TOP2A

Gene Summary

Gene:TOP2A; topoisomerase (DNA) II alpha 170kDa
Aliases: TOP2, TP2A
Location:17q21-q22
Summary:This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. It catalyzes the transient breaking and rejoining of two strands of duplex DNA which allows the strands to pass through one another, thus altering the topology of DNA. Two forms of this enzyme exist as likely products of a gene duplication event. The gene encoding this form, alpha, is localized to chromosome 17 and the beta gene is localized to chromosome 3. The gene encoding this enzyme functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. Reduced activity of this enzyme may also play a role in ataxia-telangiectasia. [provided by RefSeq, Jul 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:DNA topoisomerase 2-alpha
HPRD
Source:NCBIAccessed: 16 March, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 16 March 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 16 March, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: TOP2A (cancer-related)

Özdemiri M, Öznur M, Çiftçi E, et al.
Detection of kinase amplifications in gastric adenocarcinomas.
Turk J Med Sci. 2014; 44(3):461-70 [PubMed] Related Publications
AIM: To determine the incidences of copy number aberrations of receptor kinases and their relations in Turkish patients with gastric adenocarcinoma.
MATERIALS AND METHODS: The prevalence of genomic copy number aberrations of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2)/topoisomerase IIa (TOP2A), centrosome-associated kinase aurora A (AURK A), centrosome-associated kinase aurora B (AURK B), and mesenchymal-epithelial transition factor (MET) genes and polysomies of related chromosomes were analyzed by fluorescent in situ hybridization (FISH) in tumor samples from 35 patients with gastric cancer.
RESULTS: There were 28.6%, 65.7%, 20.0%, 17.1%, 60.0%, and 45.7% cases considered FISH-positive for EGFR, MET, HER2, TOP2A, AURK A, and AURK B genes, respectively. Statistically significant associations were determined in detection of amplifications of 1) EGFR gene with chromosome 7 polysomy, 2) MET gene in nonpolysomic chromosome 7 nuclei, 3) HER2/TOP2A genes in nonpolysomic chromosome 17 nuclei, 4) coamplification of HER2/TOP2A in poorly differentiated carcinomas, and 5) AURK A gene in nonpolysomic chromosome 20 nuclei. Most of the aberrations were predominantly seen in poorly differentiated tumors, but a high rate of the amplified MET gene was also detected in moderately differentiated carcinomas.
CONCLUSION: Chromosome 7 polysomy may be responsible for EGFR gene amplifications, and we concluded that MET and AURK A genes amplifications were commonly seen aberrations in gastric adenocarcinomas and may offer information about disease progression and administration of individualized treatment for gastric cancer patients.

Min W, Wang B, Li J, et al.
The expression and significance of five types of miRNAs in breast cancer.
Med Sci Monit Basic Res. 2014; 20:97-104 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This study aimed to investigate the expression and significance of 5 types of miRNAs in breast cancer to provide a theoretical and practical foundation for using these miRNAs in the diagnosis and treatment of breast cancer, thereby improving medical services.
MATERIAL/METHODS: Stem-loop real-time RT-PCR was used to detect the expression levels of miR-145, miR-21, miR-10b, miR-125a, and miR-206 in 35 cases of breast cancer and adjacent normal breast tissues, and to analyze the relationship of miRNAs expression with clinicopathological features of breast cancer. The expression levels of estrogen receptor (ER) and progesterone receptor (PR) were examined by immunohistochemistry. Fluorescence in situ hybridization was used for the detection of HER-2 and TOP 2A.
RESULTS: The expression levels of miR-145, miR-125a, and miR-206 in breast cancer were lower than those in adjacent normal tissues. MiR-145 was negatively correlated with tumor size, lymph node metastasis, ER, HER-2, and TOP 2A (P<0.05), regardless of age, menstruation, and PR. MiR-125a was correlated with negative node status, negative HER-2 status (P<0.05), whereas tumor size, age, menstruation, ER, and PR were independent factors. MiR-206 expression was correlated with negative ER status, negative PR status, and negative HER-2 status (P<0.05), regardless of age, menstruation, lymph node metastasis, and TOP 2A. MiR-21 and miR-10b expression in breast cancer tissues was significantly higher than that in adjacent tissues (P<0.05). MiR-21 in post-menstrual patients with lymph node metastasis was highly expressed (P<0.05), and had no correlations with tumor size, ER, PR, and TOP 2A expression. MiR-10b expression was positively correlated with breast cancer tumor size, lymph node metastasis, and TOP 2A status (P<0.05), but had no correlations with age, menstruation, ER, PR, and HER-2.
CONCLUSIONS: MiR-145, miR-21, miR-10b, miR-125a, and miR-206 may play important roles in breast cancer development and invasion.

Fu Y, Zhou S, Liu Y, et al.
The cytotoxicity of benzaldehyde nitrogen mustard-2-pyridine carboxylic acid hydrazone being involved in topoisomerase IIα inhibition.
Biomed Res Int. 2014; 2014:527042 [PubMed] Free Access to Full Article Related Publications
The antitumor property of iron chelators and aromatic nitrogen mustard derivatives has been well documented. Combination of the two pharmacophores in one molecule in drug designation is worth to be explored. We reported previously the syntheses and preliminary cytotoxicity evaluation of benzaldehyde nitrogen mustard pyridine carboxyl acid hydrazones (BNMPH) as extended study, more tumor cell lines (IC50 for HepG2: 26.1 ± 3.5 μM, HCT-116: 57.5 ± 5.3 μM, K562: 48.2 ± 4.0 μM, and PC-12: 19.4 ± 2.2 μM) were used to investigate its cytotoxicity and potential mechanism. In vitro experimental data showed that the BNMPH chelating Fe(2+) caused a large number of ROS formations which led to DNA cleavage, and this was further supported by comet assay, implying that ROS might be involved in the cytotoxicity of BNMPH. The ROS induced changes of apoptosis related genes, but the TFR1 and NDRG1 metastatic genes were not obviously regulated, prompting that BNMPH might not be able to deprive Fe(2+) of ribonucleotide reductase. The BNMPH induced S phase arrest was different from that of iron chelators (G1) and alkylating agents (G2). BNMPH also exhibited its inhibition of human topoisomerase IIα. Those revealed that the cytotoxic mechanism of the BNMPH could stem from both the topoisomerase II inhibition, ROS generation and DNA alkylation.

