Gene Summary

Gene:RHOBTB2; Rho related BTB domain containing 2
Aliases: DBC2, EIEE64
Summary:The protein encoded by this gene is a small Rho GTPase and a candidate tumor suppressor. The encoded protein interacts with the cullin-3 protein, a ubiquitin E3 ligase necessary for mitotic cell division. This protein inhibits the growth and spread of some types of breast cancer. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:rho-related BTB domain-containing protein 2
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (7)

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.

  • Single Nucleotide Polymorphism
  • DNA Methylation
  • Tumor Suppressor Gene
  • Promoter Regions
  • Cell Line
  • Multiple Myeloma
  • Gene Expression Profiling
  • Base Sequence
  • Neoplasm Proteins
  • Gene Silencing
  • Chromosome 8
  • Up-Regulation
  • Bladder Cancer
  • Gene Deletion
  • Biomarkers, Tumor
  • DNA Mutational Analysis
  • Head and Neck Cancers
  • Transfection
  • Messenger RNA
  • Drug Resistance
  • Genetic Predisposition
  • Cancer Gene Expression Regulation
  • Signal Transduction
  • Receptors, Progesterone
  • Cell Proliferation
  • Breast Cancer
  • Young Adult
  • Neoplasm Invasiveness
  • Case-Control Studies
  • Apoptosis
  • rho GTP-Binding Proteins
  • Down-Regulation
  • Tumor Necrosis Factor Decoy Receptors
  • Proteasome Endopeptidase Complex
  • GTP-Binding Proteins
  • HeLa Cells
  • Loss of Heterozygosity
  • Tumor Suppressor Proteins
  • Cell Movement
Tag cloud generated 31 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: RHOBTB2 (cancer-related)

McKinnon CM, Mellor H
The tumor suppressor RhoBTB1 controls Golgi integrity and breast cancer cell invasion through METTL7B.
BMC Cancer. 2017; 17(1):145 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: RhoBTB1 and 2 are atypical members of the Rho GTPase family of signaling proteins. Unlike other Rho GTPases, RhoBTB1 and 2 undergo silencing or mutation in a wide range of epithelial cancers; however, little is known about the consequences of this loss of function.
METHODS: We analyzed transcriptome data to identify transcriptional targets of RhoBTB2. We verified these using Q-PCR and then used gene silencing and cell imaging to determine the cellular function of these targets downstream of RhoBTB signaling.
RESULTS: RhoBTB1 and 2 regulate the expression of the methyltransferases METTL7B and METTL7A, respectively. RhoBTB1 regulates the integrity of the Golgi complex through METTL7B. RhoBTB1 is required for expression of METTL7B and silencing of either protein leads to fragmentation of the Golgi. Loss of RhoBTB1 expression is linked to Golgi fragmentation in breast cancer cells. Restoration of normal RhoBTB1 expression rescues Golgi morphology and dramatically inhibits breast cancer cell invasion.
CONCLUSION: Loss of RhoBTB1 expression in breast cancer cells leads to Golgi fragmentation and hence loss of normal polarity.

Choi YM, Kim KB, Lee JH, et al.
DBC2/RhoBTB2 functions as a tumor suppressor protein via Musashi-2 ubiquitination in breast cancer.
Oncogene. 2017; 36(20):2802-2812 [PubMed] Free Access to Full Article Related Publications
The gene encoding 'deleted in breast cancer 2' (DBC2), also referred to as RHOBTB2 (Rho-related BTB domain-containing protein 2), is classified as a tumor suppressor gene. DBC2 is a substrate-specific adaptor protein for a novel class of Cullin-3 (CUL3)-based E3 ubiquitin ligases; however, it is unclear if the substrate adaptor function of DBC2 is required for its tumor suppressor activity. Furthermore, the key substrates of DBC2-mediated ubiquitination have yet to be identified. In the present study, we established a genome-wide human cDNA library-based in vitro ubiquitination target screening assay and identified Musashi-2 (MSI2) as a novel ubiquitination target protein of DBC2. MSI2 directly interacted with DBC2, and this interaction promoted MSI2 polyubiquitination and proteasomal degradation in breast cancer cells. Overexpression and knockdown experiments demonstrated that DBC2 suppressed MSI2-associated oncogenic functions and induced apoptosis. Immunohistochemistry analysis of a breast cancer tissue microarray revealed that DBC2 and MSI2 protein levels are inversely correlated in both normal breast tissues and breast cancer tissues. Taken together, these findings provide evidence that DBC2 suppresses tumorigenesis in breast cancer by ubiquitinating MSI2.

Iranshahi N, Zafari P, Yari KH, Alizadeh E
The most common genes involved in epigenetics modifications among Iranian patients with breast cancer: A systematic review.
Cell Mol Biol (Noisy-le-grand). 2016; 62(12):116-122 [PubMed] Related Publications
Breast cancer, with a lifelong risk of one in nine, is the most common cancer among women. In Iran, breast cancer is one of the growing and important women's health problems. Several environmental, genetic and epigenetics factors have been suggested to have a role in breast cancer development. Epigenetics alterations are heritable changes in gene expression that occur without causing any change in DNA sequence. DNA methylation as a main epigenetics modification in human cancer is found as a promising biomarker in early detection of breast cancer. Association between epigenetics changes of many gene promoters with the risk of breast cancer has been investigated worldwide. This aberrant methylation may be occur in specific genes related to cell cycle, cell adhesion, apoptosis and DNA repairing mechanisms and results in silencing of these important genes. In this review study, we have gathered all the data until December 2015 about epigenetics modifications among Iranian population with breast cancer.  We searched international web databases such as: PubMed, Scopus, and Persian web databases; IranMedex and Magiran to investigate the association of epigenetics change and incidence of breast cancer among Iranian population. Using "methylation" or "epigenetics" key words and "Iran" as affiliation, all the published data were 31. After arbitrary limitation in search keywords the result have been 20 articles.  Data analysis show that "ER-α" and "E-Cadherin" are most common studied genes in epigenetics modifications. Also, maximum studies were done in Tehran and Tabriz. We thought that more studies will be helpful to reveal the relation of methylation status in candidate genes with the breast cancer risk in Iranian populations.

