lymphomas. Recent gene expression profiling studies have identified at least two molecular subgroups (GATA3 and TBX2). Standard treatment and outcomes remain poor. High-dose chemotherapy with autologous stem cell transplantation is incorporated into primary therapy for young fit patients but remains ineffective for most and has not been tested in a randomized study. Several novel agents have been approved for use in relapsed/refractory PTCLs, and although response rates are modest for most, durable remissions have been reported. Selecting rationale combinations and incorporating predictive biomarkers will be important moving forward to improve outcomes in patients with PTCL.

Nandana S, Tripathi M, Duan P, et al.
Bone Metastasis of Prostate Cancer Can Be Therapeutically Targeted at the TBX2-WNT Signaling Axis.
Cancer Res. 2017; 77(6):1331-1344 [PubMed] Free Access to Full Article Related Publications
Identification of factors that mediate visceral and bone metastatic spread and subsequent bone remodeling events is highly relevant to successful therapeutic intervention in advanced human prostate cancer. TBX2, a T-box family transcription factor that negatively regulates cell-cycle inhibitor p21, plays critical roles during embryonic development, and recent studies have highlighted its role in cancer. Here, we report that TBX2 is overexpressed in human prostate cancer specimens and bone metastases from xenograft mouse models of human prostate cancer. Blocking endogenous TBX2 expression in PC3 and ARCaP

Farkas SA, Sorbe BG, Nilsson TK
Epigenetic changes as prognostic predictors in endometrial carcinomas.
Epigenetics. 2017; 12(1):19-26 [PubMed] Free Access to Full Article Related Publications
Endometrial carcinoma is one of the most frequent gynecological malignancies of the female. The diagnostic and prognostic markers for the high-risk subgroups with unfavorable prognosis are under intense debate worldwide, and, therefore, the aim of this study was to identify new potential DNA methylation markers for the high-risk groups. We used the Illumina Infinium HumanMethylation450 BeadChip to analyze the DNA methylation pattern and investigated its association with clinicopathological features important for defining the high-risk (FIGO-grade 3) and low-risk (FIGO-grade 1) groups of patients with endometrial cancer (n = 31 and n = 39, respectively). We identified specific DNA methylation signature in high-risk endometrial tumors, and potential molecular biomarker genes (TBX2, CHST11, and NID2) associated with unfavorable clinical predictive and prognostic factors.

Ashaie MA, Chowdhury EH
Cadherins: The Superfamily Critically Involved in Breast Cancer.
Curr Pharm Des. 2016; 22(5):616-38 [PubMed] Related Publications
Breast cancer, one of the leading causes of mortality and morbidity among females, is regulated in part by diverse classes of adhesion molecules one of which is known as cadherins. Located at adherens junctions, the members of this superfamily are responsible for upholding proper cell-cell adhesion. Cadherins possess diverse structures and functions and any alteration in their structures or functions causes impeding of normal mammary cells development and maintenance, thus leading to breast malignancy. E-, N-, P-, VE-, Proto-, desmosomal and FAT cadherins have been found to regulate breast cancer in positive as well as negative fashion, whereby both Ecadherin (CDH1) and N-cadherin (CDH2) contribute significantly towards transitioning from epithelial state to mesenchymal state (EMT) and enacting the abnormal cells to invade and metastasize nearby and distant tissues. Aberration in gene expression of cadherins can be either due to somatic or epigenetic silencing or via transcriptional factors. Besides other cadherins, E-cadherin which serves as hallmark of EMT is associated with several regulatory factors such as Snail, Slug, Twist, Zeb, KLF4, NFI, TBX2, SIX, b-Myb, COX-2, Arf6, FOXA2, GATA3 and SMAR1, which modulate E-cadherin gene transcription to promote or represses tumor invasion and colonization. Signaling molecules such as Notch, TGF-β, estrogen receptors, EGF and Wnt initiate numerous signaling cascades via these vital factors of cell programming, controlling expression of E-cadherin at transcriptional (mRNA) and protein level. Thus, interactions of cadherins with their roles in tumor suppression and oncogenic transformation can be beneficial in providing valuable insights for breast cancer diagnosis and therapeutics development.