Ichinose J, Watanabe K, Sano A, et al.
Alternative polyadenylation is associated with lower expression of PABPN1 and poor prognosis in non-small cell lung cancer.
Cancer Sci. 2014; 105(9):1135-41 [PubMed] Related Publications
Alternative polyadenylation (APA), which induces shortening of the 3'UTR, is emerging as an important phenomenon in gene regulation. APA is involved in development, cancer and cell proliferation. APA may lead to disruption of microRNA-mediated gene silencing in cancer cells via detachment of microRNA binding sites. We studied the correlation between the APA profile and the tumor aggressiveness in cases of lung cancer. We selected the top 10 genes showing significant 3'UTR shortening in lung cancer, using the package of the Bioconductor for probe-level analyses of expression microarrays. We established and evaluated the APA score by quantitative RT-PCR in 147 clinical specimens of non-small cell lung cancer and compared the results with the clinical outcomes and expression levels of APA-related genes, including PABPN1, CPEB1, E2F1 and proliferation markers (MKI67, TOP2A and MCM2). High APA scores were correlated with an advanced tumor stage and a poor prognosis (P < 0.001). Multivariate analysis identified the APA score as an independent prognostic factor (hazard ratio, 3.0; P = 0.03). Both lower expression of PABPN1 and higher expression of the proliferation markers were correlated with high APA scores and a poor prognosis, with suppression of PABPN1 exerting its influence independent of gain of the proliferation markers. Moreover, the APA score was correlated with the maximum standardized uptake value of the tumors on positron emission tomography (r = 0.53; P < 0.001). Our results indicate that the loss of PABPN1, a suppressor of APA, might promote tumor aggressiveness by releasing the cancer cells from microRNA-mediated gene regulation.

Salvo P, Henry OY, Dhaenens K, et al.
Fabrication and functionalization of PCB gold electrodes suitable for DNA-based electrochemical sensing.
Biomed Mater Eng. 2014; 24(4):1705-14 [PubMed] Related Publications
The request of high specificity and selectivity sensors suitable for mass production is a constant demand in medical research. For applications in point-of-care diagnostics and therapy, there is a high demand for low cost and rapid sensing platforms. This paper describes the fabrication and functionalization of gold electrodes arrays for the detection of deoxyribonucleic acid (DNA) in printed circuit board (PCB) technology. The process can be implemented to produce efficiently a large number of biosensors. We report an electrolytic plating procedure to fabricate low-density gold microarrays on PCB suitable for electrochemical DNA detection in research fields such as cancer diagnostics or pharmacogenetics, where biosensors are usually targeted to detect a small number of genes. PCB technology allows producing high precision, fast and low cost microelectrodes. The surface of the microarray is functionalized with self-assembled monolayers of mercaptoundodecanoic acid or thiolated DNA. The PCB microarray is tested by cyclic voltammetry in presence of 5 mM of the redox probe K3Fe(CN6) in 0.1 M KCl. The voltammograms prove the correct immobilization of both the alkanethiol systems. The sensor is tested for detecting relevant markers for breast cancer. Results for 5 nM of the target TACSTD1 against the complementary TACSTD1 and non-complementary GRP, MYC, SCGB2A1, SCGB2A2, TOP2A probes show a remarkable detection limit of 0.05 nM and a high specificity.

Miura JT, Johnston FM, Thomas J, et al.
Molecular profiling in gastric cancer: examining potential targets for chemotherapy.
J Surg Oncol. 2014; 110(3):302-6 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Current NCCN guidelines recommend epirubicin (E), cisplatin (C), and 5-fluorouracil (F) as a first-line therapeutic approach for operable gastric adenocarcinoma (GC). Molecular profiling (MP) was used to evaluate the expression of chemotherapy targeted biomarkers associated with ECF therapy and other first-line cytotoxic regimens for GC.
METHODS: GC specimens were analyzed by immunohistochemistry (IHC) for TOP2A, TS, ERCC1, PGP, and TOPO1 expression (Caris Life Sciences, Phoenix, AZ) from 2009 to 2012.
RESULTS: A total of 230 GC specimens were analyzed. The median age of patients was 61 (IQR: 50-72) years with the majority being male (n = 139, 60%). IHC actionable targets included: 60% (n = 138) high TOP2A, 55% (n = 127) negative ERCC1, and 63% (n = 145) negative TS, indicating potential benefit from E, C, and F, respectively. Simultaneous expression analysis demonstrated only 24% (n = 55) of patients had gene expression levels that suggested uniform sensitivity to ECF. Biomarker results of 6.5% (n = 15) of patients revealed a potential complete lack of sensitivity to first-line ECF.
CONCLUSIONS: MP of GC has the potential to define patients who would derive the greatest benefit from current therapies. Prospective controlled studies are required to validate the role of biomarkers in the management of GC patients.

Smith NA, Byl JA, Mercer SL, et al.
Etoposide quinone is a covalent poison of human topoisomerase IIβ.
Biochemistry. 2014; 53(19):3229-36 [PubMed] Article available free on PMC after 28/04/2015 Related Publications
Etoposide is a topoisomerase II poison that is utilized to treat a broad spectrum of human cancers. Despite its wide clinical use, 2-3% of patients treated with etoposide eventually develop treatment-related acute myeloid leukemias (t-AMLs) characterized by rearrangements of the MLL gene. The molecular basis underlying the development of these t-AMLs is not well understood; however, previous studies have implicated etoposide metabolites (i.e., etoposide quinone) and topoisomerase IIβ in the leukemogenic process. Although interactions between etoposide quinone and topoisomerase IIα have been characterized, the effects of the drug metabolite on the activity of human topoisomerase IIβ have not been reported. Thus, we examined the ability of etoposide quinone to poison human topoisomerase IIβ. The quinone induced ~4 times more enzyme-mediated DNA cleavage than did the parent drug. Furthermore, the potency of etoposide quinone was ~2 times greater against topoisomerase IIβ than it was against topoisomerase IIα, and the drug reacted ~2-4 times faster with the β isoform. Etoposide quinone induced a higher ratio of double- to single-stranded breaks than etoposide, and its activity was less dependent on ATP. Whereas etoposide acts as an interfacial topoisomerase II poison, etoposide quinone displayed all of the hallmarks of a covalent poison: the activity of the metabolite was abolished by reducing agents, and the compound inactivated topoisomerase IIβ when it was incubated with the enzyme prior to the addition of DNA. These results are consistent with the hypothesis that etoposide quinone contributes to etoposide-related leukemogenesis through an interaction with topoisomerase IIβ.