Ye C, Tao R, Cao Q, et al.
Whole-genome DNA methylation and hydroxymethylation profiling for HBV-related hepatocellular carcinoma.
Int J Oncol. 2016; 49(2):589-602 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a common solid tumor worldwide with a poor prognosis. Accumulating evidence has implicated important regulatory roles of epigenetic modifications in the occurrence and progression of HCC. In the present study, we analyzed 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) levels in the tumor tissues and paired adjacent peritumor tissues (APTs) from four individual HCC patients using a (hydroxy)methylated DNA immunoprecipitation approach combined with deep sequencing [(h)MeDIP-Seq]. Bioinformatics analysis revealed that the 5-mC levels in the promoter regions of 2796 genes and the 5-hmC levels in 507 genes differed significantly between HCC tissues and APTs. These differential genes were grouped into various clusters and pathways and found to be particularly enriched in the 'metabolic pathways' that include 'Glycolysis/gluconeogenesis', 'Oxidative phosphorylation' and 'Citrate cycle (TCA cycle)', implicating a potential role of metabolic alterations in HCC. Furthermore, 144 genes had both 5-mC and 5-hmC changes in HCC patients, and 10 of them (PCNA, MDM2, STAG1, E2F4, FGF4, FGF19, RHOBTB2, UBE2QL1, DCN and HSP90AA1) were enriched and interconnected in five pathways including the 'Cell cycle', 'Pathway in cancer', 'Ubiquitin mediated proteolysis', 'Melanoma' and 'Prostate cancer' pathways. The genome-wide mapping of 5-mC and 5-hmC in HCC tissues and APTs indicated that both 5-mC and 5-hmC epigenetic modifications play important roles in the regulation of HCC, and there may be some interconnections between them. Taken together, in the present study we conducted the first genome-wide mapping of DNA methylation combined with hydroxymethylation in HBV-related HCC and provided a series of potential novel epigenetic biomarkers for HCC.

Duru AD, Sutlu T, Wallblom A, et al.
Deletion of Chromosomal Region 8p21 Confers Resistance to Bortezomib and Is Associated with Upregulated Decoy TRAIL Receptor Expression in Patients with Multiple Myeloma.
PLoS One. 2015; 10(9):e0138248 [PubMed] Free Access to Full Article Related Publications
Loss of the chromosomal region 8p21 negatively effects survival in patients with multiple myeloma (MM) that undergo autologous stem cell transplantation (ASCT). In this study, we aimed to identify the immunological and molecular consequences of del(8)(p21) with regards to treatment response and bortezomib resistance. In patients receiving bortezomib as a single first line agent without any high-dose therapy, we have observed that patients with del(8)(p21) responded poorly to bortezomib with 50% showing no response while patients without the deletion had a response rate of 90%. In vitro analysis revealed a higher resistance to bortezomib possibly due to an altered gene expression profile caused by del(8)(p21) including genes such as TRAIL-R4, CCDC25, RHOBTB2, PTK2B, SCARA3, MYC, BCL2 and TP53. Furthermore, while bortezomib sensitized MM cells without del(8)(p21) to TRAIL/APO2L mediated apoptosis, in cells with del(8)(p21) bortezomib failed to upregulate the pro-apoptotic death receptors TRAIL-R1 and TRAIL-R2 which are located on the 8p21 region. Also expressing higher levels of the decoy death receptor TRAIL-R4, these cells were largely resistant to TRAIL/APO2L mediated apoptosis. Corroborating the clinical outcome of the patients, our data provides a potential explanation regarding the poor response of MM patients with del(8)(p21) to bortezomib treatment. Furthermore, our clinical analysis suggests that including immunomodulatory agents such as Lenalidomide in the treatment regimen may help to overcome this negative effect, providing an alternative consideration in treatment planning of MM patients with del(8)(p21).

Khakpour G, Pooladi A, Izadi P, et al.
DNA methylation as a promising landscape: A simple blood test for breast cancer prediction.
Tumour Biol. 2015; 36(7):4905-12 [PubMed] Related Publications
Breast cancer is the most common malignancy among women worldwide. Risk assessment is one of the main services delivered by cancer clinics. Biomarker analysis on different tissues including the peripheral blood can provide crucial information. One of the potential epigenetic biomarkers (epimarkers) is introduced as the peripheral blood DNA methylation pattern. This study was conducted to evaluate the potential value of peripheral blood epimarkers as an accessible tool to predict the risk of breast cancer development. WBC's DNA was the focus of several case-control studies at both genome wide and candidate gene levels to reveal epigenetic changes accounting for predisposition to breast cancer, leading to suggest that ATM, TITF1, SFRP1, NUP155, NEUROD1, ZNF217, DBC2, DOK7 and ESR1 genes and the LINE1, Alu and Sat2 DNA elements could be considered as the potential epimarkers. To address that by which mechanisms WBC's DNA methylation patterns could be linked to the propensity to breast cancer, several contemplations have been offered. Constitutional epimutation during embryonic life, and methylation changes secondary to either environmental exposures or tumor-mediated immune response, are the two main mechanisms. One can deduce that epimarkers based on their potential properties or regulatory impacts on cancer-related genes may be employed for risk prediction, prognosis, and survival inferences that are highly required for breast cancer management toward personalized medicine.