Zhu B, Zhang M, Williams EM, et al.
TBX2 represses PTEN in rhabdomyosarcoma and skeletal muscle.
Oncogene. 2016; 35(32):4212-24 [PubMed] Free Access to Full Article Related Publications
Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children that shares many features of developing skeletal muscle. TBX2, a T-box family member, is highly upregulated in tumor cells of both major RMS subtypes where it functions as an oncogene. TBX2 is a repressor that is often overexpressed in cancer cells and functions in bypassing cell growth control, including the repression of the cell cycle regulators p14 and p21. We have found that TBX2 directly represses the tumor-suppressor phosphatase and tensin homolog (PTEN) in both RMS and normal muscle. Exogenous expression of TBX2 in normal muscle cells downregulates PTEN, and depletion or interference with TBX2 in RMS cells upregulates PTEN. Human RMS tumors show high levels of TBX2 and correspondingly low levels of PTEN. The expression of PTEN in clinical RMS samples is relatively uncharacterized, and we establish that suppression of PTEN is a frequent event in both subtypes of RMS. TBX2 represses PTEN by directly binding to the promoter and recruiting the histone deacetylase, HDAC1. RMS cells have high levels of activated AKT owing to the deregulation of phosphoinositide-3 kinase (PI3K) signaling, and depletion or interference with TBX2, which upregulates PTEN, results in a reduction of phospho-AKT. We have also found that the highly related T-box family member TBX3 does not repress PTEN in the muscle lineage. This work suggests that TBX2 is a central component of the PTEN/PI3K/AKT signaling pathway deregulation in RMS cells and that targeting TBX2 in RMS tumors may offer a novel therapeutic approach for RMS.

Beukers W, Kandimalla R, Masius RG, et al.
Stratification based on methylation of TBX2 and TBX3 into three molecular grades predicts progression in patients with pTa-bladder cancer.
Mod Pathol. 2015; 28(4):515-22 [PubMed] Related Publications
The potential risk of recurrence and progression in patients with non-muscle-invasive bladder cancer necessitates followup by cystoscopy. The risk of progression to muscle-invasive bladder cancer is estimated based on the European Organisation of Research and Treatment of Cancer score, a combination of several clinicopathological variables. However, pathological assessment is not objective and reproducibility is insufficient. The use of molecular markers could contribute to the estimation of tumor aggressiveness. We recently demonstrated that methylation of GATA2, TBX2, TBX3, and ZIC4 genes could predict progression in Ta tumors. In this study, we aimed to validate the markers in a large patient set using DNA from formalin-fixed and paraffin-embedded tissue. PALGA: the Dutch Pathology Registry was used for patient selection. We included 192 patients with pTaG1/2 bladder cancer of whom 77 experienced progression. Methylation analysis was performed and log-rank analysis was used to calculate the predictive value of each methylation marker for developing progression over time. This analysis showed better progression-free survival in patients with low methylation rates compared with the patients with high methylation rates for all markers (P<0.001) during a followup of ten-years. The combined predictive effect of the methylation markers was analyzed with the Cox-regression method. In this analysis, TBX2, TBX3, and ZIC4 were independent predictors of progression. On the basis of methylation status of TBX2 and TBX3, patients were divided into three new molecular grade groups. Survival analysis showed that only 8% of patients in the low molecular grade group progressed within 5 years. This was 29 and 63% for the intermediate- and high-molecular grade groups. In conclusion, this new molecular-grade based on the combination of TBX2 and TBX3 methylation is an excellent marker for predicting progression to muscle-invasive bladder cancer in patients with primary pTaG1/2 bladder cancer.