Shi X, Wu S, Yang Y, et al.
AQP5 silencing suppresses p38 MAPK signaling and improves drug resistance in colon cancer cells.
Tumour Biol. 2014; 35(7):7035-45 [PubMed] Related Publications
It is known that aquaporin 5 (AQP5) may represent a novel therapeutic target for treating colon cancer (CC), but whether AQP5 plays a role in the regulation of multidrug resistance (MDR) of colon cancer still remains unclear. In the present study, AQP5 and P-glycoprotein (P-gp), glutathione S-transferase-π (GST-π), topoisomerase II (TOPO II), and thymidylate synthase (TS) were checked in CC and adjacent cancer tissues; AQP5-siRNA was applied to silencing AQP5 in CC cell line HT-29, 5-fluorouracil (5-FU), and cisplatin (DDP) added on cells, and sulforhodamine B (SRB) was used; fluorescence real-time quantitative RT-PCR and Western blot were employed to detect changes in multidrug resistance factor and expression mitogen-activated protein kinase (MAPK) signaling pathway in HT-29. The results showed that AQP5 is significantly induced in cancer tissues than that in adjacent cancer tissues. The expression of AQP5 is positively correlated with drug resistance factors, as demonstrated by the increased expressions of P-gp, GST-π, and TOPO II in CC tissues compared to that in adjacent cancer tissues. Conversely, knockdown of AQP5 in HT-29 human colon cancer cells increased inhibition rates of cancer chemotherapeutic drugs such as 5-FU and DDP. The improved efficacies of chemotherapeutic drugs are associated with the decreased expression of P-gp, GST-π, and TOPO II. In addition, phosphorylation of p38 MAPK was increased by knockdown of AQP5 in HT-29 cells while phosphorylation and expression of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and Protein kinase B (AKT) were not affected. P38 MAPK inhibitor increased the drug sensitivity of HT-29 cells in a similar way as AQP5-siRNAs do. So these results indicate that AQP5 is associated with drug resistance of colon cancer, and that the AQP5-P38 MAPK pathway may represent a potential drug target to improve drug resistance of colon cancer cells.

Verschuur-Maes AH, Moelans CB, de Bruin PC, van Diest PJ
Analysis of gene copy number alterations by multiplex ligation-dependent probe amplification in columnar cell lesions of the breast.
Cell Oncol (Dordr). 2014; 37(2):147-54 [PubMed] Related Publications
BACKGROUND: Columnar cell lesions (CCLs) are possible precursors of breast cancer, but little is known about the role of breast cancer-related genes in the progression of CCL to invasive breast cancer.
METHODS: Gene copy numbers of 17 breast cancer-related genes were analyzed using Multiplex Ligation-dependent Probe Amplification (MLPA) in CCL (N = 28), ductal carcinoma in situ (DCIS) grade I likely originating from CCL (N = 5), and paired CCL (N = 14/28) with DCIS (N = 7) and/or invasive carcinoma (N = 13). The genes included were BIRC5, C11orf30, CCND1, CCNE1, CDH1, CPD, EGFR, ERBB2, ESR1, FGFR1, IKBKB, MAPT, MED1, MTDH, MYC, TOP2A and TRAF4.
RESULTS: No high level gene amplifications were observed in CCL, but copy number gains were encountered for the C11orf30 (3/28), MYC, CPD, MTDH (2/28), and CCND1, CCNE1, ESR1 and TOP2A genes (1/28). In addition, CDH1 showed loss in 2/28 and TOP2A in 1/28 cases. CCLs with or without atypia exhibited comparable numbers of copy number changes (p = 0.312). Overall, the frequency of gene copy number changes increased from CCL towards DCIS and invasive carcinoma (p = 0.004). Also in the cases with synchronous lesions, the CCLs exhibited fewer copy number changes than the DCIS/invasive carcinomas.
CONCLUSIONS: CCLs carry copy number changes of several known breast cancer-related genes, thereby substantiating their role in breast carcinogenesis. Among them, CCND1 and ESR1 copy number gains and CDH1 copy number losses are of particular interest. Since the copy number changes observed were more prevalent in DCIS and invasive carcinoma than in CCL, the corresponding gene alterations may represent rather late occurring events in low nuclear grade breast carcinogenesis.

Fasching PA, Weihbrecht S, Haeberle L, et al.
HER2 and TOP2A amplification in a hospital-based cohort of breast cancer patients: associations with patient and tumor characteristics.
Breast Cancer Res Treat. 2014; 145(1):193-203 [PubMed] Related Publications
Gene amplification is an important factor for altered gene expression in breast cancers. TOP2A-amplification often occurs concomitantly with HER2 amplification, and it has been suggested to be predictive for the response to anthracycline chemotherapy. This study assessed the correlation between HER2 status and TOP2A co-amplification, the possible association of TOP2A single-nucleotide polymorphisms with the frequency of this co-amplification as well as confirmation of association with outcome. HER2 and TOP2A amplification were analyzed in a tissue microarray from a clinical cohort study. Additionally, a common genetic variant (rs13695) in the TOP2A gene was genotyped in germline DNA. HER2 gene amplification was compared with HER2-IHC findings assessed during clinical routine work, and the association between all the biomarkers analyzed and the clinical outcome was determined. As an exploratory aim, rs13695 genotypes were compared with TOP2A amplification status. HER2 amplification was seen in 101 of 628 (16.1 %) and TOP2A amplification in 32 (5.1 %) cancers. No TOP2A amplification occurred without HER2 co-amplification. HER2 amplification was found in 8, 13.6, and 55.1 % of patients with HER2-IHC 0/1+, 2+, and 3+ tumors, respectively. HER2-IHC was not associated with an effect on the prognosis, but HER2-FISH was. There was an association between the rs13695 genotype and TOP2A amplification status (P = 0.03). Although there was a significant correlation between HER2 status determined by IHC and HER2 by FISH, only HER2 gene amplification status by FISH was correlated with outcome indicating greater utility for FISH in routine clinical settings.

Sherman-Baust CA, Kuhn E, Valle BL, et al.
A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development.
J Pathol. 2014; 233(3):228-37 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Recent evidence suggests that ovarian high-grade serous carcinoma (HGSC) originates from the epithelium of the fallopian tube. However, most mouse models are based on the previous prevailing view that ovarian cancer develops from the transformation of the ovarian surface epithelium. Here, we report the extensive histological and molecular characterization of the mogp-TAg transgenic mouse, which expresses the SV40 large T-antigen (TAg) under the control of the mouse müllerian-specific Ovgp-1 promoter. Histological analysis of the fallopian tubes of mogp-TAg mice identified a variety of neoplastic lesions analogous to those described as precursors to ovarian HGSC. We identified areas of normal-appearing p53-positive epithelium that are similar to 'p53 signatures' in the human fallopian tube. More advanced proliferative lesions with nuclear atypia and epithelial stratification were also identified that were morphologically and immunohistochemically reminiscent of human serous tubal intraepithelial carcinoma (STIC), a potential precursor of ovarian HGSC. Beside these non-invasive precursor lesions, we also identified invasive adenocarcinoma in the ovaries of 56% of the mice. Microarray analysis revealed several genes differentially expressed between the fallopian tube of mogp-TAg and wild-type (WT) C57BL/6. One of these genes, Top2a, which encodes topoisomerase IIα, was shown by immunohistochemistry to be concurrently expressed with elevated p53 and was specifically elevated in mouse STICs but not in the surrounding tissues. TOP2A protein was also found elevated in human STICs, low-grade and high-grade serous carcinoma. The mouse model reported here displays a progression from normal tubal epithelium to invasive HGSC in the ovary, and therefore closely simulates the current emerging model of human ovarian HGSC pathogenesis. This mouse therefore has the potential to be a very useful new model for elucidating the mechanisms of serous ovarian tumourigenesis, as well as for developing novel approaches for the prevention, diagnosis and therapy of this disease.