Fu G, Wang H, Wu H, Wang M
The mutation of DBC2 in breast cancer patients from the Han ethnic group in Eastern China.
Hematol Oncol Stem Cell Ther. 2014; 7(2):59-62 [PubMed] Related Publications
OBJECTIVE: To investigate DBC2 mutations in breast cancer patients and evaluate the relationship between gene mutations and breast cancer susceptibility in an Eastern China population.
METHODS: Mutation analyses of 285bp promoter sequence, coding exon 7 and its exon/intron boundaries of DBC2 were performed in 32 breast cancer specimens by polymerase chain reaction and direct sequencing. Eighteen benign breast tumor specimens were also analyzed as control.
RESULTS: No mutation in the promoter or exon 7 was found in either group. An intronic alteration (IVS7+53C>G) was detected in 13 specimens. There was no significant difference in the rate of IVS7+53C>G alteration between the study and control groups (8/32 vs 5/18, respectively, P>0.05). The G allele of IVS7+53 was correlated with HER2 and p53 expression (P<0.05), but not with age, tumor size, lymph node metastasis, ER or PR expression (P>0.05).
CONCLUSION: Mutation in the promoter and exon 7 of DBC2 gene is not common in the Chinese population and may not contribute to the susceptibility for breast cancer in China. The intronic alteration IVS7+53C>G is a common polymorphism in the Chinese Han ethnic group. Further research is warranted to evaluate the relationship between IVS7+53C>G and the susceptibility for breast cancer.

Tang W, Wang C, Fu F, Chen Q
RhoBTB2 gene in breast cancer is silenced by promoter methylation.
Int J Mol Med. 2014; 33(3):722-8 [PubMed] Related Publications
Mutation analysis in breast cancer has failed to explain the inactivation of RhoBTB2, a candidate breast cancer tumor suppressor gene on chromosome 8p. Some breast cancer-related genes in this region become inactivated by hypermethylation, and hypermethylation of RhoBTB2 abrogates its expression in bladder cancers. The aim of the present study was to determine whether RhoBTB2 was silenced by methylation in breast cancer. Nested methylation-specific PCR (nMSP) and quantitative reverse transcription PCR were used to analyze the methylation status and mRNA levels of RhoBTB2 in 50 paired breast cancer and normal tissues and the results were correlated with clinicopathological characteristics. Promoter methylation and the downregulation of RhoBTB2 mRNA was observed in tumor tissues (P<0.001). mRNA levels were decreased in samples with methylation (χ² = 15.751, P<0.001). RhoBTB2 methylation was observed preferentially in progesterone receptor (PR)-negative samples (P<0.05). The results demonstrated that aberrant methylation of RhoBTB2 may be responsible for the suppression of RhoBTB2 mRNA expression in breast cancer, a significant event during the genesis of breast cancer that correlated with PR status.

Jin Z, Han YX, Han XR
Downregulated RhoBTB2 expression contributes to poor outcome in osteosarcoma patients.
Cancer Biother Radiopharm. 2013; 28(10):709-16 [PubMed] Related Publications
PURPOSE: Osteosarcoma is a malignant bone tumor. RhoBTB2 protein participated in various cellular activities and influenced pathways responsible for cell cycle and apoptosis. To address its potential as a therapeutic target for osteosarcoma, this study investigated the effect of RhoBTB2 expression on osteosarcoma tissue and cell.
MATERIALS AND METHODS: Real-time PCR and immunohistochemistry analysis were performed to evaluate the level of RhoBTB2 mRNA and protein in 121 osteosarcoma specimens. The relationship of RhoBTB2 expression with clinicopathological parameters of osteosarcoma patients was analyzed using Chi-square test. In addition, a plasmid expressing the RhoBTB2 gene was transfected into human osteosarcoma (HOS) cell using Lipofectamine 2000, and the effects of RhoBTB2 on HOS cell were investigated using 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazoliumbromide assay and flow cytometry.
RESULTS: This study reports that RhoBTB2 protein is weakly expressed in osteosarcoma specimens, but highly in normal parts of specimens. RhoBTB2 expression is significantly associated with primary location and local recurrence of osteosarcoma. Overexpression of RhoBTB2 results in significant G1 phase arrest and apoptosis in HOS cell.
CONCLUSION: Taken together, we identified the role RhoBTB2 in osteosarcoma tissue and cell. The results might not only be of relevance for diagnosis and prognosis, but potentially also provide a novel target for osteosarcoma therapies.

Han L, Hou L, Song J, et al.
Decreased expression of the DBC2 gene and its clinicopathological significance in breast cancer: correlation with aberrant DNA methylation.
Biotechnol Lett. 2013; 35(8):1175-81 [PubMed] Related Publications
Loss of DBC2 (deleted in breast cancer 2) gene expression is frequent in breast cancer tissues. This can be explained by homozygous deletions or other mutations in a minority of cases but alternative mechanisms need to be investigated. Here, DBC2 expression was significantly suppressed compared with normal breast tissues in breast cancer tissues when analyzed by RT-PCR. Furthermore, DNA methylation on DBC2 was more prevalent in breast tumors than in normal tissues. DBC2 mRNA levels correlated with the degree of DBC2 methylation in breast cancer tissues and in a breast cancer cell line (T47D). Clinico-pathological correlation analysis showed that DBC2 promoter methylation was associated with tumor-node-metastasis stages II and III/IV, lymph node metastasis, p53 mutation, and HER2-positive status. Thus loss of DBC2 expression is caused by abnormal methylation of DBC2 and might have a role in breast cancer development.

Xu RS, Wu XD, Zhang SQ, et al.
The tumor suppressor gene RhoBTB1 is a novel target of miR-31 in human colon cancer.
Int J Oncol. 2013; 42(2):676-82 [PubMed] Related Publications
miRNAs are a class of endogenous non-coding RNA, which can regulate downstream target genes through binding to the 3'UTR of those genes. Numerous studies have indicated that abnormal expression of miRNAs is implicated in tumor development. Aberrant expression of miR-31 has been found in various cancers, including colorectal cancer. Here, we show that miR-31 is upregulated in human colon cancer tissues and cell lines, and that repression of miR-31 inhibited colon cancer cell proliferation and colony formation in soft agarose. To further elucidate the mechanism underlying the role of miR-31 in promoting colon cancer, we used online miRNA target prediction databases and found that the tumor suppressor RhoTBT1 may be a target of miR-31. Imunohistochemistry assay revealed that RhoBTB1 was significantly decreased in HT29 cells. In addition, ectopic expression of miR-31 reduced RhoBTB1 in the colon cancer cell line HT29. The results suggested that suppression of RhoBTB1 may be responsible for colon tumorigenesis, which was inhibited directly by miR-31. The results of MTT and soft agarose colony-formation assays showed that knockdown of RhoBTB1 by RNAi induced cell proliferation, and colony formation in soft agarose, which mimicked the function of miR-31. This further suggested that suppression of RhoBTB1 was responsible for colon tumorigenesis. In conclusion, we found that miR-31 acts as an oncogene in colon cancer and identified RhoBTB1 as a new target of miR-31 further study demonstrated that miR-31 contributed to the development of colon cancer at least partly by targeting RhoBTB1.