Shen J, Lu J, Sui L, et al.
The orthologous Tbx transcription factors Omb and TBX2 induce epithelial cell migration and extrusion in vivo without involvement of matrix metalloproteinases.
Oncotarget. 2014; 5(23):11998-2015 [PubMed] Free Access to Full Article Related Publications
The transcription factors TBX2 and TBX3 are overexpressed in various human cancers. Here, we investigated the effect of overexpressing the orthologous Tbx genes Drosophila optomotor-blind (omb) and human TBX2 in the epithelium of the Drosophila wing imaginal disc and observed two types of cell motility. Omb/TBX2 overexpressing cells could move within the plane of the epithelium. Invasive cells migrated long-distance as single cells retaining or regaining normal cell shape and apico-basal polarity in spite of attenuated apical DE-cadherin concentration. Inappropriate levels of DE-cadherin were sufficient to drive cell migration in the wing disc epithelium. Omb/TBX2 overexpression and reduced DE-cadherin-dependent adhesion caused the formation of actin-rich lateral cell protrusions. Omb/TBX2 overexpressing cells could also delaminate basally, penetrating the basal lamina, however, without degradation of extracellular matrix. Expression of Timp, an inhibitor of matrix metalloproteases, blocked neither intraepithelial motility nor basal extrusion. Our results reveal an MMP-independent mechanism of cell invasion and suggest a conserved role of Tbx2-related proteins in cell invasion and metastasis-related processes.

D'Costa ZC, Higgins C, Ong CW, et al.
TBX2 represses CST6 resulting in uncontrolled legumain activity to sustain breast cancer proliferation: a novel cancer-selective target pathway with therapeutic opportunities.
Oncotarget. 2014; 5(6):1609-20 [PubMed] Free Access to Full Article Related Publications
TBX2 is an oncogenic transcription factor known to drive breast cancer proliferation. We have identified the cysteine protease inhibitor Cystatin 6 (CST6) as a consistently repressed TBX2 target gene, co-repressed through a mechanism involving Early Growth Response 1 (EGR1). Exogenous expression of CST6 in TBX2-expressing breast cancer cells resulted in significant apoptosis whilst non-tumorigenic breast cells remained unaffected. CST6 is an important tumor suppressor in multiple tissues, acting as a dual protease inhibitor of both papain-like cathepsins and asparaginyl endopeptidases (AEPs) such as Legumain (LGMN). Mutation of the CST6 LGMN-inhibitory domain completely abrogated its ability to induce apoptosis in TBX2-expressing breast cancer cells, whilst mutation of the cathepsin-inhibitory domain or treatment with a pan-cathepsin inhibitor had no effect, suggesting that LGMN is the key oncogenic driver enzyme. LGMN activity assays confirmed the observed growth inhibitory effects were consistent with CST6 inhibition of LGMN. Knockdown of LGMN and the only other known AEP enzyme (GPI8) by siRNA confirmed that LGMN was the enzyme responsible for maintaining breast cancer proliferation. CST6 did not require secretion or glycosylation to elicit its cell killing effects, suggesting an intracellular mode of action. Finally, we show that TBX2 and CST6 displayed reciprocal expression in a cohort of primary breast cancers with increased TBX2 expression associating with increased metastases. We have also noted that tumors with altered TBX2/CST6 expression show poor overall survival. This novel TBX2-CST6-LGMN signaling pathway, therefore, represents an exciting opportunity for the development of novel therapies to target TBX2 driven breast cancers.

Zhu B, Zhang M, Byrum SD, et al.
TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells.
Int J Cancer. 2014; 135(4):785-97 [PubMed] Free Access to Full Article Related Publications
Rhabdomyosarcomas (RMSs) are the most frequent soft tissue sarcomas in children that share many features of developing skeletal muscle. We have discovered that a T-box family member, TBX2, is highly upregulated in tumor cells of both major RMS subtypes. TBX2 is a repressor that is often overexpressed in cancer cells and is thought to function in bypassing cell growth control, including repression of p14 and p21. The cell cycle regulator p21 is required for the terminal differentiation of skeletal muscle cells and is silenced in RMS cells. We have found that TBX2 interacts with the myogenic regulatory factors MyoD and myogenin and inhibits the activity of these factors. TBX2 is expressed in primary myoblasts and C2C12 cells, but is strongly downregulated upon differentiation. TBX2 recruits the histone deacetylase HDAC1 and is a potent inhibitor of the expression of muscle-specific genes and the cell cycle regulators, p21 and p14. TBX2 promotes the proliferation of RMS cells and either depletions of TBX2 or dominant negative TBX2 upregulate p21- and muscle-specific genes. Significantly, depletion or interference with TBX2 completely inhibits tumor growth in a xenograft assay, highlighting the oncogenic role of TBX2 in RMS cells. Thus, the data demonstrate that elevated expression of TBX2 contributes to the pathology of RMS cells by promoting proliferation and repressing differentiation-specific gene expression. These results show that deregulated TBX2 serves as an oncogene in RMS, suggesting that TBX2 may serve as a new diagnostic marker or therapeutic target for RMS tumors.