Tabarestani S, Ghaderian SM, Rezvani H, et al.
Prognostic and predictive value of copy number alterations in invasive breast cancer as determined by multiplex ligation-dependent probe amplification.
Cell Oncol (Dordr). 2014; 37(2):107-18 [PubMed] Related Publications
BACKGROUND: Breast cancer is a leading cause of morbidity and mortality in women worldwide. About 70 % of breast cancers are estrogen receptor (ER) positive. Blocking estrogen action by tamoxifen has been the treatment of choice in ER positive breast cancers for more than 30 years. In the past, several studies have revealed associations between gene copy number alterations and responsiveness to tamoxifen therapy, but so far no single gene copy number alteration could completely explain the response variation observed between individual breast cancer patients. Here, we set out to perform a simultaneous analysis of copy number alterations of several genes involved in the prognosis and response to therapy by multiplex ligation-dependent probe amplification (MLPA).
METHODS: A case-control study was designed encompassing 170 non-metastatic ER positive breast cancer patients (case group = 85, control group = 85). All patients in the control group had received standard adjuvant tamoxifen treatment for 5 years without any evidence of recurrence. Patients in the case group had experienced early recurrences while receiving tamoxifen treatment. 76 % of the patients of the case group and 73 % of the patients of the control group had received anthracycline-based adjuvant chemotherapy. Gene copy number alterations detected by MLPA in both groups were compared.
RESULTS: Amplification of CCND1 (OR = 3.13; 95 % CI = 1.35 to 7.26; p = 0.006) and TOP2A (OR = 3.05; 95 % CI = 1.13 to 8.24; p = 0.022) were significantly more prevalent in the case group, compared to the control group. In a multivariate analysis CCND1 (p = 0.01) and TOP2A (p = 0.041) amplifications remained significant predictors of recurrence.
CONCLUSIONS: Our results indicate that CCND1 amplification may serve as a useful biomarker for hormone responsiveness, and that TOP2A amplification may serve as a useful prognostic biomarker.

Latorre E, Castiglioni I, Gatto P, et al.
Loss of protein kinase Cδ/HuR interaction is necessary to doxorubicin resistance in breast cancer cell lines.
J Pharmacol Exp Ther. 2014; 349(1):99-106 [PubMed] Related Publications
The protein kinase Cδ (PKCδ) interacts with and phosphorylates HuR, dictating its functionality. We show here that the genotoxic stimulus induced by doxorubicin triggers PKCδ interaction with HuR and leads to HuR phosphorylation on serines 221 and 318 and cytoplasmic translocation. This series of events is crucial to elicit the death pathway triggered by doxorubicin and is necessary to promote HuR function in post-transcriptional regulation of gene expression, because genetic ablation of PKCδ caused the inability of HuR to bind its target mRNAs, topoisomerase IIα (TOP2A) included. In in vitro select doxorubicin-resistant human breast cancer cell lines upregulating the multidrug resistance marker ABCG2, PKCδ, and HuR proteins were coordinately downregulated together with the doxorubicin target TOP2A protein whose mRNA was HuR-regulated. Therefore, we show here that PKCδ, HuR, and TOP2A constitute a network mediating doxorubicin efficacy in breast cancer cells. The importance of these molecular events in cancer therapy is suggested by their being profoundly suppressed in cells selected for doxorubicin resistance.

Engstrøm MJ, Ytterhus B, Vatten LJ, et al.
TOP2A gene copy number change in breast cancer.
J Clin Pathol. 2014; 67(5):420-5 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
AIMS: The clinical significance of TOP2A as a prognostic marker has not been clarified. The aims of this study were to investigate the frequency of TOP2A copy number change; to correlate TOP2A with HER2 status, hormone receptor (HR) status and molecular subtype, and further to explore differences in breast cancer-specific survival according to TOP2A and HER2.
METHODS: In this study, TOP2A, HER2 and chromosome 17 copy number were assessed in 670 cases of breast cancer using in situ hybridisation techniques. Gene to chromosome ratios ≥2 were classified as amplification. TOP2A deletion (gene to chromosome ratio ≤0.8) or monosomy (only one signal for both gene and chromosome in more than 75% of nuclei) were classified as gene loss.
RESULTS: A strong association between TOP2A change and HR and HER2 status was found. During the first 5 years after diagnosis, the risk of death from breast cancer was significantly higher for cases with HER2 amplification irrespective of TOP2A status.
CONCLUSIONS: TOP2A copy number change was strongly associated with HR and HER2 status and as a prognostic marker TOP2A is probably of limited value.

Tornesello ML, Buonaguro L, Giorgi-Rossi P, Buonaguro FM
Viral and cellular biomarkers in the diagnosis of cervical intraepithelial neoplasia and cancer.
Biomed Res Int. 2013; 2013:519619 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Cervical cancer arises from cells localized in the ectoendocervical squamocolumnar junction of the cervix persistently infected with one of about 13 human papillomavirus (HPV) genotypes. The majority of HPV infections induces low grade squamous epithelial lesions that in more than 90% of cases spontaneously regress and in about 10% eventually progress to high grade lesions and even less frequently evolve to invasive cancer. Tumor progression is characterized by (1) increased expression of E6 and E7 genes of high risk HPVs, known to bind to and inactivate p53 and pRb oncosuppressors, respectively; (2) integration of viral DNA into host genome, with disruption of E2 viral genes and host chromosomal loci; and (3) molecular alterations of key regulators of cell cycle. Molecular markers with high sensitivity and specificity in differentiating viral infections associated with cellular abnormalities with high risk of progression are strongly needed for cervical cancer screening and triage. This review will focus on the analysis of clinical validated or candidate biomarkers, such as HPV DNA, HPV E6/E7 mRNA, HPV proteins, p16(INK4a) and Ki67, TOP2A and MCM2 cellular factors, and DNA methylation profiles, which will likely improve the identification of premalignant lesions that have a high risk to evolve into invasive cervical cancer.