Heselmeyer-Haddad K, Berroa Garcia LY, Bradley A, et al.
Single-cell genetic analysis of ductal carcinoma in situ and invasive breast cancer reveals enormous tumor heterogeneity yet conserved genomic imbalances and gain of MYC during progression.
Am J Pathol. 2012; 181(5):1807-22 [PubMed] Free Access to Full Article Related Publications
Ductal carcinoma in situ (DCIS) is a precursor lesion of invasive ductal carcinoma (IDC) of the breast. To understand the dynamics of genomic alterations in this progression, we used four multicolor fluorescence in situ hybridization probe panels consisting of the oncogenes COX2, MYC, HER2, CCND1, and ZNF217 and the tumor suppressor genes DBC2, CDH1, and TP53 to visualize copy number changes in 13 cases of synchronous DCIS and IDC based on single-cell analyses. The DCIS had a lower degree of chromosomal instability than the IDC. Despite enormous intercellular heterogeneity in DCIS and IDC, we observed signal patterns consistent with a nonrandom distribution of genomic imbalances. CDH1 was most commonly lost, and gain of MYC emerged during progression from DCIS to IDC. Four of 13 DCISs showed identical clonal imbalances in the IDCs. Six cases revealed a switch, and in four of those, the IDC had acquired a gain of MYC. In one case, the major clone in the IDC was one of several clones in the DCIS, and in another case, the major clone in the DCIS became one of the two major clones in the IDC. Despite considerable chromosomal instability, in most cases the evolution from DCIS to IDC is determined by recurrent patterns of genomic imbalances, consistent with a biological continuum.

Dong W, Meng L, Shen HC, Du JJ
Loss of DBC2 expression is an early and progressive event in the development of lung adenocarcinoma.
Asian Pac J Cancer Prev. 2012; 13(5):2021-3 [PubMed] Related Publications
PURPOSE: DBC2 (Deleted in Breast Cancer 2) has been indicated to be a tumor suppressor gene in many cancers including lung adenocarcinoma recently. In this study, we aimed to explore the expression status of DBC2 in different subtypes of lung adenocarcinoma (from pre-invasive to invasive lesions), and to determine if downregulation becomes more marked with pathological progression.
METHODS: We collected 172 tissue samples from different subtypes of lung adenocarcinoma and investigated the frequency of DBC2 loss by immunohistochemistry.
RESULTS: Our results indicated that DBC2 downregulation is a relatively frequent event in lung adenocarcinoma. Moreover, as the adenocarcinoma subtype turns to be more invasive, more downregulation occurred.
CONCLUSION: We conclude that loss of DBC2 expression is an early and progressive event in the pathogenesis of lung adenocarcinoma. Positive DBC2 immunohistochemistry may become an indicator for early stage disease and better prognosis of lung adenocarcinomas.

Mao H, Zhang L, Yang Y, et al.
RhoBTB2 (DBC2) functions as tumor suppressor via inhibiting proliferation, preventing colony formation and inducing apoptosis in breast cancer cells.
Gene. 2011; 486(1-2):74-80 [PubMed] Related Publications
RhoBTB2 was isolated recently as a tumor suppressor gene from sporadic breast cancer. Although RhoBTB2 was found to be frequently lost in breast cancer and a variety of cancers, its antitumor effect, however, remains unclear. In this study, we constructed a recombinant expression vector pEGFP-N1-RhoBTB2 and transfected it into RhoBTB2-negative breast tumor cell line T-47D. Stable transformanted cells were identified by fluorescence microscope, RT-PCR and Western blot. Cell viability was measured by MTT assay. Colony forming efficiency of breast tumor cells was detected by colony formation assay. Morphological change of apoptotic cells was observed by hematoxylin-eosin staining. Apoptotic ratio was determined by flow cytometry. Cell invasion and migration ability assay were performed using transwell system. Overexpression of RhoBTB2 in breast tumor cells significantly inhibited the proliferation and colony formation of tumor cells. In addition, RhoBTB2 also elevated the apoptotic ratio and caused typical changes of apoptotic morphology in breast tumor cells of RhoBTB2 overexpression. But RhoBTB2 did not influence the invasion and migration ability of breast tumor cells. Therefore, RhoBTB2 is an important tumor suppressor gene related with breast cancer and may play antitumor roles by inhibiting proliferation, preventing colony formation and promoting the apoptosis of tumor cells. However, the precise mechanism behind the antitumor effects of RhoBTB2 needs to be investigated further.