Douglas NC, Papaioannou VE
The T-box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer.
J Mammary Gland Biol Neoplasia. 2013; 18(2):143-7 [PubMed] Free Access to Full Article Related Publications
TBX2 and TBX3, closely related members of the T-box family of transcription factor genes, are expressed in mammary tissue in both humans and mice. Ulnar mammary syndrome (UMS), an autosomal dominant disorder caused by mutations in TBX3, underscores the importance of TBX3 in human breast development, while abnormal mammary gland development in Tbx2 or Tbx3 mutant mice provides models for experimental investigation. In addition to their roles in mammary development, aberrant expression of TBX2 and TBX3 is associated with breast cancer. TBX2 is preferentially amplified in BRCA1/2-associated breast cancers and TBX3 overexpression has been associated with advanced stage disease and estrogen-receptor-positive breast tumors. The regulation of Tbx2 and Tbx3 and the downstream targets of these genes in development and disease are not as yet fully elucidated. However, it is clear that the two genes play unique, context-dependent roles both in mammary gland development and in mammary tumorigenesis.

Burgucu D, Guney K, Sahinturk D, et al.
Tbx3 represses PTEN and is over-expressed in head and neck squamous cell carcinoma.
BMC Cancer. 2012; 12:481 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Despite advances in diagnostic and treatment strategies, head and neck squamous cell cancer (HNSCC) constitutes one of the worst cancer types in terms of prognosis. PTEN is one of the tumour suppressors whose expression and/or activity have been found to be reduced in HNSCC, with rather low rates of mutations within the PTEN gene (6-8%). We reasoned that low expression levels of PTEN might be due to a transcriptional repression governed by an oncogene. Tbx2 and Tbx3, both of which are transcriptional repressors, have been found to be amplified or over-expressed in various cancer types. Thus, we hypothesize that Tbx3 may be over expressed in HNSCC and may repress PTEN, thus leading to cancer formation and/or progression.
METHODS: Using immunohistochemistry and quantitative PCR (qPCR), protein and mRNA levels of PTEN and Tbx3 were identified in samples excised from cancerous and adjacent normal tissues from 33 patients who were diagnosed with HNSCC. In addition, HeLa and HEK cell lines were transfected with a Tbx3 expressing plasmid and endogenous PTEN mRNA and protein levels were determined via qPCR and flow cytometry. Transcription assays were performed to demonstrate effects of Tbx3 on PTEN promoter activity. Mann-Whitney, Spearman's Correlation and Wilcoxon signed-rank tests were used to analyze the data.
RESULTS: We demonstrate that in HNSCC samples, Tbx3 mRNA levels are increased with respect to their normal tissue counterparts (p<0.001), whereas PTEN mRNA levels are significantly reduced in cancer tissues. Moreover, Tbx3 protein is also increased in HNSCC tissue sections. Over-expression of Tbx3 in HeLa and HEK cell lines causes reduction in endogenous PTEN mRNA and protein levels. In addition, transcription activity assays reveal that Tbx3 is capable of repressing both the basal and induced promoter activity of PTEN.
CONCLUSIONS: We show that Tbx3 is up-regulated in tissue samples of HNSCC patients and that Tbx3 represses PTEN transcription. Thus, our data not only reveals a new mechanism that may be important in cancer formation, but also suggests that Tbx3 can be used as a potential biomarker in cancer.