Abdel-Fatah TM, Perry C, Moseley P, et al.
Clinicopathological significance of human apurinic/apyrimidinic endonuclease 1 (APE1) expression in oestrogen-receptor-positive breast cancer.
Breast Cancer Res Treat. 2014; 143(3):411-21 [PubMed] Related Publications
Oestrogen metabolites can induce oxidative DNA base damage and generate potentially mutagenic apurinic sites (AP sites) in the genomic DNA. If unrepaired, mutagenic AP sites could drive breast cancer pathogenesis and aggressive phenotypes. Human apurinic/apyrimidinic endonuclease 1 (APE1) is a key DNA base excision repair (BER) protein and essential for processing AP sites generated either directly by oestrogen metabolites or during BER of oxidative base damage. Our hypothesis is that altered APE1 expression may be associated with aggressive tumour biology and impact upon clinical outcomes in breast cancer. In the current study, we have investigated APE1 protein expression in a large cohort of breast cancers (n = 1285) and correlated to clinicopathological features and survival outcomes. Low APE1 protein expression was associated with high histological grade (p < 0.000001), high mitotic index (p < 0.000001), glandular de-differentiation (p < 0.000001), pleomorphism (p = 0.003), absence of hormonal receptors (ER-/PgR-/AR-) (p < 0.0001) and presence of triple negative phenotype (p = 0.001). Low APE1 protein expression was associated with loss of BRCA1, low XRCC1, low FEN1, low SMUG1 and low pol β (ps < 0.0001). High MIB1 (p = 0.048), bcl-2 negativity (p < 0.0001) and low TOP2A (p < 0.0001) were likely in low APE1 tumours. In the ER-positive sub-group, specifically, low APE1 remains significantly associated with high histological grade, high mitotic index, glandular de-differentiation (ps < 0.00001) and poor breast cancer specific survival (p = 0.007). In the ER-positive cohort that received adjuvant endocrine therapy, low APE1 protein expression is associated with poor survival (p = 0.006). In multivariate analysis, low APE1 remains independently associated with poor survival in ER-positive tumours (p = 0.048). We conclude that low APE1 expression may have prognostic and predictive significance in ER-positive breast cancers.

Mikulová V, Cabiňaková M, Janatková I, et al.
Detection of circulating tumor cells during follow-up of patients with early breast cancer: Clinical utility for monitoring of therapy efficacy.
Scand J Clin Lab Invest. 2014; 74(2):132-42 [PubMed] Related Publications
INTRODUCTION: Circulating tumor cells (CTCs) detection prior to and during therapy is considered as an independent and strong prognostic marker. The present study was designed to isolate and characterize CTCs in peripheral blood of an early breast cancer (BC) patient as a biomarker for monitoring treatments efficacy.
MATERIALS AND METHODS: In total, 54 early breast cancer patients undergoing neoadjuvant and/or adjuvant chemotherapy regimens were enrolled into a prospective study. CTC detection in blood was performed by AdnaTest BreastCancer(™) (AdnaGen AG, Germany), which is based on the detection of EpCAM, HER2 and MUC1 specific transcripts in enriched CTC-lysates. Additionally, cDNA from isolated CTCs and PBMC was used for qPCR gene expression analysis of TOP1, TOP2A, CTSD, ST6, CK19 and reference gene actin.
RESULTS: We found that CTCs can be detected in the peripheral blood of approximately 31% of early stage breast cancer patients. The presence of CTCs was detected in 36% ER positive, 32% PR positive and 30% HER2 positive patients. We found no correlation between CTCs and tumor size, tumor grade, histological grade and receptor status. Only 7% of all patients remained CTCs positive after adjuvant therapy. Gene expression analysis revealed a particular heterogeneity of the studied genes.
CONCLUSIONS: In conclusion, CTC detection may be a promising early marker of disease progression potentially enhancing the difficult therapeutic decisions. Further studies should, however, clearly demonstrate its utility for both the prediction of outcome and monitoring the effect of treatment.

Supernat A, Łapińska-Szumczyk S, Majewska H, et al.
A multimarker qPCR platform for the characterisation of endometrial cancer.
Oncol Rep. 2014; 31(2):1003-13 [PubMed] Related Publications
The molecular background of endometrial cancer (EC) has not been fully elucidated. In the present study, we developed a quantitative PCR (qPCR) platform to examine the gene dosages of the potential molecular markers MGB1, TOP2A, ERBB1-4, MYC, CCND1, ESR1 and PI3K. The platform was applied in samples collected from 157 EC patients (stage I-IV) to verify its clinical utility and to examine the diagnostic and prognostic significance of the analysed biomarkers. The gene dosage pattern of the ERBB family and its downstream effectors PI3K and MYC showed particularly strong correlations with clinicopathological data. The ERBB PI3K/Akt pathway was upregulated in 31 (20%) of 156 cases. Activation of the ERBB PI3K/Akt pathway was positively correlated with a higher stage (p=0.001), higher grade (p=0.001), histological type II disease (p=0.0003) and metastases (p=0.02). The implemented hierarchical clustering revealed that cluster 2 was characterised by high copy numbers of the studied genes. Cluster 2 was associated with shorter overall survival (p=0.05). The platform was found to be a fast and simple method for direct analysis of the genes involved in uterine carcinogenesis, making it feasible for EC biology characterisation.

Smith KA, Cowell IG, Zhang Y, et al.
The role of topoisomerase II beta on breakage and proximity of RUNX1 to partner alleles RUNX1T1 and EVI1.
Genes Chromosomes Cancer. 2014; 53(2):117-28 [PubMed] Related Publications
Rearrangements involving the RUNX1 gene account for approximately 15% of balanced translocations in therapy-related acute myeloid leukemia (t-AML) patients and are one of the most common genetic abnormalities observed in t-AML. Drugs targeting the topoisomerase II (TOP2) enzyme are implicated in t-AML; however, the mechanism is not well understood and to date a single RUNX1-RUNX1T1 t-AML breakpoint junction sequence has been published. Here we report an additional five breakpoint junction sequences from t-AML patients with the RUNX1- RUNX1T1 translocation. Using a leukemia cell line model, we show that TOP2 beta (TOP2B) is required for induction of RUNX1 chromosomal breaks by the TOP2 poison etoposide and that, while TOP2 alpha (TOP2A) and TOP2B proteins are both present on RUNX1 and RUNX1T1 chromatin, only the TOP2B enrichment reached significance following etoposide exposure at a region on RUNX1 where translocations occur. Furthermore, we demonstrate that TOP2B influences the separation between RUNX1 and two translocation partners (RUNX1T1 and EVI) in the nucleus of lymphoid cells. Specifically, we identified a TOP2B-dependent increase in the number of nuclei displaying juxtaposed RUNX1 and RUNX1T1 loci following etoposide treatment.