Ling LJ, Lu C, Zhou GP, Wang S
Ectopic expression of RhoBTB2 inhibits migration and invasion of human breast cancer cells.
Cancer Biol Ther. 2010; 10(11):1115-22 [PubMed] Related Publications
RhoBTB2, or Deleted in Breast Cancer 2 (DBC2), identified as a candidate tumor suppressor gene for breast cancer and other human malignancies, is an atypical member of a novel gene family encoding small GTPases. In this study, we found that ectopic expression of RhoBTB2 inhibits the migration and invasion of the human metastatic breast cancer cell lines MDA-MB-231 and MDA-MB-435 in a dose-dependent manner. Western blotting analysis revealed that ectopic expression of RhoBTB2 induces a significant increase in the breast cancer metastasis suppressor, BRMS1. siRNA suppression of BRMS1 expression markedly reversed the inhibitory effects of RhoBTB2 on the migration and invasion abilities of both cell lines. Ezrin is a member of the ezrin-radixin-moesin cytoskeleton-associated protein family and is a key signaling molecule that regulates cancer migration and invasion. Western blotting analysis demonstrated that ectopic expression of RhoBTB2 results in decreased phosphorylation of ezrin and Akt2 in both MDA-MB-231 and MDA-MB-435 cells. Therefore, we conclude that up-regulation of the breast cancer metastasis suppressor BRMS1 and down-regulation of the phosphorylation of the cancer metastasis-related gene, ezrin, contributed to RhoBTB2-induced inhibition of metastatic breast carcinoma cell migration and invasion. Our findings suggest that understanding RhoBTB2-mediated migration and suppression of invasion is critical to the development of new therapies designed to prevent and treat patients with breast cancer metastasis.

Broyl A, Corthals SL, Jongen JL, et al.
Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial.
Lancet Oncol. 2010; 11(11):1057-65 [PubMed] Related Publications
BACKGROUND: Bortezomib-induced peripheral neuropathy is a dose-limiting toxicity in patients with multiple myeloma, often requiring adjustment of treatment and affecting quality of life. We investigated the molecular profiles of early-onset (within one treatment cycle) versus late-onset (after two or three treatment cycles) bortezomib-induced peripheral neuropathy and compared them with those of vincristine-induced peripheral neuropathy during the induction phase of a prospective phase 3 trial.
METHODS: In the induction phase of the HOVON-65/GMMG-HD4 trial, patients (aged 18-65 years) with newly diagnosed Salmon and Durie stage 2 or 3 multiple myeloma were randomly assigned to three cycles of bortezomib-based or vincristine-based induction treatment. We analysed the gene expression profiles and single-nucleotide polymorphisms (SNPs) of pretreatment samples of myeloma plasma cells and peripheral blood, respectively. This study is registered, number ISRCTN64455289.
FINDINGS: We analysed gene expression profiles of myeloma plasma cells from 329 (39%) of 833 patients at diagnosis, and SNPs in DNA samples from 369 (44%) patients. Early-onset bortezomib-induced peripheral neuropathy was noted in 20 (8%) patients, and 63 (25%) developed the late-onset type. Early-onset and late-onset vincristine-induced peripheral neuropathy was noted in 11 (4%) and 17 (7%) patients, respectively. Significant genes in myeloma plasma cells from patients that were associated with early-onset bortezomib-induced peripheral neuropathy were the enzyme coding genes RHOBTB2 (upregulated by 1·59 times; p=4·5×10(-5)), involved in drug-induced apoptosis, CPT1C (1·44 times; p=2·9×10(-7)), involved in mitochondrial dysfunction, and SOX8 (1·68 times; p=4·28×10(-13)), involved in development of peripheral nervous system. Significant SNPs in the same patients included those located in the apoptosis gene caspase 9 (odds ratio [OR] 3·59, 95% CI 1·59-8·14; p=2·9×10(-3)), ALOX12 (3·50, 1·47-8·32; p=3·8×10(-3)), and IGF1R (0·22, 0·07-0·77; p=8·3×10(-3)). In late-onset bortezomib-induced peripheral neuropathy, the significant genes were SOD2 (upregulated by 1·18 times; p=9·6×10(-3)) and MYO5A (1·93 times; p=3·2×10(-2)), involved in development and function of the nervous system. Significant SNPs were noted in inflammatory genes MBL2 (OR 0·49, 95% CI 0·26-0·94; p=3·0×10(-2)) and PPARD (0·35, 0·15-0·83; p=9·1×10(-3)), and DNA repair genes ERCC4 (2·74, 1·56-4·84; p=1·0×10(-3)) and ERCC3 (1·26, 0·75-2·12; p=3·3×10(-3)). By contrast, early-onset vincristine-induced peripheral neuropathy was characterised by upregulation of genes involved in cell cycle and proliferation, including AURKA (3·31 times; p=1·04×10(-2)) and MKI67 (3·66 times; p=1·82×10(-3)), and the presence of SNPs in genes involved in these processes-eg, GLI1 (rs2228224 [0·13, 0·02-0·97, p=1·18×10(-2)] and rs2242578 [0·14, 0·02-1·12, p=3·00×10(-2)]). Late-onset vincristine-induced peripheral neuropathy was associated with the presence of SNPs in genes involved in absorption, distribution, metabolism, and excretion-eg, rs1413239 in DPYD (3·29, 1·47-7·37, 5·40×10(-3)) and rs3887412 in ABCC1 (3·36, 1·47-7·67, p=5·70×10(-3)).
INTERPRETATION: Our results strongly suggest an interaction between myeloma-related factors and the patient's genetic background in the development of treatment-induced peripheral neuropathy, with different molecular pathways being implicated in bortezomib-induced and vincristine-induced peripheral neuropathy.

Mao H, Qu X, Yang Y, et al.
A novel tumor suppressor gene RhoBTB2 (DBC2): frequent loss of expression in sporadic breast cancer.
Mol Carcinog. 2010; 49(3):283-9 [PubMed] Related Publications
RhoBTB2 was isolated recently as a tumor suppressor gene from human chromosome 8p21.3. Although RhoBTB2 was found to be frequently lost in breast cancer lines, expression status of RhoBTB2 in sporadic breast cancer tissues and its clinical and prognostic value, however, remain unclear. Tissue samples from breast cancer patients and normal controls and cell samples from cell lines were collected and reverse transcription (RT)-PCR was used to monitor the presence of RhoBTB2 mRNA. The protein expression of RhoBTB2 was detected by immunohistochemical staining. Cumulative survival time was assessed by the Kaplan-Meier method and Cox regression model. We discovered that RhoBTB2 expression was lacking in a breast ductal epithelial carcinoma cell line T-47D but was expressed in other types of tumor cell lines and normal tissues we tested. The results from tissue samples showed that RhoBTB2 was absent in 60% of breast cancers on both the mRNA and protein level. The results from RT-PCR were completely uniform with those from immunohistochemistry. We demonstrated that loss of RhoBTB2 more frequently occurred in postmenopausal patients of age >or=50 yr old and in patients with infiltrating ductal carcinoma of the breast. The prognostic value of RhoBTB2 in breast cancers also be assessed by a long-term follow-up investigation and we found that patients with RhoBTB2-negative breast cancer were linked to poor clinical prognosis. Therefore, the loss of RhoBTB2 expression is a common occurrence in breast cancers and it is an important factor in the development and prognosis of sporadic breast cancer.