Liu F, Cao J, Lv J, et al.
TBX2 expression is regulated by PAX3 in the melanocyte lineage.
Pigment Cell Melanoma Res. 2013; 26(1):67-77 [PubMed] Free Access to Full Article Related Publications
The paired box homeotic gene 3 (PAX3) is a crucial regulator for the maintenance of melanocytic progenitor cells and has a poorly defined role in melanoma. To understand how PAX3 affects melanocyte and melanoma proliferation, we identified potential PAX3 downstream targets through gene expression profiling. Here, we identify T-box 2 (TBX2), a key developmental regulator of cell identity and an antisenescence factor in melanoma, as a directly regulated PAX3 target. We also found that TBX2 is involved in the survival of melanoma cells and is overexpressed in some melanoma specimens. The identification of TBX2 as a target for PAX3 provides a key insight into how PAX3 may contribute to melanoma evolution and may provide opportunities for prosenescence therapeutic intervention aimed at disrupting the ability of PAX3 to regulate TBX2.

Wang B, Lindley LE, Fernandez-Vega V, et al.
The T box transcription factor TBX2 promotes epithelial-mesenchymal transition and invasion of normal and malignant breast epithelial cells.
PLoS One. 2012; 7(7):e41355 [PubMed] Free Access to Full Article Related Publications
The T box transcription factor TBX2, a master regulator of organogenesis, is aberrantly amplified in aggressive human epithelial cancers. While it has been shown that overexpression of TBX2 can bypass senescence, a failsafe mechanism against cancer, its potential role in tumor invasion has remained obscure. Here we demonstrate that TBX2 is a strong cell-autonomous inducer of the epithelial-mesenchymal transition (EMT), a latent morphogenetic program that is key to tumor progression from noninvasive to invasive malignant states. Ectopic expression of TBX2 in normal HC11 and MCF10A mammary epithelial cells was sufficient to induce morphological, molecular, and behavioral changes characteristic of EMT. These changes included loss of epithelial adhesion and polarity gene (E-cadherin, ß-catenin, ZO1) expression, and abnormal gain of mesenchymal markers (N-cadherin, Vimentin), as well as increased cell motility and invasion. Conversely, abrogation of endogenous TBX2 overexpression in the malignant human breast carcinoma cell lines MDA-MB-435 and MDA-MB-157 led to a restitution of epithelial characteristics with reciprocal loss of mesenchymal markers. Importantly, TBX2 inhibition abolished tumor cell invasion and the capacity to form lung metastases in a Xenograft mouse model. Meta-analysis of gene expression in over one thousand primary human breast tumors further showed that high TBX2 expression was significantly associated with reduced metastasis-free survival in patients, and with tumor subtypes enriched in EMT gene signatures, consistent with a role of TBX2 in oncogenic EMT. ChIP analysis and cell-based reporter assays further revealed that TBX2 directly represses transcription of E-cadherin, a tumor suppressor gene, whose loss is crucial for malignant tumor progression. Collectively, our results uncover an unanticipated link between TBX2 deregulation in cancer and the acquisition of EMT and invasive features of epithelial tumor cells.

Luo Y, Ellis LZ, Dallaglio K, et al.
Side population cells from human melanoma tumors reveal diverse mechanisms for chemoresistance.
J Invest Dermatol. 2012; 132(10):2440-2450 [PubMed] Free Access to Full Article Related Publications
Side population (SP) cells are identified as cells capable of excluding the fluorescent Hoechst dye and anticancer drugs, and it represents hematopoietic stem cells and chemoresistant cells from several solid tumors. In this study, we confirmed the presence of SP cells in tumors from melanoma patients. Melanoma SP cells overexpressed ATP-binding-cassette (ABC) transporters, ABCB1 and ABCB5. We generated a direct in vivo xenograft model, and demonstrated that SP cells were resistant to paclitaxel, a substrate of ABCB1, both in vitro and in vivo. However, melanoma SP cells were also resistant to temozolomide, which is not a substrate for ABC transporters, through IL-8 upregulation. In addition, gene profiling studies identified three signaling pathways (NF-κB, α6-β4-integrin, and IL-1) as differentially upregulated in melanoma SP cells, and there was a significant increase of PCDHB11 and decrease of FUK and TBX2 in these cells. Therefore, we provide evidence that SP is an enriched source of chemoresistant cells in human melanomas, and suggest that the selected genes and signaling pathways of SP cells may be a potential target for effective melanoma therapies. To our knowledge, this is a previously unreported study to isolate SP cells from melanoma patients and to investigate the gene expression profiling of these cells.