Sayed-Ahmed MM, Hafez MM, Al-Shabanah OA, et al.
Increased expression of biological markers as potential therapeutic targets in Saudi women with triple-negative breast cancer.
Tumori. 2013 Jul-Aug; 99(4):545-54 [PubMed] Related Publications
AIMS AND BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks the expression of hormone receptors and human epidermal growth factor receptor 2 (HER2). Although TNBC represents only 15% of all types of breast cancer, it accounts for a large number of metastatic cases and deaths. Because of the high metastatic rate and both local and systemic recurrence associated with TNBC, extensive research efforts are actively looking for target therapies to effectively treat this aggressive disease. Accordingly, this study has been initiated to investigate the differential expression of biological markers in TNBC and non-TNBC Saudi women that might be utilized as potential targeted therapy and/or predict the sensitivity to currently available therapeutic regimens.
METHODS AND STUDY DESIGN: Two hundred formalin-fixed, paraffin-embedded (FFPE) breast cancer tissues were selected and divided into 3 groups: benign breast tissues (20), TNBC tissues (80) and non-TNBC tissues (100). Expression of mRNA in FFPE tissues was analyzed using real-time polymerase chain reaction (RT-PCR) for the following genes: poly (ADP-ribose) polymerase 1 (PARP-1), topoisomerase 2A (TOPO-2A), vascular endothelial growth factor (VEGF), C-MYC, basic fibroblast growth factor (bFGF), matrix metalloproteinases (MMP-2 and MMP-9), human epidermal growth factor 1 (HER1) and multidrug resistance (MDR) genes.
RESULTS: In the TNBC group, expression of PARP-1, TOPO-2A, HER1, C-MYC, VEGF, bFGF and MMP-2 showed a highly significant increase compared to the non-TNBC group.
CONCLUSIONS: The results of this study suggest that (1) TNBC patients will benefit more from TOPO-2A inhibitors as well as antiangiogenic and antimetastatic therapies; (2) inhibition of these target genes is emerging as one of the most exciting and promising targeted therapeutic strategies to treat TNBC in which the intended targets are DNA repair, tumor angiogenesis and metastasis.

García-Caballero T, Prieto O, Vázquez-Boquete A, et al.
Dual-colour CISH is a reliable alternative to FISH for assessment of topoisomerase 2-alpha amplification in breast carcinomas.
Breast Cancer Res Treat. 2014; 143(1):81-9 [PubMed] Related Publications
Anthracyclines are among the most powerful antineoplastic drugs available for breast cancer treatment. Although HER2 amplification has been postulated to predict anthracycline benefit, numerous reports have demonstrated that HER2/TOP2A co-amplification is the clinically useful predictive marker of response to anthracyclines. The standard technique to evaluate gene status for target therapy selection is fluorescence in situ hybridization (FISH), but this technique has some disadvantages. Dual-colour chromogenic in situ hybridization (CISH) is an extension of the FISH protocol that allows bright-field microscopy and thus represents a user-friendly alternative to FISH. In order to evaluate whether dual-colour CISH is a reliable alternative to FISH in determining TOP2A gene amplification and to determine the frequency with which TOP2A and HER2 were co-amplified, we analysed 100 invasive breast cancer specimens (70 consecutive and 30 HER2-amplified samples) using tissue microarrays. Thus, a 99 % agreement was found between TOP2A status determined by dual-colour CISH and FISH, as well as a high degree of correlation in TOP2A ratios using both techniques. TOP2A gene amplification was present in 8.6 % of the 70 consecutive samples studied, all of which were HER2-amplified. Co-amplification of TOP2A was observed in 46.5 % of the additional 30 HER2-amplified samples (no TOP2A amplification was seen in non-amplified HER2 samples). We conclude that dual-colour CISH represents an excellent alternative to FISH for determination of TOP2A gene status in invasive breast cancer. Our results showing TOP2A amplification only in HER2-amplified cases also add to the evidence that TOP2A determination should be restricted to those cases.

Qiu Y, Zhang ZY, Du WD, et al.
Association analysis of ERBB2 amplicon genetic polymorphisms and STARD3 expression with risk of gastric cancer in the Chinese population.
Gene. 2014; 535(2):225-32 [PubMed] Related Publications
The purpose of this study was to investigate whether risk of gastric cancer (GC) was associated with single nucleotide polymorphisms (SNPs) in a gene cluster on the chromosome 17q12-q21 (ERBB2 amplicon) in the Chinese Han population. We detected twenty-six SNPs in this gene cluster containing steroidogenic acute regulatory-related lipid transfer domain containing 3 (STARD3), protein phosphatase 1 regulatory subunit 1B (PPP1R1B/DARPP32), titin-cap (TCAP), per1-like domain containing 1(PERLD1/CAB2), human epidermal growth factor receptor-2 (ERBB2/HER2), zinc-finger protein subfamily 1A 3 (ZNFN1A3/IKZF3) and DNA topoisomerase 2-alpha (TOP2A) genes in 311 patients with GC and in 425 controls by Sequenom. We found no associations between genetic variations and GC risk. However, haplotype analysis implied that the haplotype CCCT of STARD3 (rs9972882, rs881844, rs11869286 and rs1877031) conferred a protective effect on the susceptibility to GC (P=0.043, odds ratio [OR]=0.805, 95% confidence intervals [95% CI]=0.643-0.992). The STARD3 rs1877031 TC genotype endued histogenesis of gastric mucinous adenocarcinoma and signet-ring cell carcinoma (P=0.021, OR=2.882, 95% CI=1.173-7.084). We examined the expression of STARD3 in 243 tumor tissues out of the 311 GC patients and 20 adjacent normal gastric tissues using immumohistochemical (IHC) analysis and tissue microarrays (TMA). The expression of STARD3 was observed in the gastric parietal cells and in gastric tumor tissues and significantly correlated with gender (P=0.004), alcohol drinking (P<0.001), tumor location (P=0.007), histological type (P=0.005) and differentiation (P=0.023) in GC. We concluded that the combined effect of haplotype CCCT of STARD3 might affect GC susceptibility. STARD3 expression might be related to the tumorigenesis of GC in the Chinese population.