McKinnon CM, Lygoe KA, Skelton L, et al.
The atypical Rho GTPase RhoBTB2 is required for expression of the chemokine CXCL14 in normal and cancerous epithelial cells.
Oncogene. 2008; 27(54):6856-65 [PubMed] Related Publications
The Rho family of small GTPases control cell migration, cell invasion and cell cycle. Many of these processes are perturbed in cancer and several family members show altered expression in a number of tumor types. RhoBTB2/DBC2 is an atypical member of this family of signaling proteins, containing two BTB domains in addition to its conserved Rho GTPase domain. RhoBTB2 is mutated, deleted or silenced in a large percentage of breast and lung cancers; however, the functional consequences of this loss are unclear. Here we use RNA interference in primary human epithelial cells to mimic the loss of RhoBTB2 seen in cancer cells. Through microarray analysis of global gene expression, we show that loss of RhoBTB2 results in downregulation of CXCL14-a chemokine that controls leukocyte migration and angiogenesis, and whose expression is lost through unknown mechanisms in a wide range of epithelial cancers. Loss of RhoBTB2 expression correlates with loss of CXCL14 secretion by head and neck squamous cell carcinoma cell lines, whereas reintroduction of RhoBTB2 restores CXCL14 secretion. Our studies identify CXCL14 as a gene target of RhoBTB2 and support downregulation of CXCL14 as a functional outcome of RhoBTB2 loss in cancer.

Shi Y, Chen JY, Yang J, et al.
DBC2 gene is silenced by promoter methylation in bladder cancer.
Urol Oncol. 2008 Sep-Oct; 26(5):465-9 [PubMed] Related Publications
Deletions at 8p are frequent in many human cancers and represent a genetic marker associated with a more aggressive tumor phenotype. Previous mutational analysis of DBC2 (deleted in breast cancer 2), a tumor suppressor gene located in the region of loss of heterozygosity (LOH) on 8p21, failed to show a high frequency of mutation linked to low expression in bladder cancer. Promoter hypermethylation may be an alternative mechanism of inactivation of the second allele. We detected the methylation status and expression of the DBC2 gene in 75 bladder cancer samples and 57 corresponding normal tissues. Aberrant methylation and down-regulation of DBC2 were observed preferentially in tumor samples (P < 0.05), and the expression changes were associated with methylation (P < 0.05). These findings, together with the previously mutation reports, suggest that aberrant methylation in DBC2 promoter may be responsible for the expression loss of DBC2 expression in bladder cancer and this hypermethylation event could play a crucial role in the early stage of bladder tumorigenesis.

Berthold J, Schenkova K, Rivero F
Rho GTPases of the RhoBTB subfamily and tumorigenesis.
Acta Pharmacol Sin. 2008; 29(3):285-95 [PubMed] Related Publications
RhoBTB proteins constitute a subfamily of atypical members within the Rho family of small guanosine triphosphatases (GTPases). Their most salient feature is their domain architecture: a GTPase domain (in most cases, non-functional) is followed by a prolinerich region, a tandem of 2 broadcomplex, tramtrack, bric a brac (BTB) domains, and a conserved Cterminal region. In humans, the RhoBTB subfamily consists of 3 isoforms: RhoBTB1, RhoBTB2, and RhoBTB3. Orthologs are present in several other eukaryotes, such as Drosophila and Dictyostelium, but have been lost in plants and fungi. Interest in RhoBTB arose when RHOBTB2 was identified as the gene homozygously deleted in breast cancer samples and was proposed as a candidate tumor suppressor gene, a property that has been extended to RHOBTB1. The functions of RhoBTB proteins have not been defined yet, but may be related to the roles of BTB domains in the recruitment of cullin3, a component of a family of ubiquitin ligases. A model emerges in which RhoBTB proteins are required to maintain constant levels of putative substrates involved in cell cycle regulation or vesicle transport through targeting for degradation in the 26S proteasome. RhoBTB proteins are engrossing the list of Rho GTPases involved in tumorigenesis. Unlike typical Rho GTPases (usually overexpressed or hyperactive), RhoBTB proteins appear to play a part in the carcinogenic process through a mechanism that involves the decreased or abolished expression of the corresponding genes, or more rarely, mutations that result in impaired functioning of the protein, presumably leading to the accumulation of RhoBTB substrates and alterations of the cellular homeostasis.

Cho YG, Choi BJ, Kim CJ, et al.
Genetic analysis of the DBC2 gene in gastric cancer.
Acta Oncol. 2008; 47(3):366-71 [PubMed] Related Publications
The DBC2 (Deleted in breast cancer, RhoBTB2) has been identified as a tumor suppressor gene that has growth inhibitory function. To investigate whether genetic alterations of the DBC2 gene are involved in the development of gastric cancer, we analyzed mutations and allelic loss in the DBC2 gene in 95 primary gastric cancers by PCR-SSCP, sequencing and LOH analysis. In the mutational analysis, we found one missense somatic mutation (CGG-->TGG, R275W) in the BTB/POZ domain of the gene in a patient with advanced gastric cancer and lymph node metastasis. In addition, we found one known polymorphism and three novel polymorphisms in the coding region of DBC2, which showed an amino acid change, and was detected in both the cancer cells and corresponding normal cells. On LOH analysis, 62 cases were heterozygous for at least one marker and 18 cases (29.0%) showed allelic loss at these markers. In conclusion, the mutations and allelic loss in the DBC2 gene are uncommon in gastric cancers in Korean patients. Further studies to identify the target gene at 8q21 responsible for the development of gastric cancer should be explored.