Kandimalla R, van Tilborg AA, Kompier LC, et al.
Genome-wide analysis of CpG island methylation in bladder cancer identified TBX2, TBX3, GATA2, and ZIC4 as pTa-specific prognostic markers.
Eur Urol. 2012; 61(6):1245-56 [PubMed] Related Publications
BACKGROUND: DNA methylation markers could serve as useful biomarkers, both as markers for progression and for urine-based diagnostic assays.
OBJECTIVE: Identify bladder cancer (BCa)-specific methylated DNA sequences for predicting pTa-specific progression and detecting BCa in voided urine.
DESIGN, SETTING, AND PARTICIPANTS: Genome-wide methylation analysis was performed on 44 bladder tumours using the Agilent 244K Human CpG Island Microarray (Agilent Technologies, Santa Clara, CA, USA). Validation was done using a custom Illumina 384-plex assay (Illumina, San Diego, CA, USA) in a retrospective group of 77 independent tumours. Markers for progression were identified in pTa (n = 24) tumours and validated retrospectively in an independent series of 41 pTa tumours by the SNaPshot method (Applied Biosystems, Foster City, CA, USA).
MEASUREMENTS: The percentage of methylation in tumour and urine samples was used to identify markers for detection and related to the end point of progression to muscle-invasive disease with Kaplan-Meier models and multivariate analysis.
RESULTS AND LIMITATIONS: In the validation set, methylation of the T-box 2 (TBX2), T-box 3 (TBX3), GATA binding protein 2 (GATA2), and Zic family member 4 (ZIC4) genes was associated with progression to muscle-invasive disease in pTa tumours (p = 0.003). Methylation of TBX2 alone showed a sensitivity of 100%, a specificity of 80%, a positive predictive value of 78%, and a negative predictive value of 100%, with an area under the curve of 0.96 (p<0.0001) for predicting progression. Multivariate analysis showed that methylation of TBX3 and GATA2 are independent predictors of progression when compared to clinicopathologic variables (p = 0.04 and p = 0.03, respectively). The predictive accuracy improved by 23% by adding methylation of TBX2, TBX3, and GATA2 to the European Organisation for Research and Treatment of Cancer risk scores. We further identified and validated 110 CpG islands (CGIs) that are differentially methylated between tumour cells and control urine. The limitation of this study is the small number of patients analysed for testing and validating the prognostic markers.
CONCLUSIONS: We have identified four methylation markers that predict progression in pTa tumours, thereby allowing stratification of patients for personalised follow-up. In addition, we identified CGIs that will enable detection of bladder tumours in voided urine.

Begum S, Papaioannou VE
Dynamic expression of Tbx2 and Tbx3 in developing mouse pancreas.
Gene Expr Patterns. 2011; 11(8):476-83 [PubMed] Free Access to Full Article Related Publications
Tbx2 and Tbx3 are closely related members of the T-box family of transcription factors that are important regulators during normal development as well as major contributors to human developmental syndromes when mutated. Although there is evidence for the involvement of Tbx2 and Tbx3 in pancreatic cancer, so far there are no reports characterizing the normal expression pattern of these genes in the pancreas. In this study, we examined spatial and temporal expression of Tbx2 and Tbx3 in mouse pancreas during development and in the adult using in situ hybridization and immunohistochemistry. Our results show that Tbx2 and Tbx3 are both expressed in the pancreatic mesenchyme throughout development beginning at embryonic day (E) 9.5. In addition, Tbx2 is expressed in pancreatic vasculature during development and in epithelial-derived endocrine and ductal cells during late fetal stages, postnatal development and in adult pancreas. In contrast, Tbx3 is expressed in exocrine tissue in the postnatal and adult pancreas. Further our results demonstrate that Tbx2 and Tbx3 are expressed in tumor-derived endocrine and exocrine cell lines, respectively. These dynamic changes in the expression pattern of these transcription factors lay the foundation for investigation of potential roles in pancreas development.