Kolar Z, Burdova A, Jamaspishvili T, et al.
Relation of ETS transcription factor family member ERG, androgen receptor and topoisomerase 2β expression to TMPRSS2-ERG fusion status in prostate cancer.
Neoplasma. 2014; 61(1):9-16 [PubMed] Related Publications
Fusion of TMPRSS2 with ERG in prostate cells is determined by double-strand DNA breaks induced by androgen signaling and transcription stress. The enzyme topoisomerase 2β (TOP2B) mediating DNA processing, plays an important role in DNA cleavage. The aim of this study was to analyse expression of AR, TOP2B and ERG in relation to TMPRSS2-ERG gene rearrangement and relevant clinicopathological characteristics in prostate cancer (CaP). Immunohistochemical staining and FISH were used for investigation. ERG expression in prostate cell lesions positively correlated with levels of TMPRSS2-ERG fusion gene (p<0.0001). The most significant co-expression of ERG was found with AR in CaP (p=0.001). Significantly more frequent co-expression of ERG was also revealed with TOP2B (p=0.028). ERG protein expression did not correlate with CaP differentiation status as we found no significant differences in ERG expression for different Gleason categories. We demonstrated a statistically significant positive correlation between the percentage of cells with fusion gene TMPRSS2-ERG in CaP and metastatic potential of tumors (p=0.011). Besides these positive corelations of AR with ERG (p=0.001) and TOP2B with ERG (p=0.028), we also demonstrated a significant co-expression of AR with TOP2B (p=0.007) in CaP. There was a statistically significant increase in the TOP2B H-index in locally advanced CaP in comparison with localized tumors (p=0.046). ERG expression correlates with occurrence of TMPRSS2-ERG fusion and with AR-driven malignant transformation. The results indicate that detection of the TMPRSS2-ERG fusion gene and parallel immunohistochemical examination of AR, TOP2B and ERG has diagnostic significance and may be useful in assessing the biological character of the prostate cancer as well as selecting the best treatment.

Ma H, Rao L, Wang HL, et al.
Transcriptome analysis of glioma cells for the dynamic response to γ-irradiation and dual regulation of apoptosis genes: a new insight into radiotherapy for glioblastomas.
Cell Death Dis. 2013; 4:e895 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Ionizing radiation (IR) is of clinical importance for glioblastoma therapy; however, the recurrence of glioma characterized by radiation resistance remains a therapeutic challenge. Research on irradiation-induced transcription in glioblastomas can contribute to the understanding of radioresistance mechanisms. In this study, by using the total mRNA sequencing (RNA-seq) analysis, we assayed the global gene expression in a human glioma cell line U251 MG at various time points after exposure to a growth arrest dose of γ-rays. We identified 1656 genes with obvious changes at the transcriptional level in response to irradiation, and these genes were dynamically enriched in various biological processes or pathways, including cell cycle arrest, DNA replication, DNA repair and apoptosis. Interestingly, the results showed that cell death was not induced even many proapoptotic molecules, including death receptor 5 (DR5) and caspases were activated after radiation. The RNA-seq data analysis further revealed that both proapoptosis and antiapoptosis genes were affected by irradiation. Namely, most proapoptosis genes were early continually responsive, whereas antiapoptosis genes were responsive at later stages. Moreover, HMGB1, HMGB2 and TOP2A involved in the positive regulation of DNA fragmentation during apoptosis showed early continual downregulation due to irradiation. Furthermore, targeting of the TRAIL/DR5 pathway after irradiation led to significant apoptotic cell death, accompanied by the recovered gene expression of HMGB1, HMGB2 and TOP2A. Taken together, these results revealed that inactivation of proapoptotic signaling molecules in the nucleus and late activation of antiapoptotic genes may contribute to the radioresistance of gliomas. Overall, this study provided novel insights into not only the underlying mechanisms of radioresistance in glioblastomas but also the screening of multiple targets for radiotherapy.

Chen G, Jundong GU, Chen J, et al.
Association between clinical pathology and multiple genes mRNA expression in Chinese patients with NSCLC.
J Cancer Res Ther. 2013; 9 Suppl 2:S98-100 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to evaluate whether there was an association between pathology type and ERCC1, BRCA1, RRM1, TUBB3, STMN1, TOP2A and epidermal growth factor receptor (EGFR) messenger ribonucleic acid (mRNA) expression level in Chinese patients with non-small cell lung carcinoma (NSCLC).
MATERIALS AND METHODS: mRNA expression level of these genes was analyzed in 181 cancer tissues by using xTAG-step liquid-chip array. The mRNA expression level of the seven genes was evaluated in association with the clinical pathology type.
RESULTS: The average mRNA expression level of the seven genes were ERCC1 (1.02 ± 0.03), BRCA1 (0.15 ± 0.04), RRM1 (0.19 ± 0.05), TUBB3 (0.31 ± 0.06), STMN1 (2.78 ± 0.42), TOP2A (3.04 ± 0.42) and EGFR (0.58 ± 0.09), respectively in Chinese patients with NSCLC. The mRNA expression level of ERCC1, STMN1 and TOP2A genes were statistical different with different pathology type (p(a) < 0.05); STMN1 and TOP2A genes mRNA expression were much higher in squamous cell lung carcinoma than that in non-squamous cell lung carcinoma (p(a) < 0.05). And ERCC1 gene expression was much lower in squamous cell carcinoma than that in non-squamous cell carcinoma (p(a) < 0.05).
CONCLUSION: mRNA expression level of STMN1, TOP2A and ERCC1 were correlated with the clinical pathology type.

Nygård SB, Christensen IJ, Smith DH, et al.
Underpinning the repurposing of anthracyclines towards colorectal cancer: assessment of topoisomerase II alpha gene copy number alterations in colorectal cancer.
Scand J Gastroenterol. 2013; 48(12):1436-43 [PubMed] Related Publications
OBJECTIVE. We propose a repurposing strategy where anthracyclines are reintroduced to a subgroup of patients with metastatic colorectal cancer with the highest likelihood of response. In breast cancer, DNA topoisomerase II alpha gene (TOP2A) alterations predict incremental benefit of anthracyclines, but this association has not been investigated in colorectal cancer. Frequency analysis of TOP2A gene alterations in colorectal cancer and the association with prognosis are evaluated and the challenges of using a TOP2A/CEN-17 FISH probe combination are addressed. MATERIAL AND METHODS. Formalin-fixed, paraffin-embedded material from 154 stage III colorectal cancer patients included in the RANX05 clinical trial was retrospectively assessed for TOP2A gene alterations using FISH. The TOP2A/CEN-17 ratio as well as the TOP2A gene copy number alone was used to define gene alterations and associations between gene status and outcomes were analyzed. RESULTS. TOP2A gene gain was a frequent finding with 9.8 % having a total of ≥4 TOP2A copies per cell. According to the TOP2A/CEN-17 ratio, 10.5 % had TOP2A gene gain. Polysomy or gain of the centromere region of chromosome-17 was not as frequent as reported in breast cancer. No prognostic characteristic of TOP2A was identified. CONCLUSION. TOP2A gene gain is present in numbers relevant to identify a subgroup of patients who may benefit from anthracycline therapy. Based on the present findings, we will initiate a prospective clinical trial designed to evaluate this hypothesis in patients with metastatic colorectal cancer who have failed 5-fluorouracil and oxaliplatin chemotherapy.