Ye H, Pungpravat N, Huang BL, et al.
Genomic assessments of the frequent loss of heterozygosity region on 8p21.3-p22 in head and neck squamous cell carcinoma.
Cancer Genet Cytogenet. 2007; 176(2):100-6 [PubMed] Free Access to Full Article Related Publications
Most human cancers are characterized by genetic instabilities. Chromosomal aberrations include segments of allelic imbalance identifiable by loss of heterozygosity (LOH) at polymorphic loci, which may be used to implicate regions harboring tumor suppressor genes. Here we performed whole-genome LOH profiling on 41 human head and neck squamous cell carcinoma (HNSCC) cell lines. Several frequent LOH regions were identified on chromosomal arms 3p, 4p, 4q, 5q, 8p, 9p, 10p, 11q, and 17p. A genomic region of approximately 7 Mb located at 8p21.3 approximately p22 exhibits the most frequent LOH (87.9%), which suggests that this region harbors one or more important tumor suppressor genes. Mitochondrial tumor suppressor gene 1 (MTUS1) is a recently identified candidate tumor suppressor gene that resides in this region. Consistent downregulation in expression was observed in HNSCC for MTUS1 as measured by real-time quantitative reverse transcriptase-polymerase chain reaction. Sequence analysis of MTUS1 gene in HNSCC revealed several important sequence variants in the exon regions of this gene. Thus, our results suggest that MTUS1 is one of the candidate tumor suppressor genes for HNSCC residing at 8p21.3 approximately p22. The identification of these candidate genes will facilitate the understanding of tumorigenesis of HNSCC.

Ohadi M, Totonchi M, Maguire P, et al.
Mutation analysis of the DBC2 gene in sporadic and familial breast cancer.
Acta Oncol. 2007; 46(6):770-2 [PubMed] Related Publications
The expression of the recently identified tumor suppressor gene, DBC2 (Deleted in Breast Cancer 2), is frequently extinguished in breast cancer cells or tissues. Mutation analysis of the essential promoter region, all exons and exon/intron boundaries of the DBC2 gene was performed in 100 sporadic breast cancer cases by PCR-SSCP, and DHPLC, followed by direct sequencing. An additional 17 breast cancer families, who were negative for the BRCA1/2 mutations, were analyzed by direct sequencing. Three novel mutations were observed in the promoter and 5'-untranslated region (UTR) of the gene; a germ-line G>A transition in the promoter at nt -238 from the transcription start site, and two tumor-specific mutations at nt -121C>T and nt +48G>A. No deleterious mutations were detected in the coding sequence of the gene in familial and sporadic breast cancer cases. The sequence variations found within the promoter and 5'-UTR region of the gene warrant expression analysis and screening more tumor samples at this region.

Collado D, Yoshihara T, Hamaguchi M
DBC2 resistance is achieved by enhancing 26S proteasome-mediated protein degradation.
Biochem Biophys Res Commun. 2007; 360(3):600-3 [PubMed] Free Access to Full Article Related Publications
Tumor suppressor gene DBC2 stops growth of tumor cells through regulation of CCND1. Interference of CCND1 down-regulation prevented growth arrest caused by DBC2 [T. Yoshihara, D. Collado, M. Hamaguchi, Cyclin D1 down-regulation is essential for DBC2's tumor suppressor function, Biochemical and biophysical research communications 358 (2007) 1076-1079]. It was also noted that DBC2 resistant cells eventually arose after repeated induction of DBC2 with muristerone A treatment [M. Hamaguchi, J.L. Meth, C. Von Klitzing, W. Wei, D. Esposito, L. Rodgers, T. Walsh, P. Welcsh, M.C. King, M.H. Wigler, DBC2, a candidate for a tumor suppressor gene involved in breast cancer, Proc. Natl. Acad. Sci. USA 99 (2002) 13647-13652]. In order to elucidate the mechanism of resistance acquisition, we analyzed DBC2 sensitive and resistant cells derived from the same progenitor cells (T-47D). We discovered that DBC2 protein was abundantly expressed in the sensitive cells when DBC2 was induced. In contrast, it was undetectable by western blot analysis in the resistant cells. We confirmed that the inducible gene expression system was responsive in both cells by detecting induced GFP. Additionally, inhibition of 26S proteasome by MG132 revealed production of DBC2 protein in the resistant cells. These findings indicate that the resistant T-47D cells survive DBC2 induction by rapid destruction of DBC2 through 26S proteasome-mediated protein degradation.

Yoshihara T, Collado D, Hamaguchi M
Cyclin D1 down-regulation is essential for DBC2's tumor suppressor function.
Biochem Biophys Res Commun. 2007; 358(4):1076-9 [PubMed] Free Access to Full Article Related Publications
The expression of tumor suppressor gene DBC2 causes certain breast cancer cells to stop growing [M. Hamaguchi, J.L. Meth, C. Von Klitzing, W. Wei, D. Esposito, L. Rodgers, T. Walsh, P. Welcsh, M.C. King, M.H. Wigler, DBC2, a candidate for a tumor suppressor gene involved in breast cancer, Proc. Natl. Acad. Sci. USA 99 (2002) 13647-13652]. Recently, DBC2 was found to participate in diverse cellular functions such as protein transport, cytoskeleton regulation, apoptosis, and cell cycle control [V. Siripurapu, J.L. Meth, N. Kobayashi, M. Hamaguchi, DBC2 significantly influences cell cycle, apoptosis, cytoskeleton, and membrane trafficking pathways. J. Mol. Biol. 346 (2005) 83-89]. Its tumor suppression mechanism, however, remains unclear. In this paper, we demonstrate that DBC2 suppresses breast cancer proliferation through down-regulation of Cyclin D1 (CCND1). Additionally, the constitutional overexpression of CCND1 prevented the negative impact of DBC2 expression on their growth. Under a CCND1 promoter, the expression of CCNE1 exhibited the same protective effect. Our results indicate that the down-regulation of CCND1 is an essential step for DBC2's growth suppression of cancer cells. We believe that this discovery contributes to a better understanding of DBC2's tumor suppressor function.