Taneja P, Maglic D, Kai F, et al.
Critical roles of DMP1 in human epidermal growth factor receptor 2/neu-Arf-p53 signaling and breast cancer development.
Cancer Res. 2010; 70(22):9084-94 [PubMed] Free Access to Full Article Related Publications
Human epidermal growth factor receptor 2 (HER2) overexpression stimulates cell growth in p53-mutated cells while it inhibits cell proliferation in those with wild-type p53, but the molecular mechanism is unknown. The Dmp1 promoter was activated by HER2/neu through the phosphatidylinositol-3'-kinase-Akt-NF-κB pathway, which in turn stimulated Arf transcription. Binding of p65 and p52 subunits of NF-κB was shown to the Dmp1 promoter and that of Dmp1 to the Arf promoter on HER2/neu overexpression. Both Dmp1 and p53 were induced in premalignant lesions from mouse mammary tumor virus-neu mice, and mammary tumorigenesis was significantly accelerated in both Dmp1+/- and Dmp1-/- mice. Selective deletion of Dmp1 and/or overexpression of Tbx2/Pokemon was found in >50% of wild-type HER2/neu carcinomas, although the involvement of Arf, Mdm2, or p53 was rare. Tumors from Dmp1+/-, Dmp1-/-, and wild-type neu mice with hemizygous Dmp1 deletion showed significant downregulation of Arf and p21Cip1/WAF1, showing p53 inactivity and more aggressive phenotypes than tumors without Dmp1 deletion. Notably, endogenous hDMP1 mRNA decreased when HER2 was depleted in human breast cancer cells. Our study shows the pivotal roles of Dmp1 in HER2/neu-p53 signaling and breast carcinogenesis.

Vance KW, Shaw HM, Rodriguez M, et al.
The retinoblastoma protein modulates Tbx2 functional specificity.
Mol Biol Cell. 2010; 21(15):2770-9 [PubMed] Free Access to Full Article Related Publications
Tbx2 is a member of a large family of transcription factors defined by homology to the T-box DNA-binding domain. Tbx2 plays a key role in embryonic development, and in cancer through its capacity to suppress senescence and promote invasiveness. Despite its importance, little is known of how Tbx2 is regulated or how it achieves target gene specificity. Here we show that Tbx2 specifically associates with active hypophosphorylated retinoblastoma protein (Rb1), a known regulator of many transcription factors involved in cell cycle progression and cellular differentiation, but not with the Rb1-related proteins p107 or p130. The interaction with Rb1 maps to a domain immediately carboxy-terminal to the T-box and enhances Tbx2 DNA binding and transcriptional repression. Microarray analysis of melanoma cells expressing inducible dominant-negative Tbx2, comprising the T-box and either an intact or mutated Rb1 interaction domain, shows that Tbx2 regulates the expression of many genes involved in cell cycle control and that a mutation which disrupts the Rb1-Tbx2 interaction also affects Tbx2 target gene selectivity. Taken together, the data show that Rb1 is an important determinant of Tbx2 functional specificity.

Liu WK, Jiang XY, Zhang ZX
Expression of PSCA, PIWIL1, and TBX2 in endometrial adenocarcinoma.
Onkologie. 2010; 33(5):241-5 [PubMed] Related Publications
BACKGROUND: Endometrial cancer is the 4th most common gynecological cancer. The expression of prostate stem cell antigen (PSCA), piwi-like 1 (PIWIL1), and T-box 2 (TBX2) in endometrial cancer remains to be elucidated.
MATERIAL AND METHODS: The expression of PSCA, PIWIL1, and TBX2 was examined using the streptavidin-peroxidase method in 64 endometrial endometrioid adenocarcinoma (EAC) and paired normal endometrium (NE) samples from the Shaanxi Province in China.
RESULTS: Positive expression rates of PSCA, PIWIL1, and TBX2 were 75% (48/64), 25% (16/64), and 56% (36/64), respectively in EACs, but 5% (3/64), 6% (4/64), and 2% (1/64), respectively in NEs. The difference was statistically significant (p < 0.05). PSCA was positively correlated with TBX2 (p = 0.003) but not PIWIL1 (p = 0.188). PIWIL1 was positively correlated with TBX2 (p = 0.003). PSCA was positively correlated with age, tumor grade, and lymph node metastasis (p < 0.05). TBX2 had an association with lymph node metastasis (p = 0.014). PIWIL1 was not associated with clinicopathological features (p > 0.05).
CONCLUSIONS: We report the first analysis of PSCA, PIWIL1, and TBX2 expression in EAC. Our findings suggest that PSCA and TBX2 might be candidate targets for cancer therapy, and have helped us further understand the carcinogenesis of endometrial cancer.