Moretti E, Desmedt C, Biagioni C, et al.
TOP2A protein by quantitative immunofluorescence as a predictor of response to epirubicin in the neoadjuvant treatment of breast cancer.
Future Oncol. 2013; 9(10):1477-87 [PubMed] Related Publications
AIM: Anthracyclines are commonly used in breast cancer, although they lack validated predictive biomarkers. We explored the interaction between TOP2A protein by quantitative immunofluorescence (QIF) and anthracycline sensitivity.
PATIENTS & METHODS: Patients with estrogen receptor-negative breast cancer received neoadjuvant epirubicin. Pretreatment biopsies were analyzed using AQUA(®). Total, cytoplasmic (C) and nuclear (N) TOP2A protein concentrations were expressed as QIF scores and compared with pathologic complete response (pCR), TOP2A by immunohistochemistry, TOP2A mRNA, TOP2A and HER2 gene status, and Ki-67 level.
RESULTS: In total, 76 cases were assessable. C, N, and total scores did not correlate with pCR, or other markers. The N:C ratio differed significantly by HER2 status. No pCRs occurred in patients in the lowest N:C quartile.
CONCLUSION: Although no relevant correlation between TOP2A QIF scores and pCR was found, N:C ratio may have a negative predictive role, and may merit further exploration in a multifactorial predictive model that includes tumor and host factors.

Mattarocci S, Abbruzzese C, Mileo AM, et al.
Identification of pivotal cellular factors involved in HPV-induced dysplastic and neoplastic cervical pathologies.
J Cell Physiol. 2014; 229(4):463-70 [PubMed] Related Publications
Cervical carcinoma represents the paradigm of virus-induced cancers, where virtually all cervical cancers come from previous "high-risk" HPV infection. The persistent expression of the HPV viral oncoproteins E6 and E7 is responsible for the reprogramming of fundamental cellular functions in the host cell, thus generating a noticeable, yet only partially explored, imbalance in protein molecular networks and cell signaling pathways. Eighty-eight cellular factors, identified as HPV direct or surrogate targets, were chosen and monitored in a retrospective analysis for their mRNA expression in HPV-induced cervical lesions, from dysplasia to cancer. Real-time quantitative PCR (qPCR) was performed by using formalin-fixed, paraffin embedded archival samples. Gene expression analysis identified 40 genes significantly modulated in LSIL, HSIL, and squamous cervical carcinoma. Interestingly, among these, the expression level of a panel of four genes, TOP2A, CTNNB1, PFKM, and GSN, was able to distinguish between normal tissues and cervical carcinomas. Immunohistochemistry was also done to assess protein expression of two genes among those up-regulated during the transition between dysplasia and carcinoma, namely E2F1 and CDC25A, and their correlation with clinical parameters. Besides the possibility of significantly enhancing the use of some of these factors in diagnostic or prognostic procedures, these data clearly outline specific pathways, and thus key biological processes, altered in cervical dysplasia and carcinoma. Deeper insight on how these molecular mechanisms work may help widen the spectrum of novel innovative approaches to these virus-induced cell pathologies.

Wang N, Zhu M, Tsao SW, et al.
MiR-23a-mediated inhibition of topoisomerase 1 expression potentiates cell response to etoposide in human hepatocellular carcinoma.
Mol Cancer. 2013; 12(1):119 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: microRNAs have been shown to regulate the chemosensitivity of cancer cells. The aim of this study is to investigate the role and mechanism of mir-23a in enhancing the anti-tumor effect of topoisomerase 2A (TOP2A) poison etoposide in human hepatocellular carcinoma (HCC).
METHODS: The anti-tumor effect of chemotherapeutic agents in HCC cells were examined in vitro and in vivo xenograft model. Expression of mRNA and miRNAs were determined by quantitative real-time PCR. Protein expression was analyzed by immunoblotting.
RESULTS: Overexpression of mir-23a could significantly potentiate the in vitro and in vivo anti-tumor effect of etoposide; however, ectopic expression of miR-23a fails to sensitize HCC cells to 5-fluorouracil treatment, indicating the miR-23a-induced cancer cell hypersensitivity in chemotherapy is TOP2A-specific though miR-23a overexpression could not directly up-regulate TOP2A expression. Topoisomerase 1(TOP1) is down-regulated in miR-23a-overexpressed HCC cells. MiR-23a could directly bind to 3'untranslated region of TOP1 mRNA, and suppress the corresponding protein expression and inhibition of miR-23a further arguments the expression of TOP1. MiR-23a was up-regulated during DNA damage in cancer cells in line with the p53 expression. Up-regulation of p53 induces mir-23a expression, while suppression of p53 inhibits miR-23a in HCC cells.
CONCLUSION: Our study sheds light on the role of miR-23a as a potential target in regulating chemosensitivity of HCC cells.

Schildhaus HU, Schroeder L, Merkelbach-Bruse S, et al.
Therapeutic strategies in male breast cancer: clinical implications of chromosome 17 gene alterations and molecular subtypes.
Breast. 2013; 22(6):1066-71 [PubMed] Related Publications
Male breast cancer (MBC) is a rare disease. To date, therapy is mainly based on studies and clinical experiences with breast cancer in women. Only little is known about molecular typing of MBC, particularly with regard to potential biological predictors for adjuvant therapy. In female breast cancer tumors with chromosome 17 centromere (CEP17) duplication, HER2 and/or Topoisomerase II alpha (Topo II-α) gene alterations have been suggested to be associated with poor prognosis and increased sensitivity to anthracycline-containing regimens. In a well characterized cohort of 96 primary invasive MBC, we studied CEP17, HER2 and Topo II-α alterations by fluorescence in-situ hybridization (FISH), and expression of hormone receptors (HR), HER2 and Ki67 by immunohistochemistry to define molecular subtypes. Tumor characteristics and follow-up data were available and correlated with molecular findings. HER2 amplification and Topo II-α amplification/deletion were exceptionally rare in MBC (6.3% and 3.1%, respectively). CEP17 polysomy were found in 9.4% of tumors. HER2, Topo II-α and CEP17 gene alterations were not correlated to patients outcome. 96.9% of our cases were HR positive. Triple negative tumors were found in only 3.1% of the cases. In nodal negative tumors luminal A subtypes were significantly associated with better overall survival. Our results provide evidence for a predominant male breast cancer phenotype, characterized by HR expression and a lack of HER2/Topo II-α alterations and CEP17 duplicates. Therefore, the impact of anthracycline sensitivity linked to HER2/Topo II-α alterations as found in female breast cancer has low clinical significance for this specific male breast cancer phenotype.

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