Knowles MA, Aveyard JS, Taylor CF, et al.
Mutation analysis of the 8p candidate tumour suppressor genes DBC2 (RHOBTB2) and LZTS1 in bladder cancer.
Cancer Lett. 2005; 225(1):121-30 [PubMed] Related Publications
Genomic deletions of the short arm of chromosome 8 are common in many human cancers and are frequently associated with a more aggressive tumour phenotype. One of the regions of loss of heterozygosity (LOH) on 8p22 identified in bladder cancer contains two genes, LZTS1 (FEZ1) and DBC2 (RHOBTB2) that have been shown to be mutated at low frequency in other cancers. We screened a panel of bladder tumours and bladder tumour-derived cell lines for mutations in these genes. Forty two percent of the tumours were found to have LOH in the 8p22 region and many of the cell lines have known loss of 8p. Several known polymorphisms and novel polymorphisms were detected. One possible mutation of LZTS1 (G374S) was found in a cell line. The functional significance of this is unknown but the novel serine residue created may represent a novel phosphorylation site. In DBC2, we found a single somatic mutation in a tumour (E349D) that lies in a highly conserved region of the protein. mRNA levels for both genes were reduced in the majority of bladder cancer cell lines. We conclude that neither LZTS1 nor DBC2 is commonly mutated in bladder cancer. However, neither can yet be excluded as the target of 8p22 LOH. The finding of a somatic mutation of DBC2 in a tumour sample and the down-regulation of both gene transcripts in bladder tumour cell lines may indicate that an alternative mechanism of inactivation of the second allele, for example promoter hypermethylation, is more common than mutation and this must now be examined.

Sundararajan R, Chen G, Mukherjee C, White E
Caspase-dependent processing activates the proapoptotic activity of deleted in breast cancer-1 during tumor necrosis factor-alpha-mediated death signaling.
Oncogene. 2005; 24(31):4908-20 [PubMed] Related Publications
Deleted in breast cancer-1 (DBC-1) was initially cloned from a homozygously deleted region in breast and other cancers on human chromosome 8p21, although no function is known for the protein product it encodes. We identified the generation of amino-terminally truncated versions of DBC-1 during tumor necrosis factor (TNF)-alpha-mediated apoptosis. Full-length 150 kDa DBC-1 underwent caspase-dependent processing during TNF-alpha-mediated death signaling, to produce p120 DBC-1 and p66 DBC-1 carboxy-terminal fragments. Endogenous DBC-1 localized to the nucleus in healthy cells, but localized to the cytoplasm during TNF-alpha-mediated apoptosis, consistent with the loss of the amino-terminus containing the nuclear localization signal. Overexpression of an amino-terminal truncated DBC-1, resembling p120 DBC-1, caused mitochondrial clustering, mitochondrial matrix condensation, and sensitized cells to TNF-alpha-mediated apoptosis. The carboxy-terminal coiled-coil domain of DBC-1 was responsible for the cytoplasmic and mitochondrial localization, and for the death-promoting activity of DBC-1. Thus, caspase-dependent processing of DBC-1 may act as a feed-forward mechanism to promote apoptosis and possibly also tumor suppression. DBC-1, like its homolog cell cycle and apoptosis regulatory protein-1 (CARP-1), may function in the regulation of apoptosis.

Wilkins A, Ping Q, Carpenter CL
RhoBTB2 is a substrate of the mammalian Cul3 ubiquitin ligase complex.
Genes Dev. 2004; 18(8):856-61 [PubMed] Free Access to Full Article Related Publications
Rhobtb2 is a candidate tumor suppressor located on human chromosome 8p21, a region commonly deleted in cancer. Rhobtb2 is homozygously deleted in 3.5% of primary breast cancers, and gene expression is ablated in approximately 50% of breast and lung cancer cell lines. RhoBTB2 is an 83-kD, atypical Rho GTPase of unknown function, comprising an N-terminal Rho GTPase domain and two tandem BTB domains. In this report, we demonstrate that RhoBTB2 binds to the ubiquitin ligase scaffold, Cul3, via its first BTB domain and show in vitro and in vivo that RhoBTB2 is a substrate for a Cul3-based ubiquitin ligase complex. Moreover, we show that a RhoBTB2 missense mutant identified in a lung cancer cell line is neither able to bind Cul3 nor is it regulated by the ubiquitin/proteasome system, resulting in increased RhoBTB2 protein levels in vivo. We suggest a model in which RhoBTB2 functions as a tumor suppressor by recruiting proteins to a Cul3 ubiquitin ligase complex for degradation.

Hamaguchi M, Meth JL, von Klitzing C, et al.
DBC2, a candidate for a tumor suppressor gene involved in breast cancer.
Proc Natl Acad Sci U S A. 2002; 99(21):13647-52 [PubMed] Free Access to Full Article Related Publications
A previously uncharacterized gene, DBC2 (deleted in breast cancer), was cloned from a homozygously deleted region at human chromosome 8p21. DBC2 contains a highly conserved RAS domain and two putative protein interacting domains. Our analyses indicate that DBC2 is the best candidate tumor suppressor gene from this region. It lies within the epicenter of the deletions and is homozygously deleted in 3.5% (7/200) of breast tumors. Mutation analysis of DBC2 led to discovery of two instances of somatic missense mutations in breast tumor specimens, whereas no missense mutations were found in other candidates from the region. Unlike other genes in the region, expression of DBC2 is often extinguished in breast cancer cells or tissues. Moreover, our functional analysis revealed that DBC2 expression in breast cancer cells lacking DBC2 transcripts causes growth inhibition. By contrast, expression of a somatic mutant discovered in a breast cancer specimen does not suppress the growth of breast cancer cells.

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