Redmond KL, Crawford NT, Farmer H, et al.
T-box 2 represses NDRG1 through an EGR1-dependent mechanism to drive the proliferation of breast cancer cells.
Oncogene. 2010; 29(22):3252-62 [PubMed] Related Publications
T-box 2 (TBX2) is a transcription factor involved in mammary development and is known to be overexpressed in a subset of aggressive breast cancers. TBX2 has previously been shown to repress growth control genes such as p14(ARF) and p21(WAF1/cip1). In this study we show that TBX2 drives proliferation in breast cancer cells and this is abrogated after TBX2 small interfering RNA (siRNA) knockdown or after the expression of a dominant-negative TBX2 protein. Using microarray analysis we identified a large cohort of novel TBX2-repressed target genes including the breast tumour suppressor NDRG1 (N-myc downregulated gene 1). We show that TBX2 targets NDRG1 through a previously undescribed mechanism involving the recruitment of early growth response 1 (EGR1). We show EGR1 is required for the ability of TBX2 to repress NDRG1 and drive cell proliferation. We show that TBX2 interacts with EGR1 and that TBX2 requires EGR1 to target the NDRG1 proximal promoter. Abrogation of either TBX2 or EGR1 expression is accompanied by the upregulation of cell senescence and apoptotic markers. NDRG1 can recapitulate these effects when transfected into TBX2-expressing cells. Together, these data identify a novel mechanism for TBX2-driven oncogenesis and highlight the importance of NDRG1 as a growth control gene in breast tissue.

Liu WK, Jiang XY, Zhang ZX
Expression of PSCA, PIWIL1 and TBX2 and its correlation with HPV16 infection in formalin-fixed, paraffin-embedded cervical squamous cell carcinoma specimens.
Arch Virol. 2010; 155(5):657-63 [PubMed] Related Publications
The purpose of our study was to investigate the expression of prostate stem cell antigen (PSCA), piwi-like 1 (PIWIL1) and T-box 2 (TBX2) and its correlation with HPV16 infection in cervical squamous cell carcinoma (CSCC). HPV16 was detected by amplifying the HPV16 E7 gene by the polymerase chain reaction (PCR) method, and the expression of PSCA, PIWIL1, TBX2 and HPV16 E7 in 59 CSCCs and matched adjacent normal cervix (MANC) was examined by the streptavidin-peroxidase (SP) method. Fifty-two CSCCs and MANC specimens that were positive for the E7 gene and the E7 protein were identified as infected with HPV16 and included in present study. The rate of infection with HPV16 in CSCC was 52% (27/52), but that in matched adjacent normal cervix (MANC) samples was 4% (2/52). Infection with HPV16 was found to be statistically more frequent in CSCC (P = 0.000). The expression rates of PSCA, PIWIL1 and TBX2 in MANC were 6% (3/52), 8% (4/52) and 2% (1/52), respectively, but those in CSCC were 62% (32/52), 75% (39/52) and 52% (27/52), respectively. Higher expression rates of PSCA, PIWIL1 and TBX2 were observed in CSCC than in MANC (P = 0.000). HPV16 had a statistical positive correlation with PSCA, PIWIL1 and TBX2 in CSCC (P < 0.05). The increased expression of PSCA, PIWIL1 and TBX2 had no correlation with the patient's age or histological grade P > 0.05). The elevated expression of PSCA and PIWIL1 was associated with invasion of CSCC (P < 0.05). Up-regulated expression of TBX2 had a positive association with lymph node metastasis (P = 0.014). These findings demonstrate for the first time the expression of PSCA, PIWIL1 and TBX2 in CSCC. Their correlation with HPV16 might provide new basic information for investigating the molecular mechanism of HPV and help us to deepen our understanding of the interaction between HPV16 and host cells the carcinogenesis of CSCC.

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