Quantum dot-based immunofluorescent imaging and quantitative detection of TOP2A and prognostic value in triple-negative breast cancer

Zheng, Hongmei; Li, Xiang; Chen, Chuang; Chen, Jian; Sun, Jinzhong; Sun, Si; Li, Juanjuan; Sun, Shengrong; Wu, Xinhong

doi:10.2147/ijn.s111594

Cited by 40 publications

(27 citation statements)

References 43 publications

(53 reference statements)

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“…Thus, TOP2A serves a principal role in controlling the cell cycle and maintaining the integrity of the genome. It was reported that TOP2A was upregulated in numerous cancer types, including endometrial cancer (3,4,15), pancreatic cancer (16), prostate cancer (17) and breast cancer (18). In agreement with the present results, the increased TOP2A expression level indicated an association with more aggressive tumor behavior, including myometrial infiltration, and was associated with the prognosis in patients with EC (4,15).…”

Section: Discussionsupporting

confidence: 91%

“…In this axis, TOP2A induces cell proliferation and epithelial-mesenchymal transition (EMT) by activating the β-catenin signaling pathway, however, the process may be reversed by miR-139 (16). Zheng et al (18), demonstrated that the overexpression of TOP2A was associated with unfavorable biological behaviors of triple-negative breast cancer (TNBC), and TOP2A was confirmed as an independent prognostic indicator of 5-year disease-free survival. In prostate cancer, TOP2A was selected as a biomarker for early identification of patients with higher metastatic potential, thus these patients may receive timely adjuvant or neoadjuvant targeted therapy to improve prognosis (17).…”

Section: Discussionmentioning

confidence: 99%

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Bioinformatics analysis of key differentially expressed genes in well and poorly differentiated endometrial carcinoma

et al. 2018

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Endometrial carcinoma (EC) is one of the most common gynecological malignancies. The malignant degree increases between grade (G)1 and G3, and EC of G3 usually presents a high recurrence rate and poor prognosis. Therefore, the present study aimed to examine the principal genes associated with the degree of differentiation in EC. The microarrays GSE17025, GSE24537 and GSE35784, representing data of Type I EC samples of G1 and G3, were downloaded from the Gene Expression Omnibus. The differentially expressed genes (DEGs) and differentially expressed micro (mi)RNAs (DEMs) were identified, followed by functional enrichment analyses and interaction network construction. In total, 83 upregulated and 130 downregulated DEGs with the same expression trends in two mRNA datasets were screened. The upregulated DEGs were primarily enriched in 'mitotic cell cycle process', 'cell cycle process' and 'mitotic cell cycle'; while the downregulated DEGs were enriched in 'cellular component assembly involved in morphogenesis', 'cell projection organization' and 'microtubule‑based movement'. From the protein‑protein interaction network, DNA topoisomerase IIα, kinesin family member 11, cyclin B1 and BUB1 mitotic checkpoint serine/threonine were identified as foremost hub genes. One module was extracted and involved in 'mitotic cell cycle process' and 'cell cycle process'. Based on the analysis of DEMs and the miRNA‑target regulatory network, miRNA‑9 may be the most important upregulated DEM, and the DEGs forkhead box P1 and cyclin E1 may serve vital roles in the differentiation of EC. In conclusion, principal genes were identified that may be determinants of the carcinogenesis of poorly differentiated EC, which may facilitate the examination of potential molecular mechanisms. These genes may additionally help identify candidate biomarkers and novel therapeutic targets for poorly differentiated EC.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of key differentially expressed genes in well and poorly differentiated endometrial carcinoma

et al. 2018

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“…(Fischer et al, 2001 ; Vargas et al, 2012 ; Wu et al, 2014 ); CDC25B is a member of the CDC25 family of phosphatases, and previous studies suggested that elevated expression of CDC25B promoted the proliferation of gastric cancer, esophageal carcinoma, renal cell carcinoma, etc. (Yu et al, 2012 ; Wang et al, 2015 ; Leal et al, 2016 ); TOP2A encodes a DNA topoisomerase, and previous studies suggested that TOP2A overexpression was a poor prognostic factor in patients with breast cancer, colorectal cancer, prostate cancer, and nasopharyngeal carcinoma, etc., (de Resende et al, 2013 ; Lan et al, 2014 ; Tarpgaard et al, 2016 ; Zheng et al, 2016 ); CENPF is a component of the nuclear matrix during the G2 phase of interphase, and previous studies demonstrated that CENPF was associated with the tumor progression of patients with prostate cancer, hepatocellular carcinomas, and breast cancer, etc. (Brendle et al, 2009 ; Kim et al, 2012 ); Cell division cycle associated 3 (CDCA3) is a part of the Skp1-cullin-F-box (SCF) ubiquitin ligase and refers to a trigger of mitotic entry and mediates destruction of the mitosis inhibitory kinase, and previous studies demonstrated overexpression of CDCA3 promoted progression of several cancers (oral cancer, prostate cancer, and lung cancer, etc.)…”

Section: Discussionmentioning

confidence: 99%

Identification of Biomarkers Correlated with the TNM Staging and Overall Survival of Patients with Bladder Cancer

Liu

et al. 2017

Front. Physiol.

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Objective: To identify candidate biomarkers correlated with clinical prognosis of patients with bladder cancer (BC).Methods: Weighted gene co-expression network analysis was applied to build a co-expression network to identify hub genes correlated with tumor node metastasis (TNM) staging of BC patients. Functional enrichment analysis was conducted to functionally annotate the hub genes. Protein-protein interaction network analysis of hub genes was performed to identify the interactions among the hub genes. Survival analyses were conducted to characterize the role of hub genes on the survival of BC patients. Gene set enrichment analyses were conducted to find the potential mechanisms involved in the tumor proliferation promoted by hub genes.Results: Based on the results of topological overlap measure based clustering and the inclusion criteria, top 50 hub genes were identified. Hub genes were enriched in cell proliferation associated gene ontology terms (mitotic sister chromatid segregation, mitotic cell cycle and, cell cycle, etc.) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (cell cycle, Oocyte meiosis, etc.). 17 hub genes were found to interact with ≥5 of the hub genes. Survival analysis of hub genes suggested that lower expression of MMP11, COL5A2, CDC25B, TOP2A, CENPF, CDCA3, TK1, TPX2, CDCA8, AEBP1, and FOXM1were associated with better overall survival of BC patients. BC samples with higher expression of hub genes were enriched in gene sets associated with P53 pathway, apical junction, mitotic spindle, G2M checkpoint, and myogenesis, etc.Conclusions: We identified several candidate biomarkers correlated with the TNM staging and overall survival of BC patients. Accordingly, they might be used as potential diagnostic biomarkers and therapeutic targets with clinical utility.

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“…TOP2A (Topoisomerase 2-alpha), a nuclear enzyme involved in chromosome condensation, chromatid separation and relief of torsional stress during DNA transcription and replication [ 23 ], is a predictive marker of anthracycline efficacy. TOP2A amplification is frequent in breast cancer correlating with larger, higher grade tumors and positive lymph nodes [ 24 ]. High TOP2A amplification, especially in patients with concomitant high Her2neu amplification, is predictive of high pathologic complete response rates (> 50%) when treated with anthracycline based regimens [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

MGMT inhibition in ER positive breast cancer leads to CDC2, TOP2A, AURKB, CDC20, KIF20A, Cyclin A2, Cyclin B2, Cyclin D1, ERα and Survivin inhibition and enhances response to temozolomide

et al. 2018

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The DNA damage repair enzyme, O6-methylguanine DNA methyltransferase (MGMT) is overexpressed in breast cancer, correlating directly with estrogen receptor (ER) expression and function. In ER negative breast cancer the MGMT promoter is frequently methylated. In ER positive breast cancer MGMT is upregulated and modulates ER function. Here, we evaluate MGMT’s role in control of other clinically relevant targets involved in cell cycle regulation during breast cancer oncogenesis. We show that O6-benzylguanine (BG), an MGMT inhibitor decreases CDC2, CDC20, TOP2A, AURKB, KIF20A, cyclin B2, A2, D1, ERα and survivin and induces c-PARP and p21 and sensitizes ER positive breast cancer to temozolomide (TMZ). Further, siRNA inhibition of MGMT inhibits CDC2, TOP2A, AURKB, KIF20A, Cyclin B2, A2 and survivin and induces p21. Combination of BG+TMZ decreases CDC2, CDC20, TOP2A, AURKB, KIF20A, Cyclin A2, B2, D1, ERα and survivin. Temozolomide alone inhibits MGMT expression in a dose and time dependent manner and increases p21 and cytochrome c. Temozolomide inhibits transcription of TOP2A, AURKB, KIF20A and does not have any effect on CDC2 and CDC20 and induces p21. BG+/-TMZ inhibits breast cancer growth. In our orthotopic ER positive breast cancer xenografts, BG+/-TMZ decreases ki-67, CDC2, CDC20, TOP2A, AURKB and induces p21 expression. In the same model, BG+TMZ combination inhibits breast tumor growth in vivo compared to single agent (TMZ or BG) or control. Our results show that MGMT inhibition is relevant for inhibition of multiple downstream targets involved in tumorigenesis. We also show that MGMT inhibition increases ER positive breast cancer sensitivity to alkylator based chemotherapy.

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Quantum dot-based immunofluorescent imaging and quantitative detection of TOP2A and prognostic value in triple-negative breast cancer

Cited by 40 publications

References 43 publications

Bioinformatics analysis of key differentially expressed genes in well and poorly differentiated endometrial carcinoma

Bioinformatics analysis of key differentially expressed genes in well and poorly differentiated endometrial carcinoma

Identification of Biomarkers Correlated with the TNM Staging and Overall Survival of Patients with Bladder Cancer

MGMT inhibition in ER positive breast cancer leads to CDC2, TOP2A, AURKB, CDC20, KIF20A, Cyclin A2, Cyclin B2, Cyclin D1, ERα and Survivin inhibition and enhances response to temozolomide